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Nicholas J. White - One of the best experts on this subject based on the ideXlab platform.

  • Artemisinin based combination treatment of falciparum malaria
    American Journal of Tropical Medicine and Hygiene, 2007
    Co-Authors: Francois Nosten, Nicholas J. White
    Abstract:

    Artemisinin-based combination treatments (ACTs) are now generally accepted as the best treatments for uncomplicated falciparum malaria. They are rapidly and reliably effective. Efficacy is determined by the drug partnering the Artemisinin Derivative and, for artesunate-mefloquine, artemether-lumefantrine, and dihydroArtemisinin- piperaquine, this usually exceeds 95%. Artesunate-sulfadoxine-pyrimethamine and artesunate-amodiaquine are effec- tive in some areas, but in other areas resistance to the partner precludes their use. There is still uncertainty over the safety of Artemisinin Derivatives in the first trimester of pregnancy, when they should not be used unless there are no effective alternatives. Otherwise, except for occasional hypersensitivity reactions, the Artemisinin Derivatives are safe and remarkably well tolerated. The adverse effect profiles of the Artemisinin-based combination treatments are determined by the partner drug. Most malaria endemic countries have now adopted Artemisinin-based combination treatments as first-line treatment of falciparum malaria, but in most of these only a minority of the patients that need Artemisinin-based combination treatments actually receive them.

  • dihydroArtemisinin piperaquine against multidrug resistant plasmodium falciparum malaria in vietnam randomised clinical trial
    The Lancet, 2004
    Co-Authors: Tran Tinh Hien, Christiane Dolecek, Nguyen Thi Dung, Nguyen Thanh Truong, Le Hong Thai, Dong Thi Hoai An, Tran Tan Thanh, Kasia Stepniewska, Nicholas J. White
    Abstract:

    Southeast Asia has the most resistant malaria parasites in the world which severely limits treatment options. There is general acceptance that to combat resistance combinations of antimalarial drugs that include an Artemisinin Derivative should be used and if possible these should be formulated in a single tablet. We did a pilot randomised study in a tertiary referral hospital in Vietnam to compare the efficacy of 3-day regimens of dihydroArtemisinin-trimethoprim-piperaquine (DHA-TP total dose 4·8/13·6/48 mg/kg respectively) with the standard antimalarial regimen in Vietnam artesunate-mefloquine (A3M total dose 12/25 mg/kg respectively) in non-immune patients with uncomplicated Plasmodium falciparum malaria. 114 patients were randomised 76 to DHA-TP and 38 to A3M. The subsequent open randomised trial at a Provincial Health Station compared DHA-TP dihydroArtemisinin-piperaquine and A3M in 400 patients. In both studies all patients received directly observed therapy and were followed up for 56 days. The primary endpoint was reappearance of P falciparum malaria within 56 days of treatment. Analysis was by intention to treat. The 56-day cure rate in the pilot study adjusted for reinfections identified by PCR genotyping was 97·4% (74/76) in the DHA-TP group and 100% (38/38) in the A3M group. In the second study cure rates were similar in the three groups; DHA-TP 97·4% (153/157) dihydroArtemisinin-piperaquine 98·7% (164/166) and A3M 98·7% (76/77). The DHA-TP and dihydroArtemisinin-piperaquine regimens were well tolerated; fewer than 3% of patients had side-effects that might have been related to treatment compared with 16% of A3M patients (p<0·001). No patients were lost to follow-up. DihydroArtemisinin-piperaquine is an inexpensive safe highly efficacious fixed-dose antimalarial combination treatment that could make an important contribution to the control of multidrug-resistant falciparum malaria. (authors)

  • oral artesunate dose response relationship in acute falciparum malaria
    Antimicrobial Agents and Chemotherapy, 2002
    Co-Authors: Nicholas J. White, Brian Angus, Itaporn Thaiaporn, Kenechanh Chanthapadith, Yupin Suputtamongkol
    Abstract:

    The combination of an oral Artemisinin Derivative (usually artesunate) and mefloquine has become standard treatment for multidrug-resistant falciparum malaria in several parts of Southeast Asia. The doses of artesunate used in monotherapy and combination treatment have largely been derived empirically. In order to characterize the in vivo dose-response relationship for artesunate and thus rationalize dosing, 47 adult patients with acute uncomplicated falciparum malaria and parasitemia > or = 1% were randomized to receive a single oral dose of artesunate varying between 0 and 250 mg together with a curative dose of oral mefloquine. Acceleration of parasite clearance was used as the pharmacodynamic variable. An inhibitory sigmoidal maximum effect (Emax) pharmacodynamic model typical of a dose-response curve was fitted to the relationship between dose and shortening of parasite clearance time (PCT). The Emax was estimated as 28.6 oral h, and the 50% effective concentration was 1.6 mg/kg of body weight. These results imply that there is no reduction in PCTs with the use of single doses of artesunate higher than 2 mg/kg, and this therefore reflects the average lower limit of the maximally effective dose.

  • a comparison of the in vivo kinetics of plasmodium falciparum ring infected erythrocyte surface antigen positive and negative erythrocytes
    Blood, 2001
    Co-Authors: Paul N Newton, Sornchai Looareesuwan, Kesinee Chotivanich, Wirongrong Chierakul, Ronatrai Ruangveerayuth, Pramote Teerapong, Kamolrat Silamut, Nicholas J. White
    Abstract:

    Ring-infected erythrocyte surface antigen (RESA)-positive, Plasmodium falciparum –negative red blood cells (RBCs) are cells from which the malaria parasite has been removed by the host without the destruction of the erythrocyte (“pitting”). The survival of RESA-RBCs in vivo was assessed in 14 severe and 6 uncomplicated falciparum malaria patients. The mean RESA-RBC life of 183 hours (95% confidence interval [CI], 136-246) was longer than the median parasite clearance time of 66 hours (range, 30-108 hours) but shorter than the mean red cell life of 1027 hours (95% CI, 840-1213) ( P  = .0004), with a median ratio of 0.2:1.0 (range, 0.1-0.7). The estimated median percentage of parasites pitted/body transit was 0.003% (range, 0.001%-0.05%). The rate of rise of the RESA-RBC count during the first 24 hours after antimalarial treatment was significantly faster ( P  = .036) and the subsequent RESA-RBC survival significantly shorter ( P  = .017) after treatment with an Artemisinin Derivative than after treatment with quinine. Parasitization of red cells leads to changes in the erythrocyte that shorten their survival even if the parasite is removed subsequently.

  • adverse effects in patients with acute falciparum malaria treated with Artemisinin Derivatives
    American Journal of Tropical Medicine and Hygiene, 1999
    Co-Authors: Ric N Price, M Van Vugt, L Phaipun, Christine Luxemburger, Julie A Simpson, Rose Mcgready, F O Ter Kuile, Am Kham, T Chongsuphajaisiddhi, Nicholas J. White
    Abstract:

    In prospective studies of acute uncomplicated, multidrug-resistant falciparum malaria on the western border of Thailand, the oral Artemisinin Derivatives were used alone in the treatment of 836 patients (artesunate 630, artemether 206), were combined with mefloquine (15-25 mg base/kg) in 2,826 patients, and mefloquine alone was used in 1,303 patients. The combined regimens of mefloquine plus an Artemisinin Derivative were associated with more side effects than those with an Artemisinin Derivative alone; acute nausea (31% versus 16%), vomiting (24% versus 11%), anorexia (51% versus 34%), and dizziness (47% versus 15%) (P < 0.001). Oral artesunate and artemether alone were very well tolerated. There was no difference in the incidence of possible adverse effects between the two drugs, and no evidence that either Derivative caused allergic reactions, neurologic or psychiatric reactions, or cardiovascular or dermatologic toxicity. Blackwater fever occurred in three patients treated with mefloquine plus artesunate regimens. Oral artesunate and artemether are safe and well tolerated antimalarial drugs.

Jianping Zuo - One of the best experts on this subject based on the ideXlab platform.

  • therapeutic effects of the Artemisinin analog sm934 on lupus prone mrl lpr mice via inhibition of tlr triggered b cell activation and plasma cell formation
    Cellular & Molecular Immunology, 2016
    Co-Authors: Luyao Zhang, Wei Tang, Jianping Zuo, Fenghua Zhu, Lu Xue, Xiaoqia Yang
    Abstract:

    We previously reported that SM934, a water-soluble Artemisinin Derivative, was a viable treatment in murine lupus models. In the current study, we further investigated the therapeutic effects of a modified dosage regimen of SM934 on lupus-prone MRL/lpr mice and explored its effects on B cell responses, a central pathogenic event in systemic lupus erythematosus (SLE). When orally administered twice-daily, SM934 significantly prolonged the life-span of MRL/lpr mice, ameliorated the lymphadenopathy symptoms and decreased the levels of serum anti-nuclear antibodies (ANAs) and of the pathogenic cytokines IL-6, IL-10 and IL-21. Furthermore, SM934 treatment restored the B-cell compartment in the spleen of MRL/lpr mice by increasing quiescent B cell numbers, maintaining germinal center B-cell numbers, decreasing activated B cell numbers and reducing plasma cell (PC) numbers. Ex vivo, SM934 suppressed the Toll-like receptor (TLR)-triggered activation and proliferation of B cells, as well as antibody secretion. Moreover, the present study demonstrated that SM934 interfered with the B-cell intrinsic pathway by downregulating TLR7/9 mRNA expression, MyD88 protein expression and NF-κB phosphorylation. In human peripheral blood mononuclear cells (PBMCs), consistent with the results in MRL/lpr mice, SM934 inhibited TLR-associated B-cell activation and PC differentiation. In conclusion, a twice daily dosing regimen of SM934 had therapeutic effects on lupus-prone MRL/lpr mice by suppressing B cell activation and plasma cell formation.

  • Artemisinin analogue sm934 ameliorates the proteinuria and renal fibrosis in rat experimental membranous nephropathy
    Acta Pharmacologica Sinica, 2015
    Co-Authors: Xiaohui Zhang, Wei Tang, Jingfeng Jing, Xiaoqian Yang, Fenghua Zhu, Jianping Zuo
    Abstract:

    SM934 is a novel water-soluble Artemisinin Derivative with immunoregulatory activities that has been used to treat murine lupus nephritis. In the current study, we investigated the effects of SM934 on rat experimental membranous nephropathy. Passive Heymann nephritis (PHN) was induced in SD rats by intraperitoneal injection of anti-Fx1A serum. The rats were orally administered SM934 (12.5 and 25 mg·kg−1·d−1) or prednisolone (5 mg·kg−1·d−1) for 28 d. Blood and urine sample, and kidney tissue were collected for analyses. Human complement C3a-induced injury of HK-2 cells was used for in vitro experiments. Treatment of PHN rats with SM934 or prednisolone attenuated the progression of glomerulonephritis and renal fibrosis, as evidenced by the reduced level of proteinuria and circulating antibodies, as well as by the reduced immune complex deposition, reversed podocyte injuries, and attenuated tubulointerstitial fibrosis in the kidneys. Furthermore, the two drugs suppressed TGF-β1 expression and Smad2/3 phosphorylation, and increased Smad7 expression in the kidneys. The two doses of SM934 produced almost identical therapeutic effects on PHN rats. Pretreatment with SM934 or a C3a receptor antagonist blocked the C3a-induced epithelial-mesenchymal transition in HK-2 cells in vitro. SM934 ameliorates kidney injury and attenuates the tubulointerstitial fibrosis in PHN rats by down-regulation of the TGF-β1/Smad signaling pathway.

  • sm905 an Artemisinin Derivative inhibited no and pro inflammatory cytokine production by suppressing mapk and nf κb pathways in raw 264 7 macrophages
    Acta Pharmacologica Sinica, 2009
    Co-Authors: Junxia Wang, Wei Tang, Lifei Hou, Jianping Zuo, Yang Yang
    Abstract:

    To elucidate the anti-inflammatory potentials and underlying mechanisms of SM905, a novel Artemisinin Derivative, in lipopolysaccharide (LPS)-stimulated murine macrophage RAW 264.7 cells. Nitric oxide (NO) generation, cytokine production, and the protein expression levels of inducible nitric-oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) were examined using a Griess assay, an enzyme-linked immunosorbent assay (ELISA) and a Western blotting assay, respectively. The mRNA expression was measured using real-time PCR. The phosphorylation of extracellular signal-regulated kinase1/2 (ERK1/2), p38, c-jun N-terminal kinase (JNK), and the degradation of IκBα were assessed by Western blotting analysis. The nuclear translocation of nuclear factor-κB (NF-κB) was observed using confocal microscopy. Pretreatment with SM905 (0, 0.1, 1, and 10 μmol/L) suppressed LPS-induced NO, TNF-α, IL-1β, and IL-6 production, and decreased both protein and mRNA levels of iNOS and COX-2. The mRNA expression of LPS receptor Toll-like receptor 4 (TLR4) and myeloid differentiation protein-2 (MD-2) was not changed, while LPS-induced CD14 expression was slightly reduced after SM905 treatment. SM905 markedly decreased the activation of ERK1/2, p38 and JNK suppressed the degradation of IκBα, but did not modify the expression of interferon regulatory factor-1 (IRF-1), signal transducer and activator of transcription 1 (STAT1) or interferon-inducible protein-10 (IP-10). By using confocal microscopy, we further observed that NF-κB was correspondingly inhibited in SM905-treated cells. SM905 inhibited NO and pro-inflammatory cytokine production in LPS-stimulated RAW 264.7 cells and these effects are at least partially mediated through suppression of the MAPK and NF-κB signaling pathways.

  • the new water soluble Artemisinin Derivative sm905 ameliorates collagen induced arthritis by suppression of inflammatory and th17 responses
    British Journal of Pharmacology, 2009
    Co-Authors: Jiang Wang, Jin Wan, Yu Zhang, Ru Zhou, Yifu Yang, Weihua Tang, Ling Shi, Jianping Zuo
    Abstract:

    Background and purpose: Our previous study showed that SM905, a novel Artemisinin Derivative, exhibited potent immunosuppressive activity. In this study, we evaluate preventive and therapeutic effect of SM905 on collagen-induced arthritis (CIA) in DBA/1 mice, and investigate its mechanisms both in inflammatory and autoimmune aspects of the disease. Experimental approach: CIA was induced by type II bovine collagen (CII) in DBA/1 mice. SM905 was given orally either before (continuously 1 day before booster immunization) or after disease onset (continuously 14 days after booster immunization). Disease incidence and severity were monitored, mRNA expression of proinflammatory mediators was determined by real-time PCR, purified T cell proliferation was assessed using [3H]-thymidine incorporated assay, and T helper (Th) 17/Th1/Th2 type cytokine production was examined by ELISA. Key results: Oral treatment with SM905 delayed disease onset, reduced arthritis incidence and severity, and suppressed the enhanced expression of pro-inflammatory cytokines, chemokines and chemokine receptors in draining lymph nodes. The CII-induced T cell proliferation and production of interleukin (IL)-17A by T cells were strikingly inhibited. Correspondingly, the mRNA expression of IL-17A and RORγt (a specific transcription factor for Th17) was also reduced. This effect was coupled with a striking reduction of IL-6 production, which has a critical role in Th17 development. In established arthritis, SM905 profoundly inhibited disease progression, reduced IL-17A and RORγt mRNA expression, and suppressed pro-inflammatory mediator expression in arthritic joints. Conclusions and implications: SM905 had beneficial effects on CIA by suppressing inflammatory and pathogenic Th17 responses. British Journal of Pharmacology (2008) 153, 1303–1310; doi:10.1038/bjp.2008.11; published online 11 February 2008

  • a novel Artemisinin Derivative 3 12 beta Artemisininoxy phenoxyl succinic acid sm735 mediates immunosuppressive effects in vitro and in vivo
    Acta Pharmacologica Sinica, 2005
    Co-Authors: Wenliang Zhou, Junxia Wang, Yu Zhang, Ru Zhou, Yu Zhou, Yifu Yang, Jianping Zuo
    Abstract:

    To study the immunosuppressive activity of SM735 {[3 -(12-β-Artemisininoxy)] phenoxyl succinic acid}, a synthetic Artemisinin Derivative with nonsteroidal anti-inflammatory drug structure, with the aim of finding potential immunosuppressive agents. Concanavalin A (ConA), lipopolysaccharide (LPS), and mixed lymphocyte reaction (MLR), were used to induce the proliferation of splenocytes, and [3H]-thymidine incorporation was used to evaluate the proliferation of splenocytes. Cytokine production was promoted with ConA, LPS, or PMA plus ionomycin, and was detected with the enzyme-linked immunosorbent assay. Dinitrofluorobenzene (DNFB) and sheep red blood cells (SRBC) were used to induce delayed-type hypersensitivity and quantitative hemolysis of SRBC (QHS) mouse models, as criteria for the evaluation of in vivo immune activity. SM735 strongly inhibited the proliferation of splenocytes induced by ConA, LPS, or MLR, with IC50 values of 0.33 μmol/L, 0.27 μmol/L, and 0.51 μmol/L, respectively. When compared with a CC50 value of 53.1 μmol/L, SM735 had a favorable safety range. SM735 dose-dependently inhibited proinflammatory cytokine production [including interleukins (IL)-12, interferon (IFN)-γ and IL-6] induced by LPS or PMA plus ionomycin. Upon ConA stimulation, SM735 suppressed IFN-γ in a dose-dependent manner, but did not affect IL-2 secretion. SM735 also strongly suppressed both T-cell-mediated delayed-type hypersensitivity (DTH) and B-cell-mediated QHS reactions. SM735 had strong immunosuppressive activity in vitro and in vivo, suggesting a potential role for SM735 as an immunosuppressive agent, and established the groundwork for further research onSM735.

N. J. White - One of the best experts on this subject based on the ideXlab platform.

  • Antimalarial drug resistance
    J.Clin.Invest, 2004
    Co-Authors: N. J. White
    Abstract:

    Malaria, the most prevalent and most pernicious parasitic disease of humans, is estimated to kill between one and two million people, mainly children, each year. Resistance has emerged to all classes of antimalarial drugs except the Artemisinins and is responsible for a recent increase in malaria-related mortality, particularly in Africa. The de novo emergence of resistance can be prevented by the use of antimalarial drug combinations. Artemisinin-Derivative combinations are particularly effective, since they act rapidly and are well tolerated and highly effective. Widespread use of these drugs could roll back malaria

  • preventing antimalarial drug resistance through combinations
    Drug Resistance Updates, 1998
    Co-Authors: N. J. White
    Abstract:

    Throughout the tropical world antimalarial drug resistance is increasing, particularly in the potentially lethal malaria parasite Plasmodium falciparum. In some parts of Southeast Asia, parasites which are resistant to chloroquine, pyrimethamine-sulfadoxine, and mefloquine are prevalent. The characteristics of a drug that make it vulnerable to the development of resistance are a long terminal elimination half-life, a shallow concentration-effect relationship, and that one or two base-pair mutations confer a marked reduction in susceptibility. The development of resistance can be delayed or prevented by drug combinations. The Artemisinin Derivatives are the most potent of all antimalarial drugs. They reduce the infecting parasite biomass by approximately 10 000-fold per asexual life cycle. There are good arguments for combining, de novo, an Artemisinin Derivative with all newly introduced antimalarial drugs.

Jose Pedro Gil - One of the best experts on this subject based on the ideXlab platform.

  • plasmodium falciparum drug resistance phenotype as assessed by patient antimalarial drug levels and its association with pfmdr1 polymorphisms
    The Journal of Infectious Diseases, 2013
    Co-Authors: Maja Malmberg, Andreas Martensson, Anders Bjorkman, Jose Pedro Gil, Pedro Eduardo Ferreira, Joel Tarning, Johan Ursing, Billy Ngasala
    Abstract:

    The evolution and spread of Artemisinin-based combination therapy (ACT)–resistant Plasmodium falciparum may have drastic consequences on global malaria control and elimination efforts. Development of ACT resistance is likely to start with a decreased efficacy of the long–half-life partner drug, gradually transforming ACT into an unprotected Artemisinin-Derivative monotherapy. This notion underlies the World Health Organization policy that Artemisinin-Derivative agents should be exclusively used in combination with other drugs for the treatment of uncomplicated malaria and never together with a failing drug. In high-transmission areas, the development of resistance against long–half-life partner drugs is likely to occur through the posttreatment selection of less sensitive parasites, as reinfections are exposed to subtherapeutic blood levels of these slowly eliminated drugs. The posttreatment selection of drug resistance–associated single-nucleotide polymorphisms (SNPs) observed after both artemether-lumefantrine [1–3] and artesunate-amodiaquine [4, 5] treatment, involving polymorphisms of the P. falciparum multidrug resistance gene 1 (pfmdr1; National Center for Biotechnology Information Reference Sequence gene ID 813045), are examples of this. To identify useful surveillance tools such as genetic markers of resistance against the long-acting partners in ACT, a clear definition of the P. falciparum resistance phenotype is needed. Unfortunately, in vivo resistance has been difficult to define with precision. Treatment failure can be due to nonparasitological factors like poor patient drug bioavailability or adherence. Furthermore, the use of biodiversity markers such as P. falciparum merozoite surface protein 1 (pfmsp1), pfmsp2, and glutamate-rich protein (glurp) to distinguish between recrudescence (treatment failure) and reinfections may be less reliable than previously expected [6, 7]. As for field in vitro methods, these are only applicable to subsets of infections with appropriate parasitemia and tend to select for high-fitness parasites. We propose a complementary concept for defining molecular markers of in vivo P. falciparum susceptibility. In recent years, we have witnessed important technological developments in the determination of drug levels in blood, using samples collected on filter papers. The increased robustness of these techniques has allowed routine analysis of drug levels of the ACT partner drugs on the seventh day (D7) after treatment initiation as a surrogate marker for drug exposure (ie, area under the concentration-time curve [AUC]) [8]. Long-acting antimalarial drugs (eg, lumefantrine [LUM]) are in their terminal elimination phase at D7 and have a log-linear decrease of drug concentrations [8]. This enables later drug levels to be inferred using the measured D7 concentration and the terminal elimination half-life. The accuracy of the inferred drug concentrations depends on knowledge of the pharmacokinetic characteristics of the target group, especially the terminal elimination rate constant. Estimated drug concentrations can then be correlated to genotypes (SNPs, copy number variation) of recurrent parasites. As a proof of concept, we correlated polymorphisms in pfmdr1 with estimated LUM drug concentrations in patients treated with artemether-lumefantrine.

  • in vivo selection of plasmodium falciparum pfmdr1 86n coding alleles by artemether lumefantrine coartem
    The Journal of Infectious Diseases, 2005
    Co-Authors: Christin Sisowath, Johan Stromberg, Andreas Martensson, Mwinyi Msellem, Christine Obondo, Anders Bjorkman, Jose Pedro Gil
    Abstract:

    Artemisinin Derivative-based combination therapy is expected to suppress the development of Plasmodium falciparum drug resistance in Africa. We have performed an artemether-lumefantrine (Coartem; Novartis) follow-up clinical trial in Zanzibar, in which pfcrt K76T and pfmdr1 N86Y frequencies were determined before drug administration and in all recurrent parasites during a follow-up period of 42 days. A significant increase in pfmdr1 86N was observed after exposure to the drug. This points to 86N as a potential marker of lumefantrine resistance in vivo, while suggesting that Coartem is not robust enough to avoid selection of resistance-associated mutations in some malarial settings.

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

  • baseline data of parasite clearance in patients with falciparum malaria treated with an Artemisinin Derivative an individual patient data meta analysis
    Malaria Journal, 2015
    Co-Authors: Salim Abdulla, Anders Bjorkman, Elizabeth A Ashley, Umberto Dalessandro, Quique Bassat, Delia Bethell, Steffen Borrmann, Prabin Dahal, Nicholas P J Day, Mahamadou Diakite
    Abstract:

    Background: Artemisinin resistance in Plasmodium falciparum manifests as slow parasite clearance but this measure is also influenced by host immunity, initial parasite biomass and partner drug efficacy. This study collated data from clinical trials of Artemisinin Derivatives in falciparum malaria with frequent parasite counts to provide reference parasite clearance estimates stratified by location, treatment and time, to examine host factors affecting parasite clearance, and to assess the relationships between parasite clearance and risk of recrudescence during follow-up. Methods: Data from 24 studies, conducted from 1996 to 2013, with frequent parasite counts were pooled. Parasite clearance half-life (PC1/2) was estimated using the WWARN Parasite Clearance Estimator. Random effects regression models accounting for study and site heterogeneity were used to explore factors affecting PC1/2 and risk of recrudescence within areas with reported delayed parasite clearance (western Cambodia, western Thailand after 2000, southern Vietnam, southern Myanmar) and in all other areas where parasite populations are Artemisinin sensitive. Results: PC1/2 was estimated in 6975 patients, 3288 of whom also had treatment outcomes evaluate d during 28-63 days follow-up, with 93 (2.8 %) PCR-confirmed recrudescences. In areas with Artemisinin-sensitive parasites, the median PC1/2 following three-day artesunate treatment (4 mg/kg/day) ranged from 1.8 to 3.0 h and the proportion of patients with PC1/2 > 5 h from 0 to 10 %. Artesunate doses of 4 mg/kg/day decreased PC1/2 by 8.1 % (95 % CI 3.2-12.6) compared to 2 mg/kg/day, except in populations with delayed parasite clearance. PC1/2 was longer in children and in patients with fever or anaemia at enrolment. Long PC1/2 (HR = 2.91, 95 % CI 1.95-4.34 for twofold increase, p < 0.001) and high initial parasitaemia (HR = 2.23, 95 % CI 1.44-3.45 for tenfold increase, p < 0.001) were associated independently with an increased risk of recrudescence. In western Cambodia, the region with the highest prevalence of Artemisinin resistance, there was no evidence for increasing PC1/2 since 2007. Conclusions: Several factors affect PC1/2. As substantial heterogeneity in parasite clearance exists between locations, early detection of Artemisinin resistance requires reference PC1/2 data. Studies with frequent parasite count measurements to characterize PC1/2 should be encouraged. In western Cambodia, where PC1/2 values are longest, there is no evidence for recent emergence of higher levels of Artemisinin resistance.

  • in vivo parasitological measures of Artemisinin susceptibility
    The Journal of Infectious Diseases, 2010
    Co-Authors: Kasia Stepniewska, Elizabeth A Ashley, Nicholas M Anstey, Karen I Barnes, Tran Quang Binh, Umberto Dalessandro, Peter J De Vries, Grant Dorsey, Jeanpaul Guthmann, Mayfong Mayxay
    Abstract:

    Parasite clearance data from 18,699 patients with falciparum malaria treated with an Artemisinin Derivative in areas of low (n=14,539), moderate (n=2077), and high (n=2083) levels of malaria transmission across the world were analyzed to determine the factors that affect clearance rates and identify a simple in vivo screening measure for Artemisinin resistance. The main factor affecting parasite clearance time was parasite density on admission. Clearance rates were faster in high-transmission settings and with more effective partner drugs in Artemisinin-based combination treatments (ACTs). The result of the malaria blood smear on day 3 (72 h) was a good predictor of subsequent treatment failure and provides a simple screening measure for Artemisinin resistance. Artemisinin resistance is highly unlikely if the proportion of patients with parasite densities of <100,000 parasites/microL given the currently recommended 3-day ACT who have a positive smear result on day 3 is <3%; that is, for n patients the observed number with a positive smear result on day 3 does not exceed (n + 60)/24.

  • randomized controlled dose optimization studies of dihydroArtemisinin piperaquine for the treatment of uncomplicated multidrug resistant falciparum malaria in thailand
    The Journal of Infectious Diseases, 2004
    Co-Authors: Srivicha Krudsood, Rose Mcgready, Elizabeth A Ashley, Lucy Phaiphun, Siripan Srivilairit, Wattana Leowattana, Robert Hutagalung, Polrat Wilairatana
    Abstract:

    Background. DihydroArtemisinin-piperaquine (DP) is a new and relatively inexpensive Artemisinin-containing fixed-combination antimalarial treatment. An adult treatment course contained 6.4 mg/kg dihydroArtemisinin (DHA), which is >40% lower than the level in most Artemisinin-containing combinations. This raised the possibility that the efficacy of the current coformulation may not be optimal in the treatment of multidrug-resistant falciparum malaria. Methods. In 2 large randomized, controlled studies in Thailand, the recommended dose of DP was compared with a regimen with additional Artemisinin Derivative ( 12 mg/kg; DP+) and with mefloquine plus artesunate (MAS3). Results. A total of 731 patients were included: 201 in a hospital-based study and 530 in a community study. Day-28 cure rates in the hospital-based study were 100% (95% confidence interval [CI], 93.9%-100%) in the MAS3 and DP+ groups and 98.3% (95% CI, 91%-99.7%) in the DP group, with a single recrudescence on day 21. In the community study, polymerase chain reaction genotyping-adjusted cure rates on day 63 were 96.1% ( 95% CI, 92.6%-99.7%) in the DP group, 98.3% ( 95% CI, 96.1%-100%) in the DP+ group, and 94.9% (95% CI, 91.2%-98.6%) in the MAS3 group (P = .2). Adverse events were few, with an excess of mild abdominal pain in the DP group. Conclusions. The current dosage of DP ( 6.4 mg/kg DHA and 51.2 mg/kg piperaquine phosphate) given over the course of 48 h is highly effective, safe, and well tolerated for the treatment of multidrug-resistant falciparum malaria, and its efficacy is not improved by the addition of more DHA.