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Martin M Meremikwu - One of the best experts on this subject based on the ideXlab platform.

  • The Cochrane Library - Artemether for severe malaria
    The Cochrane database of systematic reviews, 2019
    Co-Authors: Ekpereonne Esu, Emmanuel E Effa, Oko N Opie, Amirahobu Uwaoma, Martin M Meremikwu
    Abstract:

    Background In 2011 the World Health Organization (WHO) recommended parenteral artesunate in preference to quinine as first-line treatment for people with severe malaria. Prior to this recommendation, many countries, particularly in Africa, had begun to use Artemether, an alternative artemisinin derivative. This review evaluates intramuscular Artemether compared with both quinine and artesunate. Objectives To assess the efficacy and safety of intramuscular Artemether versus any other parenteral medication in treating severe malaria in adults and children. Search methods We searched the Cochrane Infectious Diseases Group Specialized Register, CENTRAL (The Cochrane Library), MEDLINE, EMBASE and LILACS, ISI Web of Science, conference proceedings and reference lists of articles. We also searched the WHO clinical trial registry platform, ClinicalTrials.gov and the metaRegister of Controlled Trials (mRCT) for ongoing trials up to 9 April 2014. Selection criteria Randomized controlled trials (RCTs) comparing intramuscular Artemether with intravenous or intramuscular antimalarial for treating severe malaria. Data collection and analysis The primary outcome was all-cause death.Two authors independently assessed trial eligibility, risk of bias and extracted data. We summarized dichotomous outcomes using risk ratios (RR) and continuous outcomes using mean differences (MD), and presented both measures with 95% confidence intervals (CI). Where appropriate, we combined data in meta-analyses and assessed the quality of the evidence using the GRADE approach. Main results We included 18 RCTs, enrolling 2662 adults and children with severe malaria, carried out in Africa (11) and in Asia (7). Artemether versus quinine For children in Africa, there is probably little or no difference in the risk of death between intramuscular Artemether and quinine (RR 0.96, 95% CI 0.76 to 1.20; 12 trials, 1447 participants, moderate quality evidence). Coma recovery may be about five hours shorter with Artemether (MD -5.45, 95% CI -7.90 to -3.00; six trials, 358 participants, low quality evidence), and Artemether may result in fewer neurological sequelae, but larger trials would be needed to confirm this (RR 0.84, 95% CI 0.66 to 1.07; seven trials, 968 participants, low quality evidence). Artemether probably shortens the parasite clearance time by about nine hours (MD -9.03, 95% CI -11.43 to -6.63; seven trials, 420 participants, moderate quality evidence), and may shorten the fever clearance time by about three hours (MD -3.73, 95% CI -6.55 to -0.92; eight trials, 457 participants, low quality evidence). For adults in Asia, treatment with intramuscular Artemether probably results in fewer deaths than treatment with quinine (RR 0.59, 95% CI 0.42 to 0.83; four trials, 716 participants, moderate quality evidence). Artemether versus artesunate Artemether and artesunate have not been directly compared in randomized trials in African children. For adults in Asia, mortality is probably higher with intramuscular Artemether (RR 1.80, 95% CI 1.09 to 2.97, two trials,494 participants, moderate quality evidence). Authors' conclusions Although there is a lack of direct evidence comparing Artemether with artesunate, Artemether is probably less effective than artesunate at preventing deaths from severe malaria. In circumstances where artesunate is not available, Artemether is an alternative to quinine.

  • Artemether for severe malaria
    Cochrane Database of Systematic Reviews, 2014
    Co-Authors: Ekpereonne Esu, Emmanuel E Effa, Oko N Opie, Amirahobu Uwaoma, Martin M Meremikwu
    Abstract:

    Background In 2011 the World Health Organization (WHO) recommended parenteral artesunate in preference to quinine as first-line treatment for people with severe malaria. Prior to this recommendation, many countries, particularly in Africa, had begun to use Artemether, an alternative artemisinin derivative. This review evaluates intramuscular Artemether compared with both quinine and artesunate. Objectives To assess the efficacy and safety of intramuscular Artemether versus any other parenteral medication in treating severe malaria in adults and children. Search methods We searched the Cochrane Infectious Diseases Group Specialized Register, CENTRAL (The Cochrane Library), MEDLINE, EMBASE and LILACS, ISI Web of Science, conference proceedings and reference lists of articles. We also searched the WHO clinical trial registry platform, ClinicalTrials.gov and the metaRegister of Controlled Trials (mRCT) for ongoing trials up to 9 April 2014. Selection criteria Randomized controlled trials (RCTs) comparing intramuscular Artemether with intravenous or intramuscular antimalarial for treating severe malaria. Data collection and analysis The primary outcome was all-cause death.Two authors independently assessed trial eligibility, risk of bias and extracted data. We summarized dichotomous outcomes using risk ratios (RR) and continuous outcomes using mean differences (MD), and presented both measures with 95% confidence intervals (CI). Where appropriate, we combined data in meta-analyses and assessed the quality of the evidence using the GRADE approach. Main results We included 18 RCTs, enrolling 2662 adults and children with severe malaria, carried out in Africa (11) and in Asia (7). Artemether versus quinine For children in Africa, there is probably little or no difference in the risk of death between intramuscular Artemether and quinine (RR 0.96, 95% CI 0.76 to 1.20; 12 trials, 1447 participants, moderate quality evidence). Coma recovery may be about five hours shorter with Artemether (MD -5.45, 95% CI -7.90 to -3.00; six trials, 358 participants, low quality evidence), and Artemether may result in fewer neurological sequelae, but larger trials would be needed to confirm this (RR 0.84, 95% CI 0.66 to 1.07; seven trials, 968 participants, low quality evidence). Artemether probably shortens the parasite clearance time by about nine hours (MD -9.03, 95% CI -11.43 to -6.63; seven trials, 420 participants, moderate quality evidence), and may shorten the fever clearance time by about three hours (MD -3.73, 95% CI -6.55 to -0.92; eight trials, 457 participants, low quality evidence). For adults in Asia, treatment with intramuscular Artemether probably results in fewer deaths than treatment with quinine (RR 0.59, 95% CI 0.42 to 0.83; four trials, 716 participants, moderate quality evidence). Artemether versus artesunate Artemether and artesunate have not been directly compared in randomized trials in African children. For adults in Asia, mortality is probably higher with intramuscular Artemether (RR 1.80, 95% CI 1.09 to 2.97, two trials,494 participants, moderate quality evidence). Authors' conclusions Although there is a lack of direct evidence comparing Artemether with artesunate, Artemether is probably less effective than artesunate at preventing deaths from severe malaria. In circumstances where artesunate is not available, Artemether is an alternative to quinine.

Juntra Karbwang - One of the best experts on this subject based on the ideXlab platform.

  • Pharmacokinetic interactions of Artemether and pyrimethamine in healthy male Thais.
    Southeast Asian Journal of Tropical Medicine and Public Health, 1998
    Co-Authors: Peerapan Tan-ariya, Kesara Na-bangchang, Ratawan Ubalee, Thanavibul A, Thipawangkosol P, Juntra Karbwang
    Abstract:

    The pharmacokinetics of a single oral dose of Artemether (300 mg) and pyrimethamine (100 mg) given as each individual drug alone or as a drug combination (Artemether 300 mg plus pyrimethamine 100 mg), were investigated in 8 healthy male Thai volunteers. Both Artemether and pyrimethamine were rapidly absorbed after oral administration. Elimination of pyrimethamine was however, a relatively slow process compared with Artemether, and thus resulted in a long terminal phase elimination half-life (50-106 hours). Pharmacokinetics of Artemether and dihydroartemisinin following a single oral dose of Artemether alone or in combination with pyrimethamine were similar. In contrast, coadministration of Artemether resulted in significantly increased C max (medians of 818 vs 1,180 ng/ml) and contracted the apparent volume of distribution (medians of 3 vs 2.56 1/kg) of pyrimethamine.

  • Pharmacokinetics and bioavailability of oral and intramuscular Artemether
    European journal of clinical pharmacology, 1997
    Co-Authors: Juntra Karbwang, Kesara Na-bangchang, K Congpuong, P. Molunto, Thanavibul A
    Abstract:

    Objective: The pharmacokinetics and bioavailability of Artemether and dihydroartemisinin were investigated in eight Thai males following the administration of single oral and intramuscular doses of Artemether (300 mg) in a randomized two-way cross-over study. Results: Both oral and intramuscular Artemether were well-tolerated. In most cases, Artemether and dihydroartemisinin were detected in plasma after 30 min and declined to levels below the limit of detection within 18–24 h. Compared with intramuscular administration, oral administration of Artemether resulted in a relatively rapid but incomplete absorption [Cmax: 474 vs 540 ng · ml−1; t max: 2.0 vs 3.9 h; AUC: 2.17 vs 5.20 μg · h · ml−1]. Geographic means of lag-time and absorption half-life (t 1/2a) of oral vs intramuscular Artemether were 0.28 and 1.1 h vs 0.30 and 2 h, respectively. t 1/2z was significantly shortened after the oral dose [2.8 vs 6.9 h]. Mean oral bioavailability relative to intramuscular administration was 43.2%. The ratio of the AUCs of Artemether to dihydroartemisinin was significantly lower after the oral than after the intramuscular dose (geometric mean: 0.29 vs 0.60).

  • Activity of Artemether-azithromycin versus Artemether-doxycycline in the treatment of multiple drug resistant falciparum malaria.
    The Southeast Asian journal of tropical medicine and public health, 1996
    Co-Authors: Kesara Na-bangchang, Thanavibul A, Tozo Kanda, P Tipawangso, K Suprakob, M Ibrahim, Yupaporn Wattanagoon, Juntra Karbwang
    Abstract:

    The efficacy of the combination of Artemether with doxycycline or azithromycin was evaluated in 60 patients with acute uncomplicated falciparum malaria who attended malaria clinic in Mae Sot, Tak Province (Thai-Myanmar border). Patients (30 each) were randomized to receive (a) 300 mg Artemether together with 100 mg doxycycline as initial doses, followed by 100 mg Artemether plus 100 mg doxycycline at 12 hours later, then 100 mg doxycycline every 12 hours for another 4 days, or (b) 300 mg Artemether together with 500 mg azithromycin, followed by 250 mg azithromycin at 24 and 48 hours. The follow-up period was 28 days. Patients in either group had a rapid initial response to treatment with comparable PCT and FCT. The cure rate of Artemether-azithromycin regimen was significantly lower than that of Artemether-doxycycline regimen (14.8 vs 53.3%). Low cure rate from Artemether-azithromycin combination in this study was likely to be due to inadequate azithromycin dosage. However, with the low incidence of gastrointestinal adverse effects, the once daily dose of azithromycin could still be increased in order to enhance its clinical efficacy. The simplicity of drug administration and lesser incidence of adverse effects make azithromycin a more proper partner of Artemether than doxycycline. Further dose-finding and pharmacokinetic study with the Artemether-azithromycin combination is encouraging.

  • A comparative clinical trial of Artemether and the sequential regimen of Artemether-mefloquine in multidrug resistant falciparum malaria
    The Journal of antimicrobial chemotherapy, 1995
    Co-Authors: Juntra Karbwang, Kesara Na-bangchang, Thanavibul A, Prasart Laothavorn, Monthira Ditta-in, Tranakchit Harinasuta
    Abstract:

    A randomized, comparative clinical trial for assessment of the efficacy of two antimalarial regimens, Artemether alone and the sequential regimen Artemethermefloquine, was carried out in 109 Thai male patients with acute uncomplicated, multidrug resistant falciparum malaria who were admitted to the Bangkok Hospital for Tropical Diseases. Fifty-three patients received oral Artemether at a total dose of 700 mg (300 mg initially, followed by 100 mg daily for 4 days), and 56 patients received the sequential regimen of Artemether-mefloquine (300 mg oral Artemether initially, followed by 750 mg oral mefloquine after 24 h). Patients in both groups had a rapid initial response to treatment, with a median parasite clearance time of 40 h compared with 43.5 h for the sequential regimen. Median fever clearance times were 42.5 h and 32.5 h for Artemether and the sequential regimen respectively. Parasitaemia reoccurred in patients of both groups during the follow up period, six in the Artemether and three in the sequential regimen (cure rates were 88 and 94%). No serious adverse effects were observed in either group of patients.

  • Comparison of oral Artemether and mefloquine in acute uncomplicated falciparum malaria
    Lancet (London England), 1992
    Co-Authors: Juntra Karbwang, Kesara Na-bangchang, Thanavibul A, Danai Bunnag, Tan Chongsuphajaisiddhi, Tranakchit Harinasuta
    Abstract:

    Plasmodium falciparum malaria in Thailand is highly resistant to available antimalarials, and alternative drugs are needed urgently. Artemether is effective against falciparum malaria but associated with a high recrudescence rate. The proper dosage regimen remains to be defined. We have done a clinical trial comparing mefloquine 1250 mg in divided doses with oral Artemether at 700 mg total dose given over 5 days in acute uncomplicated falciparum malaria. 46 patients, admitted to the Bangkok Hospital for Tropical Diseases, were randomised to receive either mefloquine (12) or Artemether (34). Hospital follow-up was 28 days for the Artemether group and 42 days for the mefloquine group. Oral Artemether gave a significantly faster parasite clearance time than mefloquine (30 vs 64 h), and a significantly better cure rate (97 vs 64%) with fewer episodes of dizziness and vomiting. Oral Artemether at 700 mg given over 5 days is effective and well tolerated. The cure rate with this regimen is higher than that reported by previous studies with 600 mg intramuscular Artemether given over 5 days. Oral Artemether can be considered as an alternative drug for multiple-drug-resistant falciparum malaria.

Thanavibul A - One of the best experts on this subject based on the ideXlab platform.

  • Pharmacokinetic interactions of Artemether and pyrimethamine in healthy male Thais.
    Southeast Asian Journal of Tropical Medicine and Public Health, 1998
    Co-Authors: Peerapan Tan-ariya, Kesara Na-bangchang, Ratawan Ubalee, Thanavibul A, Thipawangkosol P, Juntra Karbwang
    Abstract:

    The pharmacokinetics of a single oral dose of Artemether (300 mg) and pyrimethamine (100 mg) given as each individual drug alone or as a drug combination (Artemether 300 mg plus pyrimethamine 100 mg), were investigated in 8 healthy male Thai volunteers. Both Artemether and pyrimethamine were rapidly absorbed after oral administration. Elimination of pyrimethamine was however, a relatively slow process compared with Artemether, and thus resulted in a long terminal phase elimination half-life (50-106 hours). Pharmacokinetics of Artemether and dihydroartemisinin following a single oral dose of Artemether alone or in combination with pyrimethamine were similar. In contrast, coadministration of Artemether resulted in significantly increased C max (medians of 818 vs 1,180 ng/ml) and contracted the apparent volume of distribution (medians of 3 vs 2.56 1/kg) of pyrimethamine.

  • Pharmacokinetics and bioavailability of oral and intramuscular Artemether
    European journal of clinical pharmacology, 1997
    Co-Authors: Juntra Karbwang, Kesara Na-bangchang, K Congpuong, P. Molunto, Thanavibul A
    Abstract:

    Objective: The pharmacokinetics and bioavailability of Artemether and dihydroartemisinin were investigated in eight Thai males following the administration of single oral and intramuscular doses of Artemether (300 mg) in a randomized two-way cross-over study. Results: Both oral and intramuscular Artemether were well-tolerated. In most cases, Artemether and dihydroartemisinin were detected in plasma after 30 min and declined to levels below the limit of detection within 18–24 h. Compared with intramuscular administration, oral administration of Artemether resulted in a relatively rapid but incomplete absorption [Cmax: 474 vs 540 ng · ml−1; t max: 2.0 vs 3.9 h; AUC: 2.17 vs 5.20 μg · h · ml−1]. Geographic means of lag-time and absorption half-life (t 1/2a) of oral vs intramuscular Artemether were 0.28 and 1.1 h vs 0.30 and 2 h, respectively. t 1/2z was significantly shortened after the oral dose [2.8 vs 6.9 h]. Mean oral bioavailability relative to intramuscular administration was 43.2%. The ratio of the AUCs of Artemether to dihydroartemisinin was significantly lower after the oral than after the intramuscular dose (geometric mean: 0.29 vs 0.60).

  • Activity of Artemether-azithromycin versus Artemether-doxycycline in the treatment of multiple drug resistant falciparum malaria.
    The Southeast Asian journal of tropical medicine and public health, 1996
    Co-Authors: Kesara Na-bangchang, Thanavibul A, Tozo Kanda, P Tipawangso, K Suprakob, M Ibrahim, Yupaporn Wattanagoon, Juntra Karbwang
    Abstract:

    The efficacy of the combination of Artemether with doxycycline or azithromycin was evaluated in 60 patients with acute uncomplicated falciparum malaria who attended malaria clinic in Mae Sot, Tak Province (Thai-Myanmar border). Patients (30 each) were randomized to receive (a) 300 mg Artemether together with 100 mg doxycycline as initial doses, followed by 100 mg Artemether plus 100 mg doxycycline at 12 hours later, then 100 mg doxycycline every 12 hours for another 4 days, or (b) 300 mg Artemether together with 500 mg azithromycin, followed by 250 mg azithromycin at 24 and 48 hours. The follow-up period was 28 days. Patients in either group had a rapid initial response to treatment with comparable PCT and FCT. The cure rate of Artemether-azithromycin regimen was significantly lower than that of Artemether-doxycycline regimen (14.8 vs 53.3%). Low cure rate from Artemether-azithromycin combination in this study was likely to be due to inadequate azithromycin dosage. However, with the low incidence of gastrointestinal adverse effects, the once daily dose of azithromycin could still be increased in order to enhance its clinical efficacy. The simplicity of drug administration and lesser incidence of adverse effects make azithromycin a more proper partner of Artemether than doxycycline. Further dose-finding and pharmacokinetic study with the Artemether-azithromycin combination is encouraging.

  • A comparative clinical trial of Artemether and the sequential regimen of Artemether-mefloquine in multidrug resistant falciparum malaria
    The Journal of antimicrobial chemotherapy, 1995
    Co-Authors: Juntra Karbwang, Kesara Na-bangchang, Thanavibul A, Prasart Laothavorn, Monthira Ditta-in, Tranakchit Harinasuta
    Abstract:

    A randomized, comparative clinical trial for assessment of the efficacy of two antimalarial regimens, Artemether alone and the sequential regimen Artemethermefloquine, was carried out in 109 Thai male patients with acute uncomplicated, multidrug resistant falciparum malaria who were admitted to the Bangkok Hospital for Tropical Diseases. Fifty-three patients received oral Artemether at a total dose of 700 mg (300 mg initially, followed by 100 mg daily for 4 days), and 56 patients received the sequential regimen of Artemether-mefloquine (300 mg oral Artemether initially, followed by 750 mg oral mefloquine after 24 h). Patients in both groups had a rapid initial response to treatment, with a median parasite clearance time of 40 h compared with 43.5 h for the sequential regimen. Median fever clearance times were 42.5 h and 32.5 h for Artemether and the sequential regimen respectively. Parasitaemia reoccurred in patients of both groups during the follow up period, six in the Artemether and three in the sequential regimen (cure rates were 88 and 94%). No serious adverse effects were observed in either group of patients.

  • Comparison of oral Artemether and mefloquine in acute uncomplicated falciparum malaria
    Lancet (London England), 1992
    Co-Authors: Juntra Karbwang, Kesara Na-bangchang, Thanavibul A, Danai Bunnag, Tan Chongsuphajaisiddhi, Tranakchit Harinasuta
    Abstract:

    Plasmodium falciparum malaria in Thailand is highly resistant to available antimalarials, and alternative drugs are needed urgently. Artemether is effective against falciparum malaria but associated with a high recrudescence rate. The proper dosage regimen remains to be defined. We have done a clinical trial comparing mefloquine 1250 mg in divided doses with oral Artemether at 700 mg total dose given over 5 days in acute uncomplicated falciparum malaria. 46 patients, admitted to the Bangkok Hospital for Tropical Diseases, were randomised to receive either mefloquine (12) or Artemether (34). Hospital follow-up was 28 days for the Artemether group and 42 days for the mefloquine group. Oral Artemether gave a significantly faster parasite clearance time than mefloquine (30 vs 64 h), and a significantly better cure rate (97 vs 64%) with fewer episodes of dizziness and vomiting. Oral Artemether at 700 mg given over 5 days is effective and well tolerated. The cure rate with this regimen is higher than that reported by previous studies with 600 mg intramuscular Artemether given over 5 days. Oral Artemether can be considered as an alternative drug for multiple-drug-resistant falciparum malaria.

Niklas Lindegardh - One of the best experts on this subject based on the ideXlab platform.

  • lopinavir ritonavir affects pharmacokinetic exposure of Artemether lumefantrine in hiv uninfected healthy volunteers
    Journal of Acquired Immune Deficiency Syndromes, 2009
    Co-Authors: Polina German, Niklas Lindegardh, Sunil Parikh, Jody Lawrence, Grant Dorsey, Philip J Rosenthal, Diane V Havlir, Edwin D Charlebois, Warunee Hanpithakpong, Francesca T Aweeka
    Abstract:

    Objectives: Antimalarial combination therapy is used in persons with HIV infection in the absence of data on drug interactions. The objective of this study was to investigate the pharmacokinetics (PK) of antimalarial combination Artemether/lumefantrine (AL) when administered with the protease inhibitor combination lopinavir/ ritonavir (LPV/r) in HIV-uninfected healthy volunteers to determine if important drug interactions exist between these agents. Design: Open-label study in healthy HIV-seronegative adults. Methods: Participants received standard 6-dose treatment courses ofAL 80/480 mg twice daily on days 1―4 and 28―31. LPV/r 400/100 mg twice daily was administered on days 16―41 after a 2-week washout period. Plasma concentrations of AL, dihydroartemisinin (DHA, Artemether metabolite), lopinavir, and ritonavir were measured. Results: PK of lumefantrine was influenced by LPV/r resulting in 2- to 3-fold increases in area under the curve (AUC) (AUC 0―264 : 413 versus 931 h·μg·mL ―1 ; AUC 0-inf : 456 versus 1073 h·μg·mL ―1 ). For Artemether, trends toward C max and AUC decreases (C max 14.3 versus 11.2 ng/mL and 42.7―62.0 versus 25.9―40.5 h·ng·mL ―1 for AUC) were noted during coadministration. For DHA, decreases in C max (58.8 versus 37.3 ng/mL) and AUC (190―198 versus 104―109 h·ng·mL ―1 ) were observed during coadministration without changes in DHA:Artemether AUC ratios. AL did not affect LPV/r PK. Conclusions: Coadministration of artmether/lumefantrine and LPV/r can be carried out for patients coinfected with malaria and HIV Formal safety analysis of concomitant therapy should be addressed by future studies among individuals living in malaria-endemic regions.

  • efficacy of Artemether lumefantrine for the treatment of uncomplicated falciparum malaria in northwest cambodia
    Tropical Medicine & International Health, 2006
    Co-Authors: Mey Bouth Denis, Reiko Tsuyuoka, Pharath Lim, Niklas Lindegardh, Sophoan Narann Top, Duong Socheat, Thierry Fandeur, Anna Annerberg, Eva Maria Christophel
    Abstract:

    Summary Objective  To determine the efficacy of Artemether–lumefantrine malaria treatment, as an alternative to artesunate + mefloquine, which is becoming ineffective in some areas of the Thai–Cambodian border. Methods  Two studies were conducted to monitor the efficacy of Artemether–lumefantrine in Sampov Lun referral hospital, Battambang Province, in 2002 and 2003, and one study was conducted to assess the efficacy of mefloquine + artesunate in 2003 for comparison. The studies were performed according to the WHO standardized protocol with a follow-up of 28 days. The therapeutic efficacy tests were complemented with in vitro tests and in 2003, with the measurement of lumefantrine plasma concentration at day 7 for the patients treated with Artemether–lumefantrine. Results  A total of 190 patients were included: 55 were treated with Artemether–lumefantrine in 2002 (AL2002), 80 with Artemether–lumefantrine and food supplementation in 2003 (AL2003) and 55 with artesunate + mefloquine in 2003 (AM2003). With the per-protocol analysis, the cure rate was 71.1% in study AL2002, 86.5% in study AL2003 and 92.4% in study AM2003. All the data were PCR corrected. The Artemether–lumefantrine cure rate was unexpectedly low in 2002, but it increased with food supplementation in 2003. There was a significant difference (P = 0.02) in lumefantrine plasma concentrations between adequate clinical and parasitological responses and treatment failure cases. In vitro susceptibility to lumefantrine was reduced for isolates sampled from patients presenting with treatment failure, but the difference was not statistically different from isolates sampled from patients who were successfully treated. Conclusion  Treatment failure cases of Artemether–lumefantrine are most probably because of low levels of lumefantrine blood concentration. Further investigations are necessary to determine whether resistance of Plasmodium falciparum isolates to lumefantrine is present in the region. Objectif  Determiner l'efficacite de l'Artemether–lumefantrine pour le traitement paludisme en tant qu'alternative a l'artesunate + mefloquine qui devient de plus en plus inefficace dans certaines zones dans la frontiere Thailando–Cambodgienne. Methodes  Deux etudes ont ete menees pour mesurer l'efficacite de l'Artemether–lumefantrine dans l'hopital de reference de Sampov Lun dans la province de Battambang en 2002 et 2003 et, dans un but de comparaison, une etude a aussi ete menee pour evaluer l'efficacite de l'artesunate + mefloquine en 2003. Les etudes ont ete menees selon les protocoles standardises de l'OMS avec un suivi de 28 jours. Les tests d'efficacite therapeutique ont ete complementes par des tests in vitro et, en 2003 par la mesure de la concentration plasmatique de lumefantrine au jour 7 pour les patients traites a l'Artemether–lumefantrine. Resultats  Au total 190 patients ont ete inclus dans l’etude parmi lesquels 55 ont ete traites a l'Artemether–lumefantrine en 2002 (AL2002), 80 a l'Artemether–lumefantrine en plus d'un complement de nourriture en 2003 (AL2003) et 55 a l'artesunate + mefloquine en 2003 (AM2003). L'analyse suivant un protocole standard a revele un taux de guerison de 71,1% pour AL2002, 86,5% pour AL2003 et 92,4% pour AM2003. Toutes les donnees ont ete ajustees avec les resultats de la PCR. Le taux de guerison pour l'Artemether–lumefantrine s'est avere bas de facon inattendue en 2002 mais il a augmente avec le complement de nourriture en 2003. Il y avait une difference significative (p = 0,02) pour les concentrations plasmatiques de lumefantrine entre d'une part les reponses cliniques et parasitologiques adequates et d'autre part les cas d’echec therapeutique. La susceptibilite in vitro pour la lumefantrine etait reduite pour les souches isolees de patients presentant un echec therapeutique mais les valeurs n’etaient pas statistiquement differentes de celles de souches isolees de patients traites avec succes. Conclusion  Les cas d’echec therapeutique a l'Artemether–lumefantrine sont plus probablement dus a des concentrations sanguines basses de lumefantrine. Des investigations supplementaires sont necessaires pour determiner s'il existe une resistance de P. falciparuma la lumefantrine dans la region. Objetivo  Determinar la eficacia del tratamiento de malaria con artemeter-lumefantrina como alternativa al artesunato + mefloquina, el cual esta dejando de ser efectivo en algunas areas de la frontera entre Tailanda y Cambodia. Metodos  Se llevaron a cabo dos estudios para monitorizar la eficacia de artemeter-lumefantrina en el hospital de referencia de Sampov Lun, provincia de Battambang, entre el 2002 y 2003, asi como un estudio durante el 2003, y a modo de comparacion, para evaluar la eficacia de la mefloquina + artesunato. Estos estudios se realizaron siguiendo el protocolo estandar de la OMS con un seguimiento de 28 dias. Las pruebas de eficacia terapeutica se complementaron con pruebas in vitro y, durante el 2003, con la medicion de la concentracion de lumefantrina en plasma en el dia 7 para los pacientes tratados con artemeter-lumefantrina. Resultados  Se incluyeron 190 pacientes: 55 fueron tratados con artemeter-lumefantrina en el 2002 (AL2002), 80 con artemeter-lumefantrina y suplementacion alimenticia en el 2003 (AL2003), y 55 con artesunato + mefloquina en el 2003. Con el analisis por protocolo, la tasa de curacion fue de 71.1% en el estudio AL2002, 86.5% en el estudio AL2003, y 92.4% en el estudio AM2003. Todos los datos fueron corregidos mediante PCR. La tasa de curacion para el tratamiento con artemeter-lumefantrina fue sorprendentemente baja en el 2002, pero aumento con la suplementacion alimenticia en el 2003. Se encontro una diferencia significativa (p = 0.02) en las concentraciones de lumefantrina en plasma entre casos con una respuesta clinica y parasitologica adecuadas y aquellos con fallo terapeutico. La susceptibilidad in vitro frente a la lumefantrina se redujo para cepas aisladas de pacientes que presentaban fallo en el tratamiento, pero la diferencia no era estadisticamente significativa de aquella para cepas aisladas de pacientes que hubiesen respondido adecuadamente al tratamiento. Conclusions  Los casos de fallo terapeutico con artemeter-lumefantrina probablemente son debidos a bajos niveles de concentracion de lumefantrina en la sangre. Se necesitan mas estudios para determinar si existe resistencia a la lumefantrina entre las cepas de P. falciparum de la region.

T G Brewer - One of the best experts on this subject based on the ideXlab platform.

  • arteether induced brain injury in macaca mulatta i the precerebellar nuclei the lateral reticular nuclei paramedian reticular nuclei and perihypoglossal nuclei
    Anatomy and Embryology, 2000
    Co-Authors: J M Petras, James O. Peggins, G D Young, R A Bauman, D E Kyle, M Gettayacamin, H K Webster, K D Corcoran, M A Vane, T G Brewer
    Abstract:

    Malaria poses a threat across several continents: Eurasia (Asia and parts of Eastern Europe), Africa, Central and South America. Bradley (1991) estimates human exposure at 2,073,000,000 with infection rates at 270,000,000, illnesses at 110,000,000, and deaths at 1,000,000. Significant mortality rates are attributed to infection by the parasite Plasmodium falciparum, with an estimated 90% among African children. A worldwide effort is ongoing to chemically and pharmacologically characterize a class of artemisinin compounds that might be promising antimalarial drugs. The U.S. Army is studying the efficacy and toxicity of several artemisinin semi-synthetic compounds: arteether, Artemether, artelinic acid, and artesunate. The World Health Organization and the U.S. Army selected arteether for drug development and possible use in the emergency therapy of acute, severe malaria. Male Rhesus monkeys (Macaca mulatta) were administered different daily doses of arteether, or the vehicle alone (sesame oil), for a period of either 14 days, or 7 days. Neuropathological lesions were found in 14-day arteether treated monkeys in the precerebellar nuclei of the medulla oblongata, namely: (1) the lateral reticular nuclei (subnuclei magnocellularis, parvicellularis, and subtrigeminalis), (2) the paramedian reticular nuclei (subnuclei accessorius, dorsalis, and ventralis), and the perihypoglossal nuclei (n. intercalatus ofStaderini, n.of Roller, and n.prepositus hypoglossi). The data demonstrate that the simian medullary precerebellar nuclei have a high degree of vulnerability when arteether is given for 14 days at dose levels between 8 mg/kg per day and 24 mg/kg per day. The neurological consequences of this treatment regimen could profoundly impair posture, gait, and autonomic regulation, while eye movement disorders might also be anticipated.

  • the pharmacokinetics and bioavailability of dihydroartemisinin arteether Artemether artesunic acid and artelinic acid in rats
    Journal of Pharmacy and Pharmacology, 1998
    Co-Authors: Qigui Li, James O. Peggins, Melvin H Heiffer, Lawrence Fleckenstein, Kelly Masonic, T G Brewer
    Abstract:

    : The pharmacokinetics and bioavailability of dihydroartemisinin (DQHS), Artemether (AM), arteether (AE), artesunic acid (AS) and artelinic acid (AL) have been investigated in rats after single intravenous, intramuscular and intragastric doses of 10 mg kg(-1). Plasma was separated from blood samples collected at different times after dosing and analysed for parent drug. Plasma samples from rats dosed with AM, AE, AS and AL were also analysed for DQHS which is known to be an active metabolite of these compounds. Plasma levels of all parent compounds decreased biexponentially and were a reasonable fit to a two-compartment open model. The resulting pharmacokinetic parameter estimates were substantially different not only between drugs but also between routes of administration for the same drug. After intravenous injection the highest plasma level was obtained with AL, followed by DQHS, AM, AE and AS. This resulted in the lowest steady-state volume of distribution (0.39 L) for AL, increasing thereafter for DQHS (0.50 L), AM (0.67 L), AE (0.72 L) and AS (0.87 L). Clearance of AL (21-41 mL min(-1) kg(-1)) was slower than that of the other drugs for all three routes of administration (DQHS, 55-64 mL min(-1) kg(-1); AM, 91-92 mL min(-1) kg(-1); AS, 191-240 mL min(-1) kg(-1); AE, 200-323 mL min(-1) kg(-1)). In addition the terminal half-life after intravenous dosing was longest for AL (1.35 h), followed by DQHS (0.95 h), AM (0.53 h), AE (0.45 h) and AS (0.35 h). Bioavailability after intramuscular injection was highest for AS (105%), followed by AL (95%) and DQHS (85%). The low bioavailability of AM (54%) and AE (34%) is probably the result of slow, prolonged absorption of the sesame-oil formulation from the injection site. After oral administration, low bioavailability (19-35%) was observed for all five drugs. In-vivo AM, AE, AS and AL were converted to DQHS to different extents; the ranking order of percentage of total dose converted to DQHS was AS (25.3-72.7), then AE (3.4-15.9), AM (3.7-12.4) and AL (1.0-4.3). The same ranking order was obtained for all formulations and routes of administration. The drug with the highest percentage conversion to DQHS was artesunic acid. Because DQHS has significant antimalarial activity, relatively low DQHS production could still contribute significantly to the antimalarial efficacy of these drugs. This is the first time the pharmacokinetics, bioavailability and conversion to DQHS of these drugs have been directly compared after different routes of administration. The results show that of all the artemisinin drugs studied the plasma level was highest for artelinic acid; this reflects its lowest extent of conversion to DQHS and its slowest rate of elimination.