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New Babesia Treatment?
Works well in Hamsters and is used in Human Malaria

  1. Cochrane Database Syst Rev. 2015 Apr 29;4:CD010458. doi: 10.1002/14651858.CD010458.pub2.

    Tafenoquine for preventing relapse in people with Plasmodium vivax malaria.

    Rajapakse S(1), Rodrigo C, Fernando SD.

    Author information: (1)Department of Clinical Medicine, Faculty of Medicine, University of Colombo, 25, Kynsey Road, Colombo, Sri Lanka.

    BACKGROUND: Plasmodium vivax malaria is widespread, and the persistent liver stage causes relapse of the disease which contributes to continued P. vivax transmission. Primaquine is currently the only drug that cures the parasite liver stage, but requires 14 days to be effective and can cause haemolysis in people with glucose-6-phosphate dehydrogenase (G6PD) deficiency. In addition, there is some evidence of parasite resistance to the drug. Tafenoquine is a new alternative with a longer half-life. OBJECTIVES: To assess the effects of tafenoquine in people with P. vivax infection. SEARCH METHODS: We searched the following databases up to 13 April 2015: the Cochrane Infectious Diseases Group Specialized Register; the Cochrane Central Register of Controlled Trials (CENTRAL), published in The Cochrane Library; MEDLINE; EMBASE; CINAHL; SCOPUS; and LILACS. We also searched the World Health Organization (WHO) International Clinical Trial Registry Platform and the metaRegister of Controlled Trials (mRCT) for ongoing trials using "tafenoquine" and "malaria" as search terms up to 13 April 2015. SELECTION CRITERIA: Randomized controlled trials (RCTs) in people with P. vivax malaria. Adverse effects of tafenoquine are assessed in populations where people with G6PD deficiency have been excluded, and in populations without screening for G6PD deficiency. DATA COLLECTION AND ANALYSIS: All review authors independently extracted data and assessed trial quality. Meta-analysis was carried out where appropriate, and estimates given as relative risk with 95% confidence intervals. We assessed the quality of the evidence using the GRADE approach. MAIN RESULTS: Three RCTs met our inclusion criteria, with the asexual infection in both the tafenoquine and comparator arm treated with chloroquine, and in all trials G6PD deficiency patients were excluded. Tafenoquine dose comparisonsThree of the included trials compared eight different dosing regimens. Tafenoquine doses of 300 mg and above resulted in fewer relapses than no hypnozoite treatment over six months follow-up in adults (300 mg single dose: RR 0.19, 95% CI 0.08 to 0.41, one trial, 110 participants, moderate quality evidence; 500 to 600 mg single dose: RR 0.14, 95%CI 0.06 to 0.34, two trials, 122 participants, moderate quality evidence; 1800 mg to 3000 mg in divided doses: RR 0.05, 95% CI 0.01 to 0.23, two trials, 63 participants, low quality evidence).In people with normal G6PD status, there may be little or no difference in serious adverse events (three trials, 358 participants, low quality evidence); or any adverse event (one trial, 272 participants, low quality evidence). Tafenoquine versus primaquine Two of the included trials compared four different dosing regimens of tafenoquine against the standard primaquine regimen of 15 mg/day for 14 days. A single tafenoquine dose of 600 mg may be more effective than primaquine in relation to relapses at six months follow-up (RR 0.29, 95% CI 0.10 to 0.84, two trials, 98 participants, low quality evidence)In people with normal G6PD status, there may be little or no difference for serious adverse events (two trials, 323 participants, low quality evidence) or any adverse event (two trials, 323 participants, low quality evidence) between tafenoquine and primaquine. AUTHORS' CONCLUSIONS: Tafenoquine prevents relapses after clinically and parasitologically confirmed P. vivax malaria. The drug is untested in pregnancy, children and in G6PD-deficient people. The shorter treatment course is an important practical advantage in people who do not have G6PD deficiency, but the longer half-life may have more substantive consequences if given inadvertently to people with G6PD deficiency.

    PMID: 25921416 [PubMed - in process]

  2. Pathog Glob Health. 2015 May;109(3):107-22. doi: 10.1179/2047773215Y.0000000013. Epub 2015 Apr 18.

    Killing the hypnozoite - drug discovery approaches to prevent relapse in Plasmodium vivax.

    Campo B, Vandal O, Wesche DL, Burrows JN.

    The eradication of malaria will only be possible if effective, well-tolerated medicines kill hypnozoites in vivax and ovale malaria, and thus prevent relapses in patients. Despite progress in the 8-aminoquinoline series, with tafenoquine in Phase III showing clear benefits over primaquine, the drug discovery challenge to identify hypnozoiticidal or hypnozoite-activating compounds has been hampered by the dearth of biological tools and assays, which in turn has been limited by the immense scientific and logistical challenges associated with accessing relevant human tissue and sporozoites. This review summarises the existing drug discovery series and approaches concerning the goal to block relapse.

    PMID: 25891812 [PubMed - in process]

  3. Antimicrob Agents Chemother. 2015 Apr 13. pii: AAC.00343-15. [Epub ahead of print]

    Differential CYP 2D Metabolism Alters Tafenoquine Pharmacokinetics.

    Vuong C(1), Xie LH(1), Potter BM(1), Zhang J(1), Zhang P(1), Duan D(1), Nolan CK(1), Sciotti RJ(1), Zottig VE(1), Dhammika Nanayakkara NP(2), Tekwani BL(3), Walker LA(3), Smith PL(1), Paris RM(1), Read LT(1), Li Q(1), Pybus BS(1), Sousa JC(1), Reichard GA(1), Smith B(4), Marcsisin SR(5).

    Author information: (1)Military Malaria Research Program, Division of Experimental Therapeutics, Walter Reed Army Institute of Research, Silver Spring, MD, 20910. (2)National Center for Natural Products Research. (3)National Center for Natural Products Research Department of BioMolecular Sciences, School of Pharmacy, University of Mississippi, MS 38677. (4)United States Army Medical Material Development Activity, Frederick, MD 21701, USA. (5)Military Malaria Research Program, Division of Experimental Therapeutics, Walter Reed Army Institute of Research, Silver Spring, MD, 20910.

    CYP 2D metabolism is required for the liver stage anti-malarial efficacy of the 8-aminoquinoline molecule tafenoquine in mice. This could be problematic for P. vivax radical cure as the human CYP 2D ortholog (2D6) is highly polymorphic. Diminished CYP 2D6 enzyme activity, as in the poor metabolizer phenotype, could compromise radical curative efficacy in humans. Despite the importance of CYP 2D metabolism on tafenoquine liver stage efficacy, the exact role that CYP 2D metabolism plays in the metabolism and pharmacokinetics of tafenoquine and other 8-aminoquinoline molecules has not been extensively studied. In this study, a series of tafenoquine pharmacokinetic experiments were conducted in mice with differential CYP 2D metabolism status including wild-type (WT, reflecting extensive metabolizers for CYP 2D6 substrates), and CYPmouse 2D knock-out (KO, reflecting poor metabolizers for CYP 2D6 substrates). Plasma and liver pharmacokinetic profiles from a single 20 mg/kg dose of tafenoquine differed between the strains; however, differences were less striking than previous results obtained for primaquine in the same model. Additionally, the presence of a 5,6 ortho-quinone tafenoquine metabolite was examined in both mouse strains. The 5,6 ortho-quinone species for tafenoquine was observed, and concentrations of this metabolite were highest in the WT extensive metabolizer phenotype. Taken together, this study indicates that CYP 2D metabolism in mice affects tafenoquine pharmacokinetics, and could have implications for human tafenoquine pharmacokinetics in polymorphic CYP 2D6 human populations.

    Copyright © 2015, American Society for Microbiology. All Rights Reserved.

    PMID: 25870069 [PubMed - as supplied by publisher]

  4. Expert Opin Investig Drugs. 2015 Mar;24(3):363-82. doi: 10.1517/13543784.2015.1000483. Epub 2015 Jan 7.

    Antimalarial compounds in Phase II clinical development.

    Held J(1), Jeyaraj S, Kreidenweiss A.

    Author information: (1)Institut für Tropenmedizin, Eberhard Karls Universität , Wilhelmstraße 27, D-72074 Tübingen , Germany +49 7071 29 85569 ; +49 7071 295189 ;

    INTRODUCTION: Malaria is a major health problem in endemic countries and chemotherapy remains the most important tool in combating it. Treatment options are limited and essentially rely on a single drug class - the artemisinins. Efforts are ongoing to restrict the evolving threat of artemisinin resistance but declining sensitivity has been reported. Fueled by the ambitious aim of malaria eradication, novel antimalarial compounds, with improved properties, are now in the progressive phase of drug development. AREAS COVERED: Herein, the authors describe antimalarial compounds currently in Phase II clinical development and present the results of these investigations. EXPERT OPINION: Thanks to recent efforts, a number of promising antimalarial compounds are now in the pipeline. First safety data have been generated for all of these candidates, although their efficacy as antimalarials is still unclear for most of them. Of particular note are KAE609, KAF156 and DSM265, which are of chemical scaffolds new to malaria chemotherapy and would truly diversify antimalarial options. Apart from SAR97276, which also has a novel chemical scaffold that has had its development stopped, all other compounds in the pipeline belong to already known substance classes, which have been chemically modified. At this moment in time, there is not one standout compound that will revolutionize malaria treatment but several compounds that will add to its control in the future.

    PMID: 25563531 [PubMed - in process]

  5. Malar J. 2014 Nov 18;13:438. doi: 10.1186/1475-2875-13-438.

    Glucose-6-phosphate dehydrogenase deficiency among malaria suspects attending Gambella hospital, southwest Ethiopia.

    Tsegaye A, Golassa L, Mamo H(1), Erko B.

    Author information: (1)Department of Microbial, Cellular and Molecular Biology, College of Natural Sciences, Addis Ababa University, P, O, Box 1176, Addis Ababa, Ethiopia.

    BACKGROUND: Glucose-6-phosphate dehydrogenase deficiency (G6PDd) is widespread across malaria endemic regions. G6PD-deficient individuals are at risk of haemolysis when exposed, among other agents, to primaquine and tafenoquine, which are capable of blocking malaria transmission by killing Plasmodium falciparum gametocytes and preventing Plasmodium vivax relapses by targeting hypnozoites. It is evident that no measures are currently in place to ensure safe delivery of these drugs within the context of G6PDd risk. Thus, determining G6PDd prevalence in malarious areas would contribute towards avoiding possible complications in malaria elimination using the drugs. This study, therefore, was aimed at determining G6PDd prevalence in Gambella hospital, southwest Ethiopia, using CareStart™ G6PDd fluorescence spot test. METHODS: Venous blood samples were collected from febrile patients (n = 449) attending Gambella hospital in November-December 2013. Malaria was diagnosed using blood films and G6PDd was screened using CareStart™ G6PDd screening test (Access Bio, New Jersey, USA). Haematological parameters were also measured. The association of G6PD phenotype with sex, ethnic group and malaria smear positivity was tested. RESULTS: Malaria prevalence was 59.2% (96.6% of the cases being P. falciparum mono infections). Totally 33 participants (7.3%) were G6PD-deficient with no significant difference between the sexes. The chance of being G6PD-deficient was significantly higher for the native ethnic groups (Anuak and Nuer) compared to the 'highlanders'/settlers (odds ratio (OD) = 3.9, 95% confidence interval (CI) 0.481-31.418 for Anuak vs 'highlanders'; OD = 4.9, 95% CI 0.635-38.00 for Nuer vs 'highlanders'). G6PDd prevalence among the Nuer (14.3%) was significantly higher than that for the Anuak (12.0%). CONCLUSIONS: G6PDd prevalence in the area is substantial with 30 (90.9%) of the 33 deficient individuals having malaria suggesting the non-protective role of the disorder at least from clinical malaria. The indigenous Nilotic people tend to have a higher chance of being G6PD-deficient as 32 (96.9%) of the total 33 cases occurred among them.

    PMCID: PMC4252010 PMID: 25406667 [PubMed - in process]

  6. Protoplasma. 2015 May;252(3):717-53. doi: 10.1007/s00709-014-0697-x. Epub 2014 Oct 17.

    New insight-guided approaches to detect, cure, prevent and eliminate malaria.

    Kumar S(1), Kumari R, Pandey R.

    Author information: (1)SKA Institution for Research, Education and Development (SKAIRED), 4/11 SarvPriya Vihar, New Delhi, 110016, India,

    New challenges posed by the development of resistance against artemisinin-based combination therapies (ACTs) as well as previous first-line therapies, and the continuing absence of vaccine, have given impetus to research in all areas of malaria control. This review portrays the ongoing progress in several directions of malaria research. The variants of RTS,S and apical membrane antigen 1 (AMA1) are being developed and test adapted as multicomponent and multistage malaria control vaccines, while many other vaccine candidates and methodologies to produce antigens are under experimentation. To track and prevent the spread of artemisinin resistance from Southeast Asia to other parts of the world, rolling circle-enhanced enzyme activity detection (REEAD), a time- and cost-effective malaria diagnosis in field conditions, and a DNA marker associated with artemisinin resistance have become available. Novel mosquito repellents and mosquito trapping and killing techniques much more effective than the prevalent ones are undergoing field testing. Mosquito lines stably infected with their symbiotic wild-type or genetically engineered bacteria that kill sympatric malaria parasites are being constructed and field tested for stopping malaria transmission. A complementary approach being pursued is the addition of ivermectin-like drug molecules to ACTs to cure malaria and kill mosquitoes. Experiments are in progress to eradicate malaria mosquito by making it genetically male sterile. High-throughput screening procedures are being developed and used to discover molecules that possess long in vivo half life and are active against liver and blood stages for the fast cure of malaria symptoms caused by simple or relapsing and drug-sensitive and drug-resistant types of varied malaria parasites, can stop gametocytogenesis and sporogony and could be given in one dose. Target-based antimalarial drug designing has begun. Some of the putative next-generation antimalarials that possess in their scaffold structure several of the desired properties of malaria cure and control are exemplified by OZ439, NITD609, ELQ300 and tafenoquine that are already undergoing clinical trials, and decoquinate, usnic acid, torin-2, ferroquine, WEHI-916, MMV396749 and benzothiophene-type N-myristoyltransferase (NMT) inhibitors, which are candidates for future clinical usage. Among these, NITD609, ELQ300, decoquinate, usnic acid, torin-2 and NMT inhibitors not only cure simple malaria and are prophylactic against simple malaria, but they also cure relapsing malaria.

    PMID: 25323622 [PubMed - in process]

  7. Malar J. 2014 Jun 10;13:228. doi: 10.1186/1475-2875-13-228.

    Mirincamycin, an old candidate for malaria combination treatment and prophylaxis in the 21st century: in vitro interaction profiles with potential partner drugs in continuous culture and field isolates.

    Starzengruber P, Fuehrer HP, Swoboda P, Ganesh D, Haque R, Khan WA, Graninger W, Noedl H(1).

    Author information: (1)Institute of Specific Prophylaxis and Tropical Medicine, Medical University of Vienna, Vienna, Austria.

    BACKGROUND: Spreading resistance of Plasmodium falciparum to existing drugs calls for the search for novel anti-malarial drugs and combinations for the treatment of falciparum malaria. METHODS: In vitro and ex vivo investigations were conducted with fresh P. falciparum field isolates and culture-adapted P. falciparum clones to evaluate the anti-malarial potential of mirincamycin, a lincosamide, alone and in combination with tafenoquine (TQ), dihydroartemisinin (DHA), and chloroquine (CQ). All samples were tested in a histidine-rich protein 2 (HRP2) drug susceptibility assay. RESULTS: Interaction analysis showed additive to synergistic interaction profiles with these potential partner drugs, with an overall geometric mean fractional inhibitory concentration at 50% inhibition (FIC₅₀) of 0.78, 0.80 and 0.80 for mirincamycin with TQ, DHA, and CQ, respectively. Antagonism was not found in any of the tested field isolates or clones. The strongest tendency toward synergy (i.e. the lowest FIC) was seen with a combination ratio of 1:0.27 to 1:7.2 (mean 1:2.7) for the combination with tafenoquine. The optimal combination ratios for DHA and CQ were 1:444.4 to 1:36,000 (mean 1:10,755.5) and 1:2.7 to 1:216 (mean 1:64.5), respectively. No evidence of an activity correlation (i.e. potential cross-resistance) with DHA, mefloquine, quinine or chloroquine was seen whereas a significant correlation with the activity of clindamycin and azithromycin was detected. CONCLUSIONS: Mirincamycin combinations may be promising candidates for further clinical investigations in the therapy and prophylaxis of multidrug-resistant falciparum malaria or in combination with 4 or 8-aminoquinolines for the treatment and relapse prevention of vivax malaria.

    PMCID: PMC4059879 PMID: 24916383 [PubMed - indexed for MEDLINE]

  8. J Parasitol. 2014 Oct;100(5):671-3. doi: 10.1645/13-480.1. Epub 2014 Apr 29.

    Causal prophylactic efficacy of primaquine, tafenoquine, and atovaquone-proguanil against Plasmodium cynomolgi in a rhesus monkey model.

    DiTusa C(1), Kozar MP, Pybus B, Sousa J, Berman J, Gettayacamin M, Im-erbsin R, Tungtaeng A, Ohrt C.

    Author information: (1)Division of Experimental Therapeutics, Walter Reed Army Institute of Research, Silver Spring, Maryland 20910; * Department of Veterinary Medicine, United States Army Medical Component-Armed Forces Research Institute of Medical Sciences (USAMC-AFRIMS), Bangkok, Thailand 10400. Correspondence should be sent to:

    Since the 1940s, the large animal model to assess novel causal prophylactic antimalarial agents has been the Plasmodium cynomolgi sporozoite-infected Indian-origin rhesus monkey. In 2009 the model was reassessed with 3 clinical standards: primaquine (PQ), tafenoquine (TQ), and atovaquone-proguanil. Both control monkeys were parasitemic on day 8 post-sporozoite inoculation on day 0. Primaquine at 1.78 mg base/kg/day on days (-1) to 8 protected 1 monkey and delayed parasitemia patency of the other monkey to day 49. Tafenoquine at 6 mg base/kg/day on days (-1) to 1 protected both monkeys. However, atovaquone-proguanil at 10 mg atovaquone/kg/day on days (-1) to 8 did not protect either monkey and delayed patency only to days 18-19. Primaquine and TQ at the employed regimens are proposed as appropriate doses of positive control drugs for the model at present.

    PMID: 24780070 [PubMed - indexed for MEDLINE]

  9. Malar J. 2014 Apr 14;13:141. doi: 10.1186/1475-2875-13-141.

    Assessment of the prophylactic activity and pharmacokinetic profile of oral tafenoquine compared to primaquine for inhibition of liver stage malaria infections.

    Li Q(1), O'Neil M, Xie L, Caridha D, Zeng Q, Zhang J, Pybus B, Hickman M, Melendez V.

    Author information: (1)Division of Experimental Therapeutics, Walter Reed Army Institute of Research, 503 Robert Grant Avenue, Silver Spring, MD 20910, USA.

    BACKGROUND: As anti-malarial drug resistance escalates, new safe and effective medications are necessary to prevent and treat malaria infections. The US Army is developing tafenoquine (TQ), an analogue of primaquine (PQ), which is expected to be more effective in preventing malaria in deployed military personnel. METHODS: To compare the prophylactic efficacy of TQ and PQ, a transgenic Plasmodium berghei parasite expressing the bioluminescent reporter protein luciferase was utilized to visualize and quantify parasite development in C57BL/6 albino mice treated with PQ and TQ in single or multiple regimens using a real-time in vivo imaging system (IVIS). As an additional endpoint, blood stage parasitaemia was monitored by flow cytometry. Comparative pharmacokinetic (PK) and liver distribution studies of oral and intravenous PQ and TQ were also performed. RESULTS: Mice treated orally with three doses of TQ at 5 mg/kg three doses of PQ at 25 mg/kg demonstrated no bioluminescence liver signal and no blood stage parasitaemia was observed suggesting both drugs showed 100% causal activity at the doses tested. Single dose oral treatment with 5 mg TQ or 25 mg of PQ, however, yielded different results as only TQ treatment resulted in causal prophylaxis in P. berghei sporozoite-infected mice. TQ is highly effective for causal prophylaxis in mice at a minimal curative single oral dose of 5 mg/kg, which is a five-fold improvement in potency versus PQ. PK studies of the two drugs administered orally to mice showed that the absolute bioavailability of oral TQ was 3.5-fold higher than PQ, and the AUC of oral TQ was 94-fold higher than oral PQ. The elimination half-life of oral TQ in mice was 28 times longer than PQ, and the liver tissue distribution of TQ revealed an AUC that was 188-fold higher than PQ. CONCLUSIONS: The increased drug exposure levels and longer exposure time of oral TQ in the plasma and livers of mice highlight the lead quality attributes that explain the much improved efficacy of TQ when compared to PQ.

    PMCID: PMC3989846 PMID: 24731238 [PubMed - indexed for MEDLINE]

  10. J Clin Pharmacol. 2014 Sep;54(9):995-1005. doi: 10.1002/jcph.302. Epub 2014 Apr 9.

    Tafenoquine at therapeutic concentrations does not prolong Fridericia-corrected QT interval in healthy subjects.

    Green JA(1), Patel AK, Patel BR, Hussaini A, Harrell EJ, McDonald MJ, Carter N, Mohamed K, Duparc S, Miller AK.

    Author information: (1)Diseases of the Developing World Group, GlaxoSmithKline Research and Development, Stockley Park West, Uxbridge, Middlesex, UK.

    Tafenoquine is being developed for relapse prevention in Plasmodium vivax malaria. This Phase I, single-blind, randomized, placebo- and active-controlled parallel group study investigated whether tafenoquine at supratherapeutic and therapeutic concentrations prolonged cardiac repolarization in healthy volunteers. Subjects aged 18-65 years were randomized to one of five treatment groups (n = 52 per group) to receive placebo, tafenoquine 300, 600, or 1200 mg, or moxifloxacin 400 mg (positive control). Lack of effect was demonstrated if the upper 90% CI of the change from baseline in QTcF following supratherapeutic tafenoquine 1200 mg versus placebo (ΔΔQTcF) was < 10 milliseconds for all pre-defined time points. The maximum ΔΔQTcF with tafenoquine 1200 mg (n = 50) was 6.39 milliseconds (90% CI 2.85, 9.94) at 72 hours post-final dose; that is, lack of effect for prolongation of cardiac depolarization was demonstrated. Tafenoquine 300 mg (n = 48) or 600 mg (n = 52) had no effect on ΔΔQTcF. Pharmacokinetic/pharmacodynamic modeling of the tafenoquine-QTcF concentration-effect relationship demonstrated a shallow slope (0.5 ms/μg mL(-1) ) over a wide concentration range. For moxifloxacin (n = 51), maximum ΔΔQTcF was 8.52 milliseconds (90% CI 5.00, 12.04), demonstrating assay sensitivity. In this thorough QT/QTc study, tafenoquine did not have a clinically meaningful effect on cardiac repolarization.

    © 2014, The American College of Clinical Pharmacology.

    PMCID: PMC4283056 PMID: 24700490 [PubMed - indexed for MEDLINE]

  11. Malar J. 2014 Feb 6;13:49. doi: 10.1186/1475-2875-13-49.

    A retrospective analysis of the protective efficacy of tafenoquine and mefloquine as prophylactic anti-malarials in non-immune individuals during deployment to a malaria-endemic area.

    Dow GS(1), McCarthy WF, Reid M, Smith B, Tang D, Shanks GD.

    Author information: (1)United States Army Medical Materiel Development Activity, 1430 Veterans Drive, Fort Detrick, Maryland 21702, USA.

    BACKGROUND: In 2000/2001, the Australian Defense Forces (ADF), in collaboration with SmithKline Beecham and the United States Army, conducted a field trial to evaluate the safety, tolerability and efficacy of tafenoquine and mefloquine/primaquine for the prophylaxis of malaria amongst non-immune Australian soldiers deployed to East Timor (now called Timor Leste) for peacekeeping operations. The lack of a concurrent placebo control arm prevented an internal estimate of the malaria attack rate and so the protective efficacy of the study regimens was not determined at the time. METHODS: In a retrospective analysis of the trial results, the all species malaria attack rate was estimated for the prophylactic phase of the study which was defined as the period between administration of the first prophylactic dose and the first dose of post-deployment medication. First, the Plasmodium vivax attack rate was estimated during the prophylactic phase of the deployment by adjusting the observed P. vivax relapse rate during post-deployment to account for the known anti-relapse efficacies (or effectiveness) of the study medications (determined from prior studies). The all species malaria attack rate (P. vivax and Plasmodium falciparum) was then determined by adjusting the P. vivax attack rate based on the ratio of P. falciparum to P. vivax observed during prior ADF deployments to Timor Leste. This estimated all species malaria attack rate was then used as the 'constant estimated attack rate' in the calculation of the protective efficacy of tafenoquine and mefloquine during the prophylactic phase of the deployment. RESULTS: The estimated attack rate during the prophylactic phase of the study was determined to be 7.88%. The protective efficacies of tafenoquine and mefloquine, with corresponding 95% confidence intervals (95% CI), were determined to be 100% (93%-100%) and 100% (79%-100%) respectively. CONCLUSIONS: The protective efficacy of tafenoquine (200 mg per day for three days, followed by weekly 200 mg maintenance doses) is similar to that of the weekly standard of care (mefloquine, 250 mg).

    PMCID: PMC3942710 PMID: 24502679 [PubMed - indexed for MEDLINE]

  12. Malar J. 2014 Jan 3;13:2. doi: 10.1186/1475-2875-13-2.

    Tafenoquine and NPC-1161B require CYP 2D metabolism for anti-malarial activity: implications for the 8-aminoquinoline class of anti-malarial compounds.

    Marcsisin SR(1), Sousa JC, Reichard GA, Caridha D, Zeng Q, Roncal N, McNulty R, Careagabarja J, Sciotti RJ, Bennett JW, Zottig VE, Deye G, Li Q, Read L, Hickman M, Dhammika Nanayakkara NP, Walker LA, Smith B, Melendez V, Pybus BS.

    Author information: (1)Division of Experimental Therapeutics, Military Malaria Research Program, Walter Reed Army Institute of Research, 503 Robert Grant Ave, Silver Spring, MD 20910, USA.

    BACKGROUND: Tafenoquine (TQ) is an 8-aminoquinoline (8AQ) that has been tested in several Phase II and Phase III clinical studies and is currently in late stage development as an anti-malarial prophylactic agent. NPC-1161B is a promising 8AQ in late preclinical development. It has recently been reported that the 8AQ drug primaquine requires metabolic activation by CYP 2D6 for efficacy in humans and in mice, highlighting the importance of pharmacogenomics in the target population when administering primaquine. A logical follow-up study was to determine whether CYP 2D activation is required for other compounds in the 8AQ structural class. METHODS: In the present study, the anti-malarial activities of NPC-1161B and TQ were assessed against luciferase expressing Plasmodium berghei in CYP 2D knock-out mice in comparison with normal C57BL/6 mice (WT) and with humanized/CYP 2D6 knock-in mice by monitoring luminescence with an in vivo imaging system. These experiments were designed to determine the direct effects of CYP 2D metabolic activation on the anti-malarial efficacy of NPC-1161B and TQ. RESULTS: NPC-1161B and TQ exhibited no anti-malarial activity in CYP 2D knock-out mice when dosed at their ED100 values (1 mg/kg and 3 mg/kg, respectively) established in WT mice. TQ anti-malarial activity was partially restored in humanized/CYP 2D6 knock-in mice when tested at two times its ED100. CONCLUSIONS: The results reported here strongly suggest that metabolism of NPC-1161B and TQ by the CYP 2D enzyme class is essential for their anti-malarial activity. Furthermore, these results may provide a possible explanation for therapeutic failures for patients who do not respond to 8AQ treatment for relapsing malaria. Because CYP 2D6 is highly polymorphic, variable expression of this enzyme in humans represents a significant pharmacogenomic liability for 8AQs which require CYP 2D metabolic activation for efficacy, particularly for large-scale prophylaxis and eradication campaigns.

    PMCID: PMC3893421 PMID: 24386891 [PubMed - indexed for MEDLINE]

  13. Lancet. 2014 Mar 22;383(9922):1020-1. doi: 10.1016/S0140-6736(13)62672-0. Epub 2013 Dec 19.

    Single-dose radical cure of Plasmodium vivax: a step closer.

    Price RN(1), Nosten F(2).

    Author information: (1)Centre for Tropical Medicine, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK; Global Health Division, Menzies School of Health Research, Charles Darwin University, Darwin, NT 0811, Australia. Electronic address: (2)Centre for Tropical Medicine, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK; Shoklo Malaria Research Unit, Mae Sot, Tak, Thailand; Mahidol-Oxford Tropical Medicine Research Unit, Bangkok, Thailand.

    Comment on Lancet. 2014 Mar 22;383(9922):1049-58.

    PMID: 24360370 [PubMed - indexed for MEDLINE]

  14. Lancet. 2014 Mar 22;383(9922):1049-58. doi: 10.1016/S0140-6736(13)62568-4. Epub 2013 Dec 19.

    Tafenoquine plus chloroquine for the treatment and relapse prevention of Plasmodium vivax malaria (DETECTIVE): a multicentre, double-blind, randomised, phase 2b dose-selection study.

    Llanos-Cuentas A(1), Lacerda MV(2), Rueangweerayut R(3), Krudsood S(4), Gupta SK(5), Kochar SK(6), Arthur P(7), Chuenchom N(3), Möhrle JJ(8), Duparc S(8), Ugwuegbulam C(9), Kleim JP(9), Carter N(9), Green JA(9), Kellam L(10).

    Author information: (1)Instituto de Medicina Tropical, Alexander von Humboldt, Universidad Peruana Cayetano Heredia, Lima, Peru. (2)Fundação de Medicina Tropical Doutor Heitor Vieira Dourado, Manaus, Amazonas, Brazil. (3)Mae Sot Hospital, Mae Sot, Tak Province, Thailand. (4)Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand. (5)MV Hospital and Research Centre, Lucknow, Uttar Pradesh, India. (6)Sardar Patel Medical College, Bikaner, Rajasthan, India. (7)Sri Ramchandra Medical College and Research Institute, Department of Medicine, Porur, Chennai, Tamil Nadu, India. (8)Medicines for Malaria Venture, Geneva, Switzerland. (9)GlaxoSmithKline, Stockley Park West, Uxbridge, Middlesex, UK. (10)GlaxoSmithKline, Stockley Park West, Uxbridge, Middlesex, UK. Electronic address:

    Comment in Lancet. 2014 Mar 22;383(9922):1020-1.

    BACKGROUND: Clinical effectiveness of previous regimens to treat Plasmodium vivax infection have been hampered by compliance. We aimed to assess the dose-response, safety, and tolerability of single-dose tafenoquine plus 3-day chloroquine for P vivax malaria radical cure. METHODS: In this double-blind, randomised, dose-ranging phase 2b study, men and women (aged ≥16 years) with microscopically confirmed P vivax monoinfection (parasite density >100 to <100,000 per μL blood) were enrolled from community health centres and hospitals across seven sites in Brazil, Peru, India, and Thailand. Patients with glucose-6-phosphate dehydrogenase enzyme activity of less than 70% were excluded. Eligible patients received chloroquine (days 1-3) and were randomly assigned (1:1:1:1:1:1) by a computer-generated randomisation schedule to receive single-dose tafenoquine 50 mg, 100 mg, 300 mg, or 600 mg, primaquine 15 mg for 14 days, or chloroquine alone. Randomisation was stratified by baseline parasite count (≤7500 and >7500 per μL blood). The primary efficacy endpoint was relapse-free efficacy at 6 months from initial dose (ie, clearance of initial infection without subsequent microscopically confirmed infection), analysed by intention to treat. This study is registered with, number NCT01376167. FINDINGS: Between Sept 19, 2011, and March 25, 2013, 329 patients were randomly assigned to a treatment group (chloroquine plus tafenoquine 50 mg [n=55], 100 mg [n=57], 300 mg [n=57], 600 mg [n=56]; or to chloroquine plus primaquine [n=50]; or chloroquine alone [n=54]). Relapse-free efficacy at 6 months was 57·7% (95% CI 43-70) with tafenoquine 50 mg, 54·1% (40-66) with tafenoquine 100 mg, 89·2% (77-95) with tafenoquine 300 mg, 91·9% (80-97) with tafenoquine 600 mg, 77·3% (63-87) with primaquine, and 37·5% (23-52) with chloroquine alone. Tafenoquine 300 mg and 600 mg had better efficacy than chloroquine alone (treatment differences 51·7% [95% CI 35-69], p<0·0001, with tafenoquine 300 mg and 54·5% [38-71], p<0·0001, with tafenoquine 600 mg), as did primaquine (treatment difference 39·9% [21-59], p=0·0004). Adverse events were similar between treatments. 29 serious adverse events occurred in 26 (8%) of 329 patients; QT prolongation was the most common serious adverse event (11 [3%] of 329), occurring in five (2%) of 225 patients receiving tafenoquine, four (8%) of 50 patients receiving primaquine, and two (4%) of 54 patients receiving chloroquine alone, with no evidence of an additional effect on QT of chloroquine plus tafenoquine coadministration. INTERPRETATION: Single-dose tafenoquine 300 mg coadministered with chloroquine for P vivax malaria relapse prevention was more efficacious than chloroquine alone, with a similar safety profile. As a result, it has been selected for further clinical assessment in phase 3. FUNDING: GlaxoSmithKline, Medicines for Malaria Venture.

    Copyright © 2014 Elsevier Ltd. All rights reserved.

    PMID: 24360369 [PubMed - indexed for MEDLINE]

  15. Malar J. 2013 Dec 17;12:450. doi: 10.1186/1475-2875-12-450.

    A SYBR Green 1-based in vitro test of susceptibility of Ghanaian Plasmodium falciparum clinical isolates to a panel of anti-malarial drugs.

    Quashie NB(1), Duah NO, Abuaku B, Quaye L, Ayanful-Torgby R, Akwoviah GA, Kweku M, Johnson JD, Lucchi NW, Udhayakumar V, Duplessis C, Kronmann KC, Koram KA.

    Author information: (1)Centre for Tropical Clinical Pharmacology and Therapeutics, University of Ghana Medical School, Accra, Ghana.

    BACKGROUND: Based on report of declining efficacy of chloroquine, Ghana shifted to the use of artemisinin-based combination therapy (ACT) in 2005 as the first-line anti-malarial drug. Since then, there has not been any major evaluation of the efficacy of anti-malarial drugs in Ghana in vitro. The sensitivity of Ghanaian Plasmodium falciparum isolates to anti-malarial drugs was, therefore, assessed and the data compared with that obtained prior to the change in the malaria treatment policy. METHODS: A SYBR Green 1 fluorescent-based in vitro drug sensitivity assay was used to assess the susceptibility of clinical isolates of P. falciparum to a panel of 12 anti-malarial drugs in three distinct eco-epidemiological zones in Ghana. The isolates were obtained from children visiting health facilities in sentinel sites located in Hohoe, Navrongo and Cape Coast municipalities. The concentration of anti-malarial drug inhibiting parasite growth by 50% (IC50) for each drug was estimated using the online program, ICEstimator. RESULTS: Pooled results from all the sentinel sites indicated geometric mean IC50 values of 1.60, 3.80, 4.00, 4.56, 5.20, 6.11, 10.12, 28.32, 31.56, 93.60, 107.20, and 8952.50 nM for atovaquone, artesunate, dihydroartemisin, artemether, lumefantrine, amodiaquine, mefloquine, piperaquine, chloroquine, tafenoquine, quinine, and doxycycline, respectively. With reference to the literature threshold value indicative of resistance, the parasites showed resistance to all the test drugs except the artemisinin derivatives, atovaquone and to a lesser extent, lumefantrine. There was nearly a two-fold decrease in the IC50 value determined for chloroquine in this study compared to that determined in 2004 (57.56 nM). This observation is important, since it suggests a significant improvement in the efficacy of chloroquine, probably as a direct consequence of reduced drug pressure after cessation of its use. Compared to that measured prior to the change in treatment policy, significant elevation of artesunate IC50 value was observed. The results also suggest the existence of possible cross-resistance among some of the test drugs. CONCLUSION: Ghanaian P. falciparum isolates, to some extent, have become susceptible to chloroquine in vitro, however the increasing trend in artesunate IC50 value observed should be of concern. Continuous monitoring of ACT in Ghana is recommended.

    PMCID: PMC3878558 PMID: 24341604 [PubMed - indexed for MEDLINE]

  16. Malar J. 2013 Sep 18;12:332. doi: 10.1186/1475-2875-12-332.

    Cytostatic versus cytocidal profiling of quinoline drug combinations via modified fixed-ratio isobologram analysis.

    Gorka AP(1), Jacobs LM, Roepe PD.

    Author information: (1)Department of Chemistry, Department of Biochemistry, Cellular, & Molecular Biology, and Center for Infectious Disease, Georgetown University, 37th and 'O' Sts, NW, Washington, DC, 20057, USA.

    BACKGROUND: Drug combination therapy is the frontline of malaria treatment. There is an ever-accelerating need for new, efficacious combination therapies active against drug resistant malaria. Proven drugs already in the treatment pipeline, such as the quinolines, are important components of current combination therapy and also present an attractive test bank for rapid development of new concepts. METHODS: The efficacy of several drug combinations versus chloroquine-sensitive and chloroquine-resistant strains was measured using both cytostatic and cytocidal potency assays. CONCLUSIONS: These screens identify quinoline and non-quinoline pairs that exhibit synergy, additivity, or antagonism using the fixed-ratio isobologram method and find tafenoquine - methylene blue combination to be the most synergistic. Also, interestingly, for selected pairs, additivity, synergy, or antagonism defined by quantifying IC50 (cytostatic potency) does not necessarily predict similar behaviour when potency is defined by LD50 (cytocidal potency). These data further support an evolving new model for quinoline anti-malarials, wherein haem and haemozoin are the principle target for cytostatic activity, but may not be the only target relevant for cytocidal activity.

    PMCID: PMC3874740 PMID: 24044530 [PubMed - indexed for MEDLINE]

  17. Br J Clin Pharmacol. 2013 Dec;76(6):858-67. doi: 10.1111/bcp.12160.

    Pharmacokinetic interactions and safety evaluations of coadministered tafenoquine and chloroquine in healthy subjects.

    Miller AK(1), Harrell E, Ye L, Baptiste-Brown S, Kleim JP, Ohrt C, Duparc S, Möhrle JJ, Webster A, Stinnett S, Hughes A, Griffith S, Beelen AP.

    Author information: (1)GSK, King of Prussia, PA, USA.

    AIMS: The long-acting 8-aminoquinoline tafenoquine (TQ) coadministered with chloroquine (CQ) may radically cure Plasmodium vivax malaria. Coadministration therapy was evaluated for a pharmacokinetic interaction and for pharmacodynamic, safety and tolerability characteristics. METHODS: Healthy subjects, 18-55 years old, without documented glucose-6-phosphate dehydrogenase deficiency, received CQ alone (days 1-2, 600 mg; and day 3, 300 mg), TQ alone (days 2 and 3, 450 mg) or coadministration therapy (day 1, CQ 600 mg; day 2, CQ 600 mg + TQ 450 mg; and day 3, CQ 300 mg + TQ 450 mg) in a randomized, double-blind, parallel-group study. Blood samples for pharmacokinetic and pharmacodynamic analyses and safety data, including electrocardiograms, were collected for 56 days. RESULTS: The coadministration of CQ + TQ had no effect on TQ AUC0-t , AUC0-∞ , Tmax or t1/2 . The 90% confidence intervals of CQ + TQ vs. TQ for AUC0-t , AUC0-∞ and t1/2 indicated no drug interaction. On day 2 of CQ + TQ coadministration, TQ Cmax and AUC0-24 increased by 38% (90% confidence interval 1.27, 1.64) and 24% (90% confidence interval 1.04, 1.46), respectively. The pharmacokinetics of CQ and its primary metabolite desethylchloroquine were not affected by TQ. Coadministration had no clinically significant effect on QT intervals and was well tolerated. CONCLUSIONS: No clinically significant safety or pharmacokinetic/pharmacodynamic interactions were observed with coadministered CQ and TQ in healthy subjects.

    © 2013 The British Pharmacological Society.

    PMCID: PMC3845309 PMID: 23701202 [PubMed - indexed for MEDLINE]

  18. Antimicrob Agents Chemother. 2013 Jan;57(1):417-24. doi: 10.1128/AAC.00793-12. Epub 2012 Nov 5.

    4(1H)-Quinolones with liver stage activity against Plasmodium berghei.

    Lacrue AN(1), Sáenz FE, Cross RM, Udenze KO, Monastyrskyi A, Stein S, Mutka TS, Manetsch R, Kyle DE.

    Author information: (1)Department of Global Health, University of South Florida, Tampa, Florida, USA.

    With the exception of primaquine, tafenoquine, and atovaquone, there are very few antimalarials that target liver stage parasites. In this study, a transgenic Plasmodium berghei parasite (1052Cl1; PbGFP-Luc(con)) that expresses luciferase was used to assess the anti-liver stage parasite activity of ICI 56,780, a 7-(2-phenoxyethoxy)-4(1H)-quinolone (PEQ), as well as two 3-phenyl-4(1H)-quinolones (P4Q), P4Q-146 and P4Q-158, by using bioluminescent imaging (BLI). Results showed that all of the compounds were active against liver stage parasites; however, ICI 56,780 and P4Q-158 were the most active, with low nanomolar activity in vitro and causal prophylactic activity in vivo. This potent activity makes these compounds ideal candidates for advancement as novel antimalarials.

    PMCID: PMC3535941 PMID: 23129047 [PubMed - indexed for MEDLINE]

  19. Chemotherapy. 2011;57(6):497-504. doi: 10.1159/000334126. Epub 2012 Jan 19.

    Risk factors for gametocyte carriage in uncomplicated falciparum malaria in children before and after artemisinin-based combination treatments.

    Sowunmi A(1), Okuboyejo TM, Gbotosho GO, Happi CT.

    Author information: (1)Department of Pharmacology and Therapeutics, University of Ibadan, Nigeria.

    BACKGROUND: Artemisinin-based combination treatments (ACTs) are the recommended first-line antimalarials globally, but their influence on the risk factors associated with gametocyte carriage has had little evaluation in endemic areas. METHODS: The risk factors associated with gametocytaemia at presentation and after ACTs were evaluated in 835 children assigned to artesunate, artesunate-amodiaquine, artesunate-mefloquine or artemether-lumefantrine. RESULTS: Gametocyte carriage at enrolment was 8.4%. During follow-up, 24 patients (2.8%) developed gametocytaemia, which in 83% (20 patients) had developed by day 7 following treatment. In a multiple regression model, 2 factors were independent risk factors for the presence of gametocytaemia at enrolment, namely age <3 years (adjusted odds ratio 2.03, 95% confidence interval 1.01-4.05; p = 0.04) and enrolment before 2009 (adjusted odds ratio 4.2, 95% confidence interval 2.09-8.44; p < 0.001). Haematocrit <25% and parasitaemia <50,000/μl blood were associated with an increased risk of gametocytaemia. Following treatment, 3 factors were independent risk factors for gametocytaemia, namely gametocytaemia at enrolment (adjusted odds ratio 46.39, 95% confidence interval 22.3-96.46; p < 0.0001) and treatment with artesunate (adjusted odds ratio 6.74, 95% confidence interval 1.79-25.27; p = 0.005) or artesunate-mefloquine (adjusted odds ratio 9.66, 95% confidence interval 2.87-32.46; p < 0.0.0001) relative to other ACTs. CONCLUSION: ACTs modified the risk factors associated with gametocyte carriage after use.

    Copyright © 2012 S. Karger AG, Basel.

    PMID: 22261842 [PubMed - indexed for MEDLINE]

  20. Malar J. 2011 Dec 12;10:351. doi: 10.1186/1475-2875-10-351.

    Primaquine in vivax malaria: an update and review on management issues.

    Fernando D(1), Rodrigo C, Rajapakse S.

    Author information: (1)Department of Parasitology, Faculty of Medicine, University of Colombo, 25, Kynsey Road, Colombo 8, Sri Lanka.

    Primaquine was officially licensed as an anti-malarial drug by the FDA in 1952. It has remained the only FDA licensed drug capable of clearing the intra-hepatic schizonts and hypnozoites of Plasmodium vivax. This update and review focuses on five major aspects of primaquine use in treatment of vivax malaria, namely: a) evidence of efficacy of primaquine for its current indications; b) potential hazards of its widespread use, c) critical analysis of reported resistance against primaquine containing regimens; d) evidence for combining primaquine with artemisinins in areas of chloroquine resistance; and e) the potential for replacement of primaquine with newer drugs.

    PMCID: PMC3306765 PMID: 22152065 [PubMed - indexed for MEDLINE]

  21. J Med Chem. 2011 Oct 13;54(19):6634-46. doi: 10.1021/jm200503s. Epub 2011 Sep 2.

    Antimalarial activities of new guanidylimidazole and guanidylimidazoline derivatives.

    Zhang L(1), Sathunuru R, Caridha D, Pybus B, O'Neil MT, Kozar MP, Lin AJ.

    Author information: (1)Division of Experimental Therapeutics, Walter Reed Army Institute of Research, 503 Robert Grant Avenue, Silver Spring, Maryland 20910, United States.

    A series of new guanidylimidazole derivatives was prepared and evaluated in mice and Rhesus monkeys infected with malarial sporozoites. The majority of the new compounds showed poor metabolic stability and weak in vitro activities in three clones of Plasmodium falciparum. Compounds 8a, 8h, 9a, 16a, and 16e cured the mice infected with sporozoites of P. berghei at 160 and 320 mg/kg/day × 3 po. Compounds 8a showed better causal prophylactic activity than primaquine, tafenoquine, and Malarone in the Rhesus test. In the radical curative test, 8a cured one monkey and delayed relapse of another for 74 days at 30 mg/kg/day × 7 by im. By oral dosing, 8a delayed relapse 81 days for one and 32 days for other vs 11-12 days for control monkeys treated with 10 mg/kg of chloroquine by po alone. Compound 8h, which showed superior activity to 8a in mouse test, delayed the relapse of treated monkeys for 21-26 days at 30 mg/kg/day × 7 by oral.

    PMID: 21848332 [PubMed - indexed for MEDLINE]

  22. Malar J. 2011 Jul 29;10:212. doi: 10.1186/1475-2875-10-212.

    Radical curative efficacy of tafenoquine combination regimens in Plasmodium cynomolgi-infected Rhesus monkeys (Macaca mulatta).

    Dow GS(1), Gettayacamin M, Hansukjariya P, Imerbsin R, Komcharoen S, Sattabongkot J, Kyle D, Milhous W, Cozens S, Kenworthy D, Miller A, Veazey J, Ohrt C.

    Author information: (1)Division of Experimental Therapeutics, Walter Reed Army Institute of Research, 503 Robert Grant Ave, Silver Spring, MD 20910, USA.

    BACKGROUND: Tafenoquine is an 8-aminoquinoline being developed for radical cure (blood and liver stage elimination) of Plasmodium vivax. During monotherapy treatment, the compound exhibits slow parasite and fever clearance times, and toxicity in glucose-6-phosphate dehydrogenase (G6PD) deficiency is a concern. Combination with other antimalarials may mitigate these concerns. METHODS: In 2005, the radical curative efficacy of tafenoquine combinations was investigated in Plasmodium cynomolgi-infected naïve Indian-origin Rhesus monkeys. In the first cohort, groups of two monkeys were treated with a three-day regimen of tafenoquine at different doses alone and in combination with a three-day chloroquine regimen to determine the minimum curative dose (MCD). In the second cohort, the radical curative efficacy of a single-day regimen of tafenoquine-mefloquine was compared to that of two three-day regimens comprising tafenoquine at its MCD with chloroquine or artemether-lumefantrine in groups of six monkeys. In a final cohort, the efficacy of the MCD of tafenoquine against hypnozoites alone and in combination with chloroquine was investigated in groups of six monkeys after quinine pre-treatment to eliminate asexual parasites. Plasma tafenoquine, chloroquine and desethylchloroquine concentrations were determined by LC-MS in order to compare doses of the drugs to those used clinically in humans. RESULTS: The total MCD of tafenoquine required in combination regimens for radical cure was ten-fold lower (1.8 mg/kg versus 18 mg/kg) than for monotherapy. This regimen (1.8 mg/kg) was equally efficacious as monotherapy or in combination with chloroquine after quinine pre-treatment to eliminate asexual stages. The same dose of (1.8 mg/kg) was radically curative in combination with artemether-lumefantrine. Tafenoquine was also radically curative when combined with mefloquine. The MCD of tafenoquine monotherapy for radical cure (18 mg/kg) appears to be biologically equivalent to a 600-1200 mg dose in humans. At its MCD in combination with blood schizonticidal drugs (1.8 mg/kg), the maximum observed plasma concentrations were substantially lower than (20-84 versus 550-1,100 ng/ml) after administration of 1, 200 mg in clinical studies. CONCLUSIONS: Ten-fold lower clinical doses of tafenoquine than used in prior studies may be effective against P. vivax hypnozoites if the drug is deployed in combination with effective blood-schizonticidal drugs.

    PMCID: PMC3161915 PMID: 21801400 [PubMed - indexed for MEDLINE]

  23. J Med Chem. 2011 Jan 13;54(1):131-42. doi: 10.1021/jm100911f. Epub 2010 Dec 8.

    Antimalarial activity of novel 5-aryl-8-aminoquinoline derivatives.

    Shiraki H(1), Kozar MP, Melendez V, Hudson TH, Ohrt C, Magill AJ, Lin AJ.

    Author information: (1)Division of Experimental Therapeutics, Walter Reed Army Institute of Research, Silver Spring, Maryland 20910, United States.

    In an attempt to separate the antimalarial activity of tafenoquine (3) from its hemolytic side effects in glucose-6-phosphate dehydrogenase (G6PD) deficiency patients, a series of 5-aryl-8-aminoquinoline derivatives was prepared and assessed for antimalarial activities. The new compounds were found metabolically stable in human and mouse microsomal preparations, with t(1/2) > 60 min, and were equal to or more potent than primaquine (2) and 3 against Plasmodium falciparum cell growth. The new agents were more active against the chloroquine (CQ) resistant clone than to the CQ-sensitive clone. Analogues with electron donating groups showed better activity than those with electron withdrawing substituents. Compounds 4bc, 4bd, and 4be showed comparable therapeutic index (TI) to that of 2 and 3, with TI ranging from 5 to 8 based on IC(50) data. The new compounds showed no significant causal prophylactic activity in mice infected with Plasmodium berghei sporozoites, but are substantially less toxic than 2 and 3 in mouse tests.

    PMID: 21141892 [PubMed - indexed for MEDLINE]

  24. Trans R Soc Trop Med Hyg. 2010 Nov;104(11):695-705. doi: 10.1016/j.trstmh.2010.08.009. Epub 2010 Sep 20.

    Efficacy and safety of chloroquine for treatment in patients with uncomplicated Plasmodium vivax infections in endemic countries.

    Naing C(1), Aung K, Win DK, Wah MJ.

    Author information: (1)International Medical University, Kuala Lumpur 57000, Malaysia.

    Chloroquine (CQ) is a relatively inexpensive drug for treatment of malaria. If efficacy of CQ is still assumed, then it should be indicated in malaria treatment policies as the drug of choice for uncomplicated Plasmodium vivax malaria in endemic countries with resource constraints. The objective of this review is to summarize the existing evidence on the relative efficacy and safety of CQ in treating patients with uncomplicated P. vivax malaria in endemic countries. We searched online data bases (PUBMED, MEDLINE, EMBASE, The Cochrane Library) and the reference lists of the retrieved articles. Fifteen randomized controlled trials (n=6215) assessing the relative efficacy and safety of CQ for treatment of uncomplicated P. vivax malaria were included. CQ monotherapy was compared to CQ plus primaquine (PQ), artemisinin/artemether, artemisinin based combination therapy, quinine, CQ plus tafenoquine, chlorguanil plus dapsone, azithromycin, or placebo. Treatment efficacy was not significantly different between the CQ monotherapy group and that of the CQ with PQ 14 day group at 28 day follow-up (55/711, 7.7% vs 35/712, 4.9%; P=0.16). Evidence from the trials identified for this review draw a fairly clear conclusion about the relative efficacy and safety of CQ for treating uncomplicated P. vivax malaria infection. However, further research in this field with well powered, randomized, non-inferiority design, using the standardized protocol is needed.

    Copyright © 2010 Royal Society of Tropical Medicine and Hygiene. Published by Elsevier Ltd. All rights reserved.

    PMID: 20850161 [PubMed - indexed for MEDLINE]

  25. Antimicrob Agents Chemother. 2010 Dec;54(12):5344-51. doi: 10.1128/AAC.00790-10. Epub 2010 Sep 13.

    Tafenoquine, an antiplasmodial 8-aminoquinoline, targets leishmania respiratory complex III and induces apoptosis.

    Carvalho L(1), Luque-Ortega JR, Manzano JI, Castanys S, Rivas L, Gamarro F.

    Author information: (1)Instituto de Parasitología y Biomedicina "López-Neyra," CSIC, Granada, Spain.

    Tafenoquine (TFQ), an 8-aminoquinoline analogue of primaquine, which is currently under clinical trial (phase IIb/III) for the treatment and prevention of malaria, may represent an alternative treatment for leishmaniasis. In this work, we have studied the mechanism of action of TFQ against Leishmania parasites. TFQ impaired the overall bioenergetic metabolism of Leishmania promastigotes, causing a rapid drop in intracellular ATP levels without affecting plasma membrane permeability. TFQ induced mitochondrial dysfunction through the inhibition of cytochrome c reductase (respiratory complex III) with a decrease in the oxygen consumption rate and depolarization of mitochondrial membrane potential. This was accompanied by ROS production, elevation of intracellular Ca(2+) levels and concomitant nuclear DNA fragmentation. We conclude that TFQ targets Leishmania mitochondria, leading to an apoptosis-like death process.

    PMCID: PMC2981264 PMID: 20837758 [PubMed - indexed for MEDLINE]

  26. Antimicrob Agents Chemother. 2010 Feb;54(2):792-8. doi: 10.1128/AAC.00354-09. Epub 2009 Dec 7.

    Randomized, double-blind study of the safety, tolerability, and efficacy of tafenoquine versus mefloquine for malaria prophylaxis in nonimmune subjects.

    Nasveld PE(1), Edstein MD, Reid M, Brennan L, Harris IE, Kitchener SJ, Leggat PA, Pickford P, Kerr C, Ohrt C, Prescott W; Tafenoquine Study Team.

    Collaborators: Rieckmann K, Cooper B, Frances S, Reid M, Auliff A, Russell B, McLeod-Robertson S, Staley J, Rowcliffe K, Ross J, Potter B, Barker K, Galvin D, Aultman A.

    Author information: (1)Australian Army Malaria Institute, Brisbane, Queensland, Australia.

    This study represents the first phase III trial of the safety, tolerability, and effectiveness of tafenoquine for malaria prophylaxis. In a randomized (3:1), double-blinded study, Australian soldiers received weekly malaria prophylaxis with 200 mg tafenoquine (492 subjects) or 250 mg mefloquine (162 subjects) for 6 months on a peacekeeping deployment to East Timor. After returning to Australia, tafenoquine-receiving subjects received a placebo and mefloquine-receiving subjects received 30 mg primaquine daily for 14 days. There were no clinically significant differences between hematological and biochemical parameters of the treatment groups. Treatment-related adverse events for the two groups were similar (tafenoquine, 13.4%; mefloquine, 11.7%). Three subjects on tafenoquine (0.6%) and none on mefloquine discontinued prophylaxis because of possible drug-related adverse events. No diagnoses of malaria occurred for either group during deployment, but 4 cases (0.9%) and 1 case (0.7%) of Plasmodium vivax infection occurred among the tafenoquine and mefloquine groups, respectively, up to 20 weeks after discontinuation of medication. In a subset of subjects recruited for detailed safety assessments, treatment-related mild vortex keratopathy was detected in 93% (69 of 74) of tafenoquine subjects but none of the 21 mefloquine subjects. The vortex keratopathy was not associated with any effect on visual acuity and was fully resolved in all subjects by 1 year. Tafenoquine appears to be safe and well tolerated as malaria prophylaxis. Although the volunteers' precise exposure to malaria could not be proven in this study, tafenoquine appears to be a highly efficacious drug for malaria prophylaxis.

    PMCID: PMC2812156 PMID: 19995933 [PubMed - indexed for MEDLINE]

  27. PLoS One. 2009 Nov 18;4(11):e7881. doi: 10.1371/journal.pone.0007881.

    Visualisation and quantitative analysis of the rodent malaria liver stage by real time imaging.

    Ploemen IH(1), Prudêncio M, Douradinha BG, Ramesar J, Fonager J, van Gemert GJ, Luty AJ, Hermsen CC, Sauerwein RW, Baptista FG, Mota MM, Waters AP, Que I, Lowik CW, Khan SM, Janse CJ, Franke-Fayard BM.

    Author information: (1)Department of Medical Microbiology, Radboud University Nijmegen Medical Centre (RUNMC), Nijmegen, The Netherlands.

    The quantitative analysis of Plasmodium development in the liver in laboratory animals in cultured cells is hampered by low parasite infection rates and the complicated methods required to monitor intracellular development. As a consequence, this important phase of the parasite's life cycle has been poorly studied compared to blood stages, for example in screening anti-malarial drugs. Here we report the use of a transgenic P. berghei parasite, PbGFP-Luc(con), expressing the bioluminescent reporter protein luciferase to visualize and quantify parasite development in liver cells both in culture and in live mice using real-time luminescence imaging. The reporter-parasite based quantification in cultured hepatocytes by real-time imaging or using a microplate reader correlates very well with established quantitative RT-PCR methods. For the first time the liver stage of Plasmodium is visualized in whole bodies of live mice and we were able to discriminate as few as 1-5 infected hepatocytes per liver in mice using 2D-imaging and to identify individual infected hepatocytes by 3D-imaging. The analysis of liver infections by whole body imaging shows a good correlation with quantitative RT-PCR analysis of extracted livers. The luminescence-based analysis of the effects of various drugs on in vitro hepatocyte infection shows that this method can effectively be used for in vitro screening of compounds targeting Plasmodium liver stages. Furthermore, by analysing the effect of primaquine and tafenoquine in vivo we demonstrate the applicability of real time imaging to assess parasite drug sensitivity in the liver. The simplicity and speed of quantitative analysis of liver-stage development by real-time imaging compared to the PCR methodologies, as well as the possibility to analyse liver development in live mice without surgery, opens up new possibilities for research on Plasmodium liver infections and for validating the effect of drugs and vaccines on the liver stage of Plasmodium.

    PMCID: PMC2775639 PMID: 19924309 [PubMed - indexed for MEDLINE]

  28. Eur J Med Chem. 2009 Mar;44(3):937-53. doi: 10.1016/j.ejmech.2008.08.011. Epub 2008 Sep 11.

    Primaquine revisited six decades after its discovery.

    Vale N(1), Moreira R, Gomes P.

    Author information: (1)Centro de Investigação em Química da Universidade do Porto, Faculdade de Ciências da Universidade do Porto, Rua do Campo Alegre, 4169-007 Porto, Portugal.

    Primaquine was firstly synthesized in 1946 in the USA, and is the most representative member of the anti-malarial 8-aminoquinolines. Six decades have passed and primaquine is still the only transmission-blocking anti-malarial clinically available, displaying a marked activity against gametocytes of all species of human malaria, including multi-resistant Plasmodium falciparum strains. Primaquine is also effective against all exoerythrocytic forms of the parasite and is used in conjunction with other anti-malarials for the treatment of vivax and ovale malaria. However, primaquine is often associated with serious adverse effects, in consequence of its toxic metabolites. 5-Hydroxyprimaquine or 6-methoxy-8-aminoquinoline has been considered to be directly responsible for complications such as hemolytic anemia. Primaquine toxicity is aggravated in people deficient of 6-glucose phosphate dehydrogenase or glutathione synthetase. Adverse effects are further amplified by the fact that primaquine must be repeatedly administered at high doses, due to its limited oral bioavailability. Over the last two decades, Medicinal Chemists have battled against primaquine's disadvantages, while keeping or even improving its unequalled performance as an anti-malarial. The present text revisits primaquine and its properties on the occasion of its 60th anniversary and aims to give a general overview of what has been the path towards the development of effective and safe primaquine-based anti-malarials. Presently, aablaquine and tafenoquine the two most promising primaquine analogues are already in the final stages of clinical trials against Plasmodium vivax and P. falciparum. Both compounds are a new hope against malaria and other primaquine-sensitive illnesses, such as Pneumocystis Pneumonia or the Chagas disease.

    PMID: 18930565 [PubMed - indexed for MEDLINE]

  29. Trans R Soc Trop Med Hyg. 2008 Nov;102(11):1095-101. doi: 10.1016/j.trstmh.2008.04.024. Epub 2008 Jun 9.

    The efficacy and tolerability of three different regimens of tafenoquine versus primaquine for post-exposure prophylaxis of Plasmodium vivax malaria in the Southwest Pacific.

    Elmes NJ(1), Nasveld PE, Kitchener SJ, Kocisko DA, Edstein MD.

    Author information: (1)Australian Army Malaria Institute, Enoggera, Brisbane, QLD 4051, Australia.

    Tafenoquine is being developed for radical cure and post-exposure prophylaxis of Plasmodium vivax malaria. In an open-label study, 1512 Australian Defence Force personnel received one of three tafenoquine 3 d regimens [400 mg once daily (od), 200 mg twice daily (bid), 200 mg od] or daily primaquine (22.5 mg) plus doxycycline (100 mg) over 14 d in Bougainville and in Timor-Leste for post-exposure prophylaxis. The relapse rate of subjects treated in Bougainville with tafenoquine (n=173) was 1.2% (200 mg bid x 3 d) and 2.3% (400 mg od x 3 d), while primaquine plus doxycycline (n=175) was 3.4%. For subjects treated in Timor-Leste with tafenoquine (n=636), the relapse rate was 4.9% (200 mg od x 3 d), 5.3% (200 mg bid x 3 d) and 11.0% (400 mg od x 3d), while primaquine plus doxycycline (n=289) was 10.0%. The most frequent adverse events reported across all groups were nausea, abdominal distress and diarrhoea. There was a dose-dependent reduction in adverse events with a reduced dose of tafenoquine, with the lowest dose (total 600 mg over 3 d) producing rates of adverse events equivalent to that of primaquine plus doxycycline. The much shorter dosing regimen of tafenoquine should increase compliance, which is often suboptimal with primaquine after leaving an endemic area. [Australian New Zealand Clinical Trials Registry Number 12607000588493].

    PMID: 18541280 [PubMed - indexed for MEDLINE]

  30. Antimicrob Agents Chemother. 2007 Aug;51(8):2709-15. Epub 2007 May 21.

    Population pharmacokinetics of tafenoquine during malaria prophylaxis in healthy subjects.

    Charles BG(1), Miller AK, Nasveld PE, Reid MG, Harris IE, Edstein MD.

    Author information: (1)The University of Queensland, Brisbane, QLD, Australia.

    The population pharmacokinetics of tafenoquine were studied in Australian soldiers taking tafenoquine for malarial prophylaxis. The subjects (476 males and 14 females) received a loading dose of 200 mg tafenoquine base daily for 3 days, followed by a weekly dose of 200 mg tafenoquine for 6 months. Blood samples were collected from each subject after the last loading dose and then at weeks 4, 8, and 16. Plasma tafenoquine concentrations were determined by liquid chromatography-tandem mass spectrometry. Population modeling was performed with NONMEM, using a one-compartment model. Typical values of the first-order absorption rate constant (K(a)), clearance (CL/F), and volume of distribution (V/F) were 0.243 h(-1), 0.056 liters/h/kg, and 23.7 liters/kg, respectively. The intersubject variability (coefficient of variation) in CL/F and V/F was 18% and 22%, respectively. The interoccasion variability in CL/F was 18%, and the mean elimination half-life was 12.7 days. A positive linear association between weight and both CL/F and V/F was found, but this had insufficient impact to warrant dosage adjustments. Model robustness was assessed by a nonparametric bootstrap (200 samples). A degenerate visual predictive check indicated that the raw data mirrored the postdose concentration-time profiles simulated (n = 1,000) from the final model. Individual pharmacokinetic estimates for tafenoquine did not predict the prophylactic outcome with the drug for four subjects who relapsed with Plasmodium vivax malaria, as they had similar pharmacokinetics to those who were free of malaria infection. No obvious pattern existed between the plasma tafenoquine concentration and the pharmacokinetic parameter values for subjects with and without drug-associated moderate or severe adverse events. This validated population pharmacokinetic model satisfactorily describes the disposition and variability of tafenoquine used for long-term malaria prophylaxis in a large cohort of soldiers on military deployment.

    PMCID: PMC1932489 PMID: 17517850 [PubMed - indexed for MEDLINE]

  31. Expert Opin Investig Drugs. 2007 May;16(5):705-15.

    Tafenoquine: a promising new antimalarial agent.

    Crockett M(1), Kain KC.

    Author information: (1)The Hospital for Sick Children, Division of Infectious Diseases, 555 University Avenue, Toronto, M5G 1X8, Canada.

    Malaria remains an important cause of global morbidity and mortality. As antimalarial drug resistance escalates, new safe and effective medications are necessary to prevent and treat malarial infection. Tafenoquine is an 8-aminoquinoline antimalarial that is presently under development. It has a long half-life of approximately 14 days and is generally safe and well tolerated, although it cannot be used in pregnant women and individuals who are deficient in the enzyme glucose-6-phosphate dehydrogenase. In well-designed studies, tafenoquine was highly effective in both the radical cure of relapsing malaria and causal prophylaxis of Plasmodium vivax and P. falciparum infections with protective efficacies of > or = 90%. Given its causal activity and safety profile, tafenoquine represents a potentially exciting alternative to standard agents for the prevention and radical cure of malaria.

    PMID: 17461742 [PubMed - indexed for MEDLINE]

  32. Am J Trop Med Hyg. 2007 Mar;76(3):494-6.

    Tafenoquine for the treatment of recurrent Plasmodium vivax malaria.

    Kitchener S(1), Nasveld P, Edstein MD.

    Author information: (1)Centre for Military and Veterans Health, University of Queensland, Herston, Queensland, Australia.

    Tafenoquine was used to treat Plasmodium vivax malaria cases who had previously failed treatment with chloroquine and primaquine. Chloroquine was followed by a loading dose of tafenoquine (200 mg base/day for 3 days) and 200 mg a week was given for 8 weeks. One of 27 treated patients relapsed after 6 months of observation. A standard course of chloroquine administered with 8 weeks of tafenoquine may be more effective than chloroquine with primaquine (22.5 mg/day for 14 days) in preventing additional P. vivax relapses. Larger studies are required to optimize the combination, but our findings suggest that an extended use of tafenoquine may be required to prevent relapses of primaquine-tolerant strains of P. vivax malaria.

    PMID: 17360873 [PubMed - indexed for MEDLINE]

  33. J Antimicrob Chemother. 2007 Apr;59(4):658-65. Epub 2007 Mar 2.

    Antimalarial efficacy and drug interactions of the novel semi-synthetic endoperoxide artemisone in vitro and in vivo.

    Vivas L(1), Rattray L, Stewart LB, Robinson BL, Fugmann B, Haynes RK, Peters W, Croft SL.

    Author information: (1)Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London WC1E 7HT, UK.

    OBJECTIVES: The in vitro and in vivo efficacy and drug-drug interactions of the novel semi-synthetic endoperoxide artemisone with standard antimalarials were investigated in order to provide the basis for the selection of the best partner drug. METHODS: Antimalarial activity and drug interactions were evaluated in vitro against Plasmodium falciparum by the incorporation of [(3)H]hypoxanthine. In vivo efficacy and drug interactions were assessed using the standard 4-day Peters' test. RESULTS: Artemisone was 10 times more potent than artesunate in vitro against a panel of 12 P. falciparum strains, independent of their susceptibility profile to antimalarial drugs, and consistently 4 to 10 times more potent than artesunate in rodent models against drug-susceptible and primaquine- or sulfadoxine/pyrimethamine-resistant Plasmodium berghei lines and chloroquine- or artemisinin-resistant lines of Plasmodium yoelii. Slight antagonistic trends were found between artemisone and chloroquine, amodiaquine, tafenoquine, atovaquone or pyrimethamine and additive to slight synergistic trends with artemisone and mefloquine, lumefantrine or quinine. Various degrees of synergy were observed in vivo between artemisone and mefloquine, chloroquine or clindamycin. CONCLUSIONS: These results confirm the increased efficacy of artemisone over artesunate against multidrug-resistant P. falciparum and provide the basis for the selection of potential partner drugs for future deployment in areas of multidrug-resistant malaria. Artemisone represents an important addition to the repertoire of artemisinin combination therapies currently in use, as it has enhanced antimalarial activity, improved bioavailability and stability over current endoperoxides.

    PMID: 17337512 [PubMed - indexed for MEDLINE]

  34. Curr Opin Infect Dis. 2006 Dec;19(6):623-31.

    8-Aminoquinolines: future role as antiprotozoal drugs.

    Tekwani BL(1), Walker LA.

    Author information: (1)National Center for Natural Products Research and Department of Pharmacology, University of Mississippi, University, Mississippi 38677, USA.

    PURPOSE OF REVIEW: This review focuses on recent developments on evaluation of 8-aminoquinoline analogs with broader efficacy and reduced toxicity, which would provide better drugs for treatment of protozoal infections. RECENT FINDINGS: The earlier efforts towards development of 8-aminoquinoline analogs have been directed to extensive derivatization programs. This has led to discovery of tafenoquine for prophylaxis against malaria infections and sitamaquine with utility for treatment of visceral leishmaniasis. Bulaquine, a primaquine pro-drug, has shown reduced methemoglobin toxicity and better malaria-transmission-blocking activity than primaquine. Stereoselective pharmacologic and toxicologic characteristics of chiral 8-aminoquinolines provided the lead for enantiomeric separation of an 8-aminoquinoline analog NPC1161B, with greatly reduced toxicity and potent antimalarial action against blood as well as tissue stages of the parasite. NPC1161B has also shown promising use as an antileishmanial agent. Better understanding of the mechanisms of toxicity and efficacy may help in development of 8-aminoquinoline analogs with superior therapeutic actions, reduced toxicity and broader utility. SUMMARY: Extensive derivatization approaches followed by better understanding of structure-activity relationships and biotransformation mechanisms of toxicity have provided 8-aminoquinoline analogs with better pharmacologic and reduced toxicologic profiles. The novel 8-aminoquinoline analogs may have broader utility in public health as future antiprotozoals.

    PMID: 17075340 [PubMed - indexed for MEDLINE]

  35. Antimicrob Agents Chemother. 2006 Sep;50(9):3225-6.

    In vitro activity of tafenoquine against the asexual blood stages of Plasmodium falciparum isolates from Gabon, Senegal, and Djibouti.

    Pradines B, Mamfoumbi MM, Tall A, Sokhna C, Koeck JL, Fusai T, Mosnier J, Czarnecki E, Spiegel A, Trape JF, Kombila M, Rogier C.

    PMCID: PMC1563556 PMID: 16940138 [PubMed - indexed for MEDLINE]

  36. Trans R Soc Trop Med Hyg. 2007 Mar;101(3):226-30. Epub 2006 Jun 30.

    Gender differences in gastrointestinal disturbances and plasma concentrations of tafenoquine in healthy volunteers after tafenoquine administration for post-exposure vivax malaria prophylaxis.

    Edstein MD(1), Nasveld PE, Kocisko DA, Kitchener SJ, Gatton ML, Rieckmann KH.

    Author information: (1)Australian Army Malaria Institute, Enoggera, Brisbane, Queensland 4051, Australia.

    In an open-label sequential cohort study, we compared gastrointestinal (GI) disturbances and plasma tafenoquine concentrations after administration of single-dose (400mg daily x 3 days; n=76 males, 11 females) and split-dose (200 mg twice daily x 3 days; n=73 males, 13 females) tafenoquine regimens in healthy Australian Defence Force volunteers for post-exposure malaria prophylaxis. The female and male volunteers had comparable demographic characteristics (age, weight, height) in the single- and split-dose treatment groups. GI disturbances were generally mild and self-limiting for both groups. The frequency of nausea and abdominal distress was over two-fold higher in females than in males for both treatment groups. Reporting of GI disturbances in the single-dose group differed significantly between males and females, but this gender difference was not seen for the split-dose group. In those volunteers who experienced GI disturbances, the mean plasma tafenoquine concentrations 12 h after the last dose of tafenoquine were approximately 1.3-fold higher in females than in males (means+/-SD: 737+/-118 ng/ml vs. 581+/-113 ng/ml). These preliminary findings suggest that further studies are required in a larger number of females to determine whether there is a need to reduce the dose of tafenoquine to minimise GI disturbances in females.

    PMID: 16814823 [PubMed - indexed for MEDLINE]

  37. Bull Soc Pathol Exot. 2001 Jul;94(2 Pt 2):149-51.

    Development of new drugs for chemoprophylaxis of malaria.

    Milhous W(1).

    Author information: (1)Walter Reed Army Institute of Research, Washington DC, USA.

    When U.S. troops first encountered drug resistant malaria during the Vietnam war, the United States Army responded by establishing a malaria drug research program. In 1988, the Walter Reed Army Institute of Research developed mefloquine (WR 149240) and halofantrine (WR 171669). Actually in association with SmithKline Beecham, the WRAIR is developing tafenoquine (WR 238605), an analogue of primaquine, which is expected to be effective in both preventing and treating malaria in deployed military personnel. Final phase III studies leading to U.S. Food and Drug Administration approval are planned for 2000. Applied research is also carried out with the association atovaquone-proguanil (Malarone) or with azithromycin, but also with primaquine, the associations paludrine-dapsone or lapudrine-dapsone, analogues of floxacrine (WR 243251), and a guanylhydrazone (WR 182393). The future scientific directions must focus on basic and applied research for a better understanding of the modes of action and mechanisms of resistance to standard and developmental drugs. Using new techniques, the design and synthesis of new drugs would hopefully result in the development of drugs that circumvent the malaria parasites elusive mechanisms of drug resistance.

    PMID: 16579068 [PubMed - indexed for MEDLINE]

  38. Drugs. 2005;65(15):2091-110.

    Modern malaria chemoprophylaxis.

    Shanks GD(1), Edstein MD.

    Author information: (1)Australian Army Malaria Institute, Brisbane, Queensland, Australia.

    Currently available medications for malaria chemoprophylaxis are efficacious but the problems of patient compliance, the advance of parasite drug resistance, and real or perceived serious adverse effects mean that new chemical compounds are needed.Primaquine, which has been widely used to treat relapsing malaria since the 1950s, has been shown to prevent malaria when taken daily. Tafenoquine is a new 8-aminoquinoline with a much longer half-life than primaquine. Field trials to date indicate that tafenoquine is efficacious and can be taken weekly or perhaps even less frequently. Both primaquine and tafenoquine require exact knowledge of a person's glucose 6-phosphate dehydrogenase status in order to prevent drug-induced haemolysis. Other potential malaria chemoprophylactic drugs such as third-generation antifol compounds and Mannich bases have reached advanced preclinical testing. Mefloquine has been seen to cause serious neuropsychiatric adverse effects on rare occasions. Recent public controversy regarding reputedly common serious adverse effects has made many Western travellers unwilling to take mefloquine. Special risk groups exposed to malaria, such as long-term travellers, children, pregnant women, aircrew and those requiring unimpeded psychomotor reactions, migrants returning to visit malarious countries of origin and febrile persons who have returned from malaria endemic areas, all require a nuanced approach to the use of drugs to prevent malaria. The carrying of therapeutic courses of antimalarial drugs to be taken only if febrile illness develops is indicated in very few travellers despite its appeal to some who fear adverse effects more than they fear potentially lethal malaria infection. Travellers with a significant exposure to malaria require a comprehensive plan for prevention that includes anti-mosquito measures but which is still primarily be based on the regular use of efficacious antimalarial medications.

    PMID: 16225366 [PubMed - indexed for MEDLINE]

  39. Infect Dis Clin North Am. 2005 Mar;19(1):185-210.

    New strategies for the prevention of malaria in travelers.

    Chen LH(1), Keystone JS.

    Author information: (1)Department of Medicine, Harvard Medical School, Boston, MA, USA.

    Malaria prevention has benefited from many diverse disciplines of research, including epidemiologic monitoring, development of laboratory techniques, assessment of insect repellents, or pharmaceutical innovations. Strategies in all these sectors have been explored in recent years, resulting in improved options to prevent travelers' malaria. The addition of atovaquone-proguanil for malaria chemoprophylaxis and the recommendation of primaquine as primary prophylaxis have been significant advances. Tafenoquine seems promising. Standby treatment recommendations have been refined. Many areas still need better strategies. Problematic areas include chemoprophylaxis for long-term travelers, expatriates, and pregnant women; optimal criteria for terminal prophylaxis; and the prevention of malaria in populations that are least likely to seek pretravel evaluations, such as those visiting friends and relatives in their home countries (VFRs). Finally, research in travel and tropical medicine should continue to focus on additional strategies to confront the ever-widening challenge of drug-resistant malaria.

    PMID: 15701554 [PubMed - indexed for MEDLINE]

  40. Arch Pediatr. 2005 Jan;12(1):53-8.

    [Malaria chemoprophylaxis in traveling children].

    [Article in French]

    Minodier P(1), Noël G, Blanc P, Tsaregorodtseva N, Retornaz K, Garnier JM.

    Author information: (1)Accueil des urgences pédiatriques, CHU Nord, Chemin-des-Bourrelly, 13920 Marseille cedex 20, France.

    In France, 4,000 imported malaria cases are reported each year (7,000 to 8,000 estimated). Chemoprophylaxis is essential for prevention in travelers. When malaria is susceptible to chloroquine, this drug (Nivaquine) has to be used. It is given daily in France (1.5 mg/kg per day), from departure to four weeks after return. When low levels of chloroquino-resistance are reported, French authorities recommend the use of chloroquine + proguanil (Savarine) if the body weight is >50 kg or Nivaquine) + Paludrine), if <50 kg), or atovaquone + proguanil (Malarone). Nivaquine) (1.5 mg/kg per day) and Paludrine) (3 mg/kg per day) have to be pursued for one month after return, although Malarone) (1 pediatric tablet/10 kg per day, in children >10 kg weight) may be disrupted after one single week. Adverse events are rarer with atovaquone + proguanil, than with chloroquine + proguanil. When chloroquino-resistance is high, Malarone) or mefloquine (Lariam) are used. Weekly drug regimen is recommended with mefloquine (5 mg/kg per weight) for the travel duration and four weeks after return and the drug tolerance is good in pediatric prophylaxis. Doxycycline is used under conditions in children >8 years of age. New drugs as for tafenoquine, an amino-8 quinoleine, might enhance patients compliance if given monthly.

    PMID: 15653056 [PubMed - indexed for MEDLINE]

  41. Trans R Soc Trop Med Hyg. 2005 Jan;99(1):2-5.

    Treatment of acute vivax malaria with tafenoquine.

    Nasveld P(1), Kitchener S.

    Author information: (1)Clinical Field Section, Australian Army Malaria Institute, Gallipoli Barracks, Enoggera, Queensland 4051, Australia.

    Tafenoquine is an 8-aminoquiniline related to primaquine with pre-clinical activity against a range of malaria species. We treated two acute cases of vivax malaria with tafenoquine (800 mg over three days) alone, instead of conventional chloroquine (1500 mg over three days) and primaquine (420 mg over 14 days). In addition to the convenience of this regimen, the rapid parasite clearances observed, coupled with a good clinical response and lack of recrudescence or relapse, indicate that further investigation of tafenoquine in the treatment of vivax malaria is warranted.

    PMID: 15550254 [PubMed - indexed for MEDLINE]

  42. Wien Klin Wochenschr. 2003;115 Suppl 3:28-32.

    In-vitro interaction of tafenoquine and chloroquine in Plasmodium falciparum from northwestern Thailand.

    Vollnberg A(1), Prajakwong S, Sirichaisinthop J, Wiedermann G, Wernsdorfer G, Wernsdorfer WH.

    Author information: (1)Department of Medical Microbiology, Institute of Hygiene, Otto-von-Guericke University, Magdeburg, Germany.

    The blood schizontocidal, pharmacodynamic interaction between tafenoquine (WR 238605--a 5-phenoxyprimaquine derivative--and chloroquine was investigated, using an in-vitro test for the inhibition of schizont maturation, in 15 fresh isolates of Plasmodium falciparum that originated from northwestern Thailand and neighbouring Myanmar. In this area the parasite is highly resistant to chloroquine. The geometric mean cut-off concentrations of schizont maturation for tafenoquine and chloroquine were 5261 nM and 7638 nM, respectively. With a mixture of tafenoquine and chloroquine, the mean cut-off concentration was 5252 nM, corresponding to 389 nM tafenoquine + 4863 nM chloroquine. Further analysis showed that the interaction between tafenoquine and chloroquine was additive within the range of EC20 and EC77. At concentrations higher than the EC77, interaction was moderately synergistic. While tafenoquine did not reverse the resistance to chloroquine to the degree of clinically relevant sensitivity, there was evidence that the blood schizontocidal efficacy of tafenoquine would be enhanced in the presence of chloroquine.

    PMID: 15508777 [PubMed - indexed for MEDLINE]

  43. Clin Infect Dis. 2004 Oct 15;39(8):1095-103. Epub 2004 Sep 24.

    Randomized trial of 3-dose regimens of tafenoquine (WR238605) versus low-dose primaquine for preventing Plasmodium vivax malaria relapse.

    Walsh DS(1), Wilairatana P, Tang DB, Heppner DG Jr, Brewer TG, Krudsood S, Silachamroon U, Phumratanaprapin W, Siriyanonda D, Looareesuwan S.

    Author information: (1)Department of Immunology and Medicine, US Army Medical Component, Armed Forces Research Institute of Medical Sciences, Bangkok, Thailand.

    BACKGROUND: Tafenoquine is an 8-aminoquinoline developed as a more effective replacement for primaquine. In a previous dose-ranging study in Thailand, 3 tafenoquine regimens with total doses ranging from 500 mg to 3000 mg prevented relapse of Plasmodium vivax malaria in most patients when administered 2 days after receipt of a blood schizonticidal dose of chloroquine. METHODS: To improve convenience and to begin comparison of tafenoquine with primaquine, 80 patients with P. vivax infection were randomized to receive 1 of the following 5 treatments 1 day after receiving a blood schizonticidal dose of chloroquine: (A) tafenoquine, 300 mg per day for 7 days (n=18); (B) tafenoquine, 600 mg per day for 3 days (n=19); (C) tafenoquine, 600 mg as a single dose (n=18); (D) no further treatment (n=13); or (E) primaquine base, 15 mg per day for 14 days (n=12). The minimum duration of protocol follow-up was 8 weeks, with additional follow-up to 24 weeks. RESULTS: Forty-six of 55 tafenoquine recipients, 10 of 13 recipients of chloroquine only, and 12 of 12 recipients of chloroquine plus primaquine completed at least 8 weeks of follow-up (or had relapse). There was 1 relapse among recipients of chloroquine plus tafenoquine, 8 among recipients of chloroquine only, and 3 among recipients of chloroquine plus primaquine. The rate of protective efficacy (determined on the basis of reduction in incidence density) for all recipients of chloroquine plus tafenoquine, compared with recipients of chloroquine plus primaquine, was 92.6% (95% confidence interval, 7.3%-99.9%; P=.042, by Fisher's exact test). CONCLUSIONS: Tafenoquine doses as low as a single 600-mg dose may be useful for prevention of relapse of P. vivax malaria in Thailand.

    PMID: 15486831 [PubMed - indexed for MEDLINE]

  44. Expert Rev Anti Infect Ther. 2004 Feb;2(1):119-32.

    Malaria chemoprophylaxis: when should we use it and what are the options?

    Petersen E(1).

    Author information: (1)Department of Infectious Diseases, Aarhus University Hospital Skejby, DK-8200 Aarhus N, Denmark.

    Malaria chemoprophylaxis concerns prescribing healthy individuals medication for an infection they have an unknown chance of getting. Sensible use of malaria chemoprophylaxis is a balance between the risk of infection and death, and the risk of side effects. The risk of infection can be broken down into the risk of being bitten by a malaria-infected mosquito and the risk of the malaria parasites being resistant to the drug used for prophylaxis. Our knowledge of these parameters is patchy. The risk of infection is not uniform at a given location and the standard of living will greatly influence risk. It is suggested that chemoprophylaxis should not be recommended in areas with less than ten reported cases of P. falciparum malaria per 1000 inhabitants per year. The resistance pattern is known to a certain extent but, for instance, diverging opinion of how much resistance to chloroquine there is in West Africa illustrates the lack of data. There is much debate on rare adverse events, which usually escape Phase III studies prior to registration and are only picked up by passive, postmarketing surveillance. The lessons over the past 20 years with the introduction of amodiaquine, pyrimethamine/dapsone (Maloprim, GlaxoSmithKline) and pyrimethamine/sulfadoxine (Fansidar, Roche), which were all withdrawn for prophylaxis after a few years, show how sensitive drugs for chemoprophylaxis are to side effects. Three levels of chemoprophylaxis are used: chloroquine in areas with sensitive P. falciparum, chloroquine plus proguanil in areas with low level chloroquine resistance, and atovaquone/proguanil (Malarone, GlaxoSmithKline), doxycycline or mefloquine (Lariam, Roche) in areas with extensive resistance against chloroquine and proguanil. Primaquine and the primaquone analog tafenoquine may be future alternatives but otherwise there are few new drugs for chemoprophylaxis on the horizon.

    PMID: 15482177 [PubMed - indexed for MEDLINE]

  45. J Infect Dis. 2004 Oct 15;190(8):1456-63. Epub 2004 Sep 20.

    Efficacy of monthly tafenoquine for prophylaxis of Plasmodium vivax and multidrug-resistant P. falciparum malaria.

    Walsh DS(1), Eamsila C, Sasiprapha T, Sangkharomya S, Khaewsathien P, Supakalin P, Tang DB, Jarasrumgsichol P, Cherdchu C, Edstein MD, Rieckmann KH, Brewer TG.

    Author information: (1)Department of Immunology and Medicine, United States Army Medical Component, Bangkok, Thailand.

    We assessed monthly doses of tafenoquine for preventing Plasmodium vivax and multidrug-resistant P. falciparum malaria. In a randomized, double-blind, placebo-controlled study, 205 Thai soldiers received either a loading dose of tafenoquine 400 mg (base) daily for 3 days, followed by single monthly 400-mg doses (n = 104), or placebo (n = 101), for up to 5 consecutive months. In volunteers completing follow-up (96 tafenoquine and 91 placebo recipients), there were 22 P. vivax, 8 P. falciparum, and 1 mixed infection. All infections except 1 P. vivax occurred in placebo recipients, giving tafenoquine a protective efficacy of 97% for all malaria (95% confidence interval [CI], 82%-99%), 96% for P. vivax malaria (95% CI, 76%-99%), and 100% for P. falciparum malaria (95% CI, 60%-100%). Monthly tafenoquine was safe, well tolerated, and highly effective in preventing P. vivax and multidrug-resistant P. falciparum malaria in Thai soldiers during 6 months of prophylaxis.

    Copyright 2004 Infectious Diseases Society of America

    PMID: 15378438 [PubMed - indexed for MEDLINE]

  46. Trans R Soc Trop Med Hyg. 2003 Jul-Aug;97(4):438-40.

    Efficacy of a 14-day primaquine regimen in preventing relapses in patients with Plasmodium vivax malaria in Mumbai, India.

    Rajgor DD(1), Gogtay NJ, Kadam VS, Kamtekar KD, Dalvi SS, Chogle AR, Aigal U, Bichile LS, Kain KC, Kshirsagar NA.

    Author information: (1)Department of Clinical Pharmacology, Seth GS Medical College & KEM Hospital, Parel, Mumbai 400 012, India.

    We studied the antirelapse efficacy of a supervised 14-d 15 mg/d regimen of primaquine therapy (n = 131) compared with no antirelapse therapy (n = 142) in 273 patients with confirmed Plasmodium vivax malaria in Mumbai, India, between July 1998 and April 2000. There were 6/131 (4.6%) recurrences in patients given primaquine compared with 13/142 (9.2%) in those not given antirelapse therapy. In the 14-d primaquine group, polymerase chain reaction-single strand conformational polymorphism (PCR-SSCP) genotyping analysis of pre- and post-treatment blood samples was done for the 6 patients who had a recurrence of parasitaemia and the results gave a true relapse rate of 2.29% (3/131), 2 samples were classified as reinfections and 1 sample did not amplify. Our results indicate probable resistance to the 14-d regimen of primaquine for the first time in India and illustrate the need to (i) monitor patients given this regimen and (ii) carry out comparative studies between primaquine and new drugs such as tafenoquine and bulaquine for preventing relapses.

    PMID: 15259476 [PubMed - indexed for MEDLINE]

  47. Mil Med. 2003 Dec;168(12):1001-6.

    Military aviators, special operations forces, and causal malaria prophylaxis.

    Chambers JA(1).

    Author information: (1)Headquarters Air Force Special Operations Command, Office of the Command Surgeon, Hurlburt Field, FL 32544, USA.

    U.S. military aviators are currently restricted to the use of chloroquine or doxycycline for malaria prophylaxis. Ground forces are allowed the additional option of taking mefloquine. These medications are begun before deployment, must be taken for 4 weeks after leaving the malarious area, and primaquine must be added to the regimen the last 2 of those 4 weeks. Compliance with this regimen is often poor, especially in populations who travel abroad frequently for short periods of time. Causal malaria prophylaxis offers potential benefits of decreased length of postdeployment regimens and obviates the need for a second medication for terminal prophylaxis. Potential obstacles include adverse drug reactions, cost, and rapid development of resistance to new medications by Plasmodium species, which should be weighed against the risks to health and mission success in each deployment.

    PMID: 14719625 [PubMed - indexed for MEDLINE]

  48. Am J Trop Med Hyg. 2003 Nov;69(5):542-7.

    Transmission-blocking activity of tafenoquine (WR-238605) and artelinic acid against naturally circulating strains of Plasmodium vivax in Thailand.

    Ponsa N(1), Sattabongkot J, Kittayapong P, Eikarat N, Coleman RE.

    Author information: (1)Department of Entomology, Armed Forces Research Institute of Medical Sciences, Bangkok, Thailand.

    The sporontocidal activity of tafenoquine (WR-238605) and artelinic acid was determined against naturally circulating isolates of Plasmodium vivax in western Thailand. Primaquine was used as a negative control and a dihydroacridine-dione (WR-250547) was used as a positive control. Laboratory-reared Anopheles dirus mosquitoes were infected with P. vivax by allowing mosquitoes to feed on blood (placed in an artificial-membrane feeding apparatus) collected from gametocytemic volunteers reporting to local malaria clinics in Tak province, Thailand. Four days post-infection, mosquitoes were refed on uninfected mice treated 90 minutes earlier with a given drug. Drug activity was determined by assessing oocyst and sporozoite development. Neither primaquine nor artelinic acid affected oocyst or sporozoite development at a dose of 100 mg of base drug/kg of mouse body weight. In contrast, tafenoquine and WR-250547 affected sporogonic development at doses as low as 25.0 and 0.39 mg/kg, respectively. The potential role of these compounds in the prevention of malaria transmission is discussed, as are alternative strategies for the use of transmission-blocking antimalarial drugs.

    PMID: 14695093 [PubMed - indexed for MEDLINE]

  49. Clin Infect Dis. 2003 Dec 15;37(12):1654-8. Epub 2003 Nov 20.

    Plasma concentrations of tafenoquine, a new long-acting antimalarial agent, in thai soldiers receiving monthly prophylaxis.

    Edstein MD(1), Kocisko DA, Walsh DS, Eamsila C, Charles BG, Rieckmann KH.

    Author information: (1)Australian Army Malaria Institute, Enoggera, QLD, Australia.

    We measured plasma tafenoquine concentrations in Thai soldiers given a monthly regimen of tafenoquine to determine whether these concentrations adequately suppressed malarial infections on the Thai-Cambodian border. After receiving a treatment course of artesunate and doxycycline, 104 male soldiers were administered a loading dose of tafenoquine (400 mg daily for 3 days), followed by tafenoquine monthly (400 mg every 4 weeks) for 5 months. Consecutive monthly mean (+/- standard deviation) trough plasma tafenoquine concentrations were 223+/-41, 127+/-29, 157+/-51, 120+/-24, and 88+/-20 ng/mL. Only 1 soldier developed malaria during the study. At the time of malaria diagnosis, his plasma tafenoquine concentration was 40 ng/mL, which was approximately 3-fold lower than the trough concentrations of the other soldiers. Although low tafenoquine concentrations appear to be uncommon, additional investigations are needed to determine the relationship between plasma tafenoquine concentrations and suppression of malaria.

    PMID: 14689348 [PubMed - indexed for MEDLINE]

  50. Clin Pharmacokinet. 2003;42(15):1359-82.

    Stereoselectivity in the pharmacodynamics and pharmacokinetics of the chiral antimalarial drugs.

    Brocks DR(1), Mehvar R.

    Author information: (1)Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada.

    Several of the antimalarial drugs are chiral and administered as the racemate. These drugs include chloroquine, hydroxychloroquine, quinacrine, primaquine, mefloquine, halofantrine, lumefantrine and tafenoquine. Quinine and quinidine are also stereoisomers, although they are given separately rather than in combination. From the perspective of antimalarial activity, most of these agents demonstrate little stereoselectivity in their effects in vitro. Mefloquine, on the other hand, displays in vitro stereoselectivity against some strains of P. falciparum, with a eudismic ratio of almost 2 : 1 in favour of the (+)-enantiomer. Additionally, for some of these agents (e.g. halofantrine, primaquine, chloroquine), stereoselectivity has been noted in the ability of the enantiomers to cause certain adverse effects. In recent years, stereospecific analytical methods capable of measuring the individual enantiomers after the administration of racemic drugs have been reported for a number of chiral antimalarial drugs. These assays have revealed that almost all the studied antimalarial drugs display stereoselectivity in their pharmacokinetics, leading to enantioselectivity in their plasma concentrations. Whereas the oral absorption of these agents appears to be non-stereoselective, stereoselectivity is often seen in their volume of distribution and/or clearance. With regard to distribution, plasma protein binding of some chiral antimalarial drugs exhibits a significant degree of stereoselectivity, leading to stereoselective distribution to blood cells and other tissues. Because of their low hepatic extraction ratios, stereoselective plasma protein binding also contributes to the stereoselectivity in the metabolism of these drugs. Chiral metabolites are formed from some parent antimalarial drugs, although stereoselective aspects of the pharmacokinetics of the metabolites are not well understood. It is concluded that knowledge of the stereoselective aspects of these agents may be helpful in better understanding their mechanisms of action and possibly optimising their clinical safety and/or effectiveness.

    PMID: 14674788 [PubMed - indexed for MEDLINE]

  51. Angew Chem Int Ed Engl. 2003 Nov 10;42(43):5274-93.

    New antimalarial drugs.

    Wiesner J(1), Ortmann R, Jomaa H, Schlitzer M.

    Author information: (1)Biochemisches Institut der Justus-Liebig-Universität, Friedrichstrasse 24, 35 392 Giessen, Germany.

    Approximately 40% of the world population live in areas with the risk of malaria. Each year, 300-500 million people suffer from acute malaria, and 0.5-2.5 million die from the disease. Although malaria has been widely eradicated in many parts of the world, the global number of cases continues to rise. The most important reason for this alarming situation is the rapid spread of malaria parasites that are resistant to antimalarial drugs, especially chloroquine, which is by far the most frequently used. The development of new antimalarial drugs has been neglected since the 1970s owing to the end colonialism, changes in the areas of military engagement, and the restricted market potential. Only in recent years, in part supported by public funding programs, has interest in the development of antimalarial drugs been renewed. New data available from the recently sequenced genome of the malaria parasite Plasmodium falciparum and the application of methods of modern drug design promise to bring significant development in the fight against this disease.

    PMID: 14613157 [PubMed - indexed for MEDLINE]

  52. Drug News Perspect. 2003 May;16(4):238.

    Molecule of the month. Tafenoquine succinate.

    [No authors listed]

    PMID: 12942153 [PubMed - indexed for MEDLINE]

  53. Ann Trop Med Parasitol. 2003 Apr;97(3):221-36.

    The chemotherapy of rodent malaria. LXI. Drug combinations to impede the selection of drug resistance, part 4: the potential role of 8-aminoquinolines.

    Peters W(1), Stewart LB, Robinson BL.

    Author information: (1)Centre for Tropical Antiprotozoal Chemotherapy, Y Block, Northwick Park Institute for Medical Research, Watford Road, Harrow HA1 3UJ, UK.

    The influence of combinations containing the blood schizontocides chloroquine (CQ) or mefloquine (MEF), together with the 8-aminoquinolines (8AQ) primaquine (PQ) or the new, long-acting compound, tafenoquine (TAF), on the rate of selection of resistance to the individual compounds was examined using the asexual, intra-erythrocytic stages in rodent malaria models. The two main procedures used were a 'serial technique' (ST) and the '2%- relapse technique' (2%RT). The ST provided evidence for the contention that a combination with PQ slowed the selection of resistance to CQ or MEF; it has been shown previously that synergism exists between CQ and either PQ or TAF in rodent malaria. Data obtained with the 2%RT, and three parasite lines derived from Plasmodium berghei N (the 238B line), P. chabaudi ASS (the 238C line) or P. yoelii ssp. NS (the 238Y line), indicated that resistance to TAF used alone is acquired rapidly under drug pressure and that this resistance is stable when selection pressure is removed. In the 2%RT, resistance to CQ developed when another line of P. chabaudi (AS15) was exposed to that compound alone, although more slowly than the development of resistance to TAF in the 238C line. However, treatment of a TC line of P. chabaudi, developed in a 2%RT using a combination of CQ with TAF, led to little resistance to either compound. A totally unforeseen phenomenon was the appearance of a high level of resistance to CQ in the 238C line of P. chabaudi that had been exposed only to TAF; this was not observed with the 238B or 238Y lines. Attention has been refocused recently on the use of 8AQ for prophylaxis in man. It remains to be determined if resistance in the asexual intra-erythrocytic forms is carried over to the other stages of the malarial life-cycle, especially the hepatic, pre-erythrocytic schizonts. The implications of the present results for the possible clinical deployment of 8AQ in the future are discussed. It is concluded that, whereas use of an 8AQ alone carries a high risk of selecting resistance, combinations containing 8AQ may have a place in the protection of blood schizontocides that are to be deployed in endemic areas. Furthermore, the inherent gametocytocidal action of the 8AQ should promote the reduction of transmission.

    PMID: 12803854 [PubMed - indexed for MEDLINE]

  54. Acta Trop. 2003 Apr;86(1):35-40.

    Blood schizontocidal activity of WR 238605 (Tafenoquine) against Plasmodium cynomolgi and Plasmodium fragile infections in rhesus monkeys.

    Puri SK(1), Dutta GP.

    Author information: (1)Division of Parasitology, Central Drug Research Institute, Lucknow 226001, India.

    A new 8-aminoquinoline antimalarial WR 238605 (Tafenoquine), developed initially as a primaquine alternative for prevention of Plasmodium vivax relapses was evaluated for blood schizontocidal activity against two simian malaria infections namely Plasmodium cynomolgi B and Plasmodium fragile in rhesus monkeys. Treatment with WR 238605 at a dose of 3.16 mg(base)/kg/day x 7 days cured established trophozoite induced infections in monkeys with both these parasites. The lower dose of 1.00 mg/kg/day cured 9 out of 12 monkeys infected with P. cynomolgi B and 10 out of 11 monkeys infected with P. fragile. Primaquine was only partially curative at 10.0 mg(base)/kg/day x 7 dose regimen against both these infections. The potent blood schizontocidal activity of tafenoquine adds to the armoury of antimalarial drugs.

    PMID: 12711101 [PubMed - indexed for MEDLINE]

  55. Trans R Soc Trop Med Hyg. 2002 Nov-Dec;96(6):683-4.

    Comparison of tafenoquine (WR238605) and primaquine in the post-exposure (terminal) prophylaxis of vivax malaria in Australian Defence Force personnel.

    Nasveld P(1), Kitchener S, Edstein M, Rieckmann K.

    Author information: (1)Australian Defence Force Combined Health Element, Loloho, North Solomons Province, Papua New Guinea.

    On return from duty in North Solomons Province (including Bougainville Island), Papua New Guinea, 586 Australian Defence Force personnel received either primaquine (14-d) or tafenoquine (3-d) post-exposure malaria prophylaxis. Within 12 months, 6 of the 214 volunteers receiving primaquine and 7 of 378 receiving tafenoquine had developed vivax malaria. Overall, volunteers preferred the shorter course of tafenoquine.

    PMID: 12625150 [PubMed - indexed for MEDLINE]

  56. Clin Infect Dis. 2003 Mar 1;36(5):541-9. Epub 2003 Feb 14.

    A randomized, double-blind, placebo-controlled, dose-ranging trial of tafenoquine for weekly prophylaxis against Plasmodium falciparum.

    Hale BR(1), Owusu-Agyei S, Fryauff DJ, Koram KA, Adjuik M, Oduro AR, Prescott WR, Baird JK, Nkrumah F, Ritchie TL, Franke ED, Binka FN, Horton J, Hoffman SL.

    Author information: (1)US Navy Medical Research Unit No. 3, Cairo, Egypt.

    Tafenoquine is a promising new 8-aminoquinoline drug that may be useful for malaria prophylaxis in nonpregnant persons with normal glucose-6-phosphate dehydrogenase (G6PD) function. A randomized, double-blind, placebo-controlled chemoprophylaxis trial was conducted with adult residents of northern Ghana to determine the minimum effective weekly dose of tafenoquine for the prevention of infection by Plasmodium falciparum. The primary end point was a positive malaria blood smear result during the 13 weeks of study drug coverage. Relative to the placebo, all 4 tafenoquine dosages demonstrated significant protection against P. falciparum infection: for 25 mg/week, protective efficacy was 32% (95% confidence interval [CI], 20%-43%); for 50 mg/week, 84% (95% CI, 75%-91%); for 100 mg/week, 87% (95% CI, 78%-93%); and for 200 mg/week, 86% (95% CI, 76%-92%). The mefloquine dosage of 250 mg/week also demonstrated significant protection against P. falciparum infection (protective efficacy, 86%; 95% CI, 72%-93%). There was little difference between study groups in the adverse events reported, and there was no evidence of a relationship between tafenoquine dosage and reports of physical complaints or the occurrence of abnormal laboratory parameters. Tafenoquine dosages of 50, 100, and 200 mg/week were safe, well tolerated, and effective against P. falciparum infection in this study population.

    PMID: 12594633 [PubMed - indexed for MEDLINE]

  57. Antimicrob Agents Chemother. 2003 Jan;47(1):170-3.

    Simple in vitro assay for determining the sensitivity of Plasmodium vivax isolates from fresh human blood to antimalarials in areas where P. vivax is endemic.

    Russell BM(1), Udomsangpetch R, Rieckmann KH, Kotecka BM, Coleman RE, Sattabongkot J.

    Author information: (1)Australian Army Malaria Institute, Enoggera QLD 4052, Australia.

    The aim of this study was to develop a simple, field-practical, and effective in vitro method for determining the sensitivity of fresh erythrocytic Plasmodium vivax isolates to a range of antimalarials. The method used is a modification of the standard World Health Organization (WHO) microtest for determination of P. falciparum drug sensitivity. The WHO method was modified by removing leukocytes and using a growth medium supplemented with AB(+) serum. We successfully carried out 34 in vitro drug assays on 39 P. vivax isolates collected from the Mae Sod malaria clinic, Tak Province, Thailand. The mean percentage of parasites maturing to schizonts (six or more merozoites) in control wells was 66.5% +/- 5.9% (standard deviation). This level of growth in the control wells enabled rapid microscopic determination (5 min per isolate per drug) of the MICs of chloroquine, dihydroartemisinin, WR238605 (tafenoquine), and sulfadoxine. P. vivax was relatively sensitive to chloroquine (MIC = 160 ng/ml, 50% inhibitory concentration [IC(50)] = 49.8 ng/ml) and dihydroartemisinin (MIC = 0.5 ng/ml, IC(50) = 0.47 ng/ml). The poor response of P. vivax to both tafenoquine (MIC = 14,000 ng/ml, IC(50) = 9,739 ng/ml) and sulfadoxine (MIC = 500,000 ng/ml, IC(50) = 249,000 ng/ml) was due to the slow action of these drugs and the innate resistance of P. vivax to sulfadoxine. The in vitro assay developed in our study should be useful both for assessing the antimalarial sensitivity of P. vivax populations and for screening new antimalarials in the absence of long-term P. vivax cultures.

    PMCID: PMC149008 PMID: 12499187 [PubMed - indexed for MEDLINE]

  58. Am J Trop Med Hyg. 2002 Jul;67(1):39-43.

    In vitro activity of tafenoquine alone and in combination with artemisinin against Plasmodium falciparum.

    Ramharter M(1), Noedl H, Thimasarn K, Wiedermann G, Wernsdorfer G, Wernsdorfer WH.

    Author information: (1)Department of Specific Prophylaxis and Tropical Medicine, Institute of Pathophysiology, University of Vienna, Austria.

    Emergence and spread of drug-resistant falciparum malaria has created an urgent demand for alternative therapeutic agents. This study was conducted to assess the in vitro blood schizontocidal activity of tafenoquine, the most advanced candidate drug of the 8-aminoquinolines, and of its 1:1 combination with artemisinin in fresh isolates of Plasmodium falciparum in an area with multi-drug resistance, measuring the inhibition of schizont maturation. In 43 successfully tested parasite isolates, the mean effective concentrations (ECs) of tafenoquine were 209 nmol/L for the EC50, and 1,414 nmol/L for the EC90. Tafenoquine showed no significant activity relationships with mefloquine, artemisinin, and chloroquine. With quinine, a highly significant activity relationship was observed at the EC50, but not at the EC90. The EC50, and EC90 of the tafenoquine-artemisinin combination were 15.9 nmol/L and 84.3 nmol/L. The combination was synergistic. Tafenoquine appears to be a promising candidate for treating multidrug-resistant falciparum malaria, especially in combination with artemisinin derivatives.

    PMID: 12363062 [PubMed - indexed for MEDLINE]

  59. Antimicrob Agents Chemother. 2002 Aug;46(8):2518-24.

    Assessment of azithromycin in combination with other antimalarial drugs against Plasmodium falciparum in vitro.

    Ohrt C(1), Willingmyre GD, Lee P, Knirsch C, Milhous W.

    Author information: (1)Department of Pharmacology, Division of Experimental Therapeutics, Walter Reed Army Institute of Research, 503 Robert Grant Avenue, Silver Spring, MD 20910-7500, USA.

    Initial field malaria prophylaxis trials with azithromycin revealed insufficient efficacy against falciparum malaria to develop azithromycin as a single agent. The objective of this in vitro study was to determine the best drug combination(s) to evaluate for future malaria treatment and prophylaxis field trials. In vitro, azithromycin was tested in combination with chloroquine against 10 representative Plasmodium falciparum isolates. Azithromycin was also assessed in combination with eight additional antimalarial agents against two or three multidrug-resistant P. falciparum isolates. Parasite susceptibility testing was carried out with a modification of the semiautomated microdilution technique. The incubation period was extended from the usual 48 h to 68 h. Fifty percent inhibitory concentrations (IC(50)s) were calculated for each drug alone and for drugs in fixed combinations of their respective IC(50)s (1:1, 3:1, 1:3, 4:1, 1:4, and 5:1). These data were used to calculate fractional inhibitory concentrations and isobolograms. Chloroquine-azithromycin studies revealed a range of activity from additive to synergistic interactions for the eight chloroquine-resistant isolates tested, while an additive response was seen for the two chloroquine-sensitive isolates. Quinine, tafenoquine, and primaquine were additive to synergistic with azithromycin, while dihydroartemisinin was additive with a trend toward antagonism. The remaining interactions appeared to be additive. These results suggest that a chloroquine-azithromycin combination should be evaluated for malaria prophylaxis and that a quinine-azithromycin combination should be evaluated for malaria treatment in areas of drug resistance.

    PMCID: PMC127390 PMID: 12121927 [PubMed - indexed for MEDLINE]

  60. Br J Clin Pharmacol. 2001 Dec;52(6):663-70.

    Population pharmacokinetics of the new antimalarial agent tafenoquine in Thai soldiers.

    Edstein MD(1), Kocisko DA, Brewer TG, Walsh DS, Eamsila C, Charles BG.

    Author information: (1)Department of Pharmacology, Australian Army Malaria Institute, Enoggera, QLD, Australia.

    AIMS: To describe the population pharmacokinetics of tafenoquine in healthy volunteers after receiving tafenoquine for malaria prophylaxis. METHODS: The population consisted of 135 male Thai soldiers (mean age 28.9 years; weight 60.3 kg). All soldiers were presumptively treated with artesunate for 3 days plus doxycycline for 7 days to remove any pre-existing malaria infections. After the treatment regime, 104 soldiers (drug group) received a loading dose of 400 mg tafenoquine base daily for 3 days followed by 400 mg tafenoquine monthly for 5 consecutive months. In the placebo group, 31 soldiers were infected with malaria during the study period. They were re-treated with artesunate for 3 days plus doxycycline for 7 days followed by a loading dose of 400 mg tafenoquine daily for 3 days and then 400 mg tafenoquine weekly for prophylaxis. Blood samples were randomly collected from each soldier on monthly and weekly prophylaxis. Plasma tafenoquine concentrations were measured by h.p.l.c. Population pharmacokinetic modelling was performed using NONMEM. RESULTS: A one-compartment model was found best to describe the pharmacokinetics of tafenoquine after oral administration. Age and weight influenced volume of distribution (V/F), and subjects who contracted malaria had higher clearance (CL/F), but none of these factors was considered to have sufficient impact to warrant change in dosing. The population estimates of the first-order absorption rate constant (Ka), CL/F and V/F were 0.694 h(-1), 3.20 l h(-1) and 1820 l, respectively. The intersubject variability in these parameters (coefficient of variation, CV%) was 61.2%, 25.3% and 14.8%, respectively. The absorption and elimination half-lives were 1.0 h and 16.4 days, respectively. The residual (unexplained) variability was 17.9%. CONCLUSIONS: The population pharmacokinetics of orally administered tafenoquine have been determined in Thai soldiers under field conditions. This information, together with its known potent antimalarial activity, portends well for the application of tafenoquine as a useful prophylactic drug or for short-term radical treatment of vivax malaria.

    PMCID: PMC2014562 PMID: 11736877 [PubMed - indexed for MEDLINE]

  61. Clin Infect Dis. 2001 Dec 15;33(12):1968-74. Epub 2001 Nov 7.

    A new primaquine analogue, tafenoquine (WR 238605), for prophylaxis against Plasmodium falciparum malaria.

    Shanks GD(1), Oloo AJ, Aleman GM, Ohrt C, Klotz FW, Braitman D, Horton J, Brueckner R.

    Author information: (1)US Army Medical Research Unit, Nairobi, Kenya.

    We tested tafenoquine (WR 238605), a new long-acting 8-aminoquinoline, for its ability to prevent malaria in an area that is holoendemic for Plasmodium falciparum. In a double-blinded, placebo-controlled, randomized clinical trial in western Kenya, adult volunteers received a treatment course of 250 mg halofantrine per day for 3 days, to effect clearance of preexisting parasites. The volunteers were then assigned to 1 of 4 drug regimens: placebo throughout; 3 days of 400 mg (base) of tafenoquine per day, followed by placebo weekly; 3 days of 200 mg of tafenoquine per day, followed by 200 mg per week; and 3 days of 400 mg of tafenoquine per day, followed by 400 mg per week. Prophylaxis was continued for up to 13 weeks. Of the evaluable subjects (223 of 249 randomized subjects), volunteers who received 400 mg tafenoquine for only 3 days had a protective efficacy of 68% (95% confidence interval [CI], 53%-79%), as compared with placebo recipients; those who received 200 mg per day for 3 days followed by 200 mg per week had a protective efficacy of 86% (95% CI, 73%-93%); and those who received 400 mg for 3 days followed by 400 mg per week had a protective efficacy of 89% (95% CI, 77%-95%). A similar number of volunteers in the 4 treatment groups reported adverse events. Prophylactic regimens of 200 mg or 400 mg of tafenoquine, taken weekly for < or =13 weeks, are highly efficacious in preventing falciparum malaria and are well tolerated.

    PMID: 11700577 [PubMed - indexed for MEDLINE]

  62. Med Trop (Mars). 2001;61(1):77-8.

    Experiences with malaria chemoprophylaxis in Dutch troops.

    Buma AH(1), van Thiel P.

    Author information: (1)Royal Netherlands Navy, La Hague, et de l'Academic Medical Centre.

    This article describes the situation for malaria chemoprophylaxis among Dutch military personnel. Any malaria chemoprophylaxis advice given to Dutch troops is based on a close co-operation between national military and civilian experts. Most studies, related to a deployment in Cambodia, describe the experiences with mefloquine. Overall it has been well tolerated. From an African deployment, it has been learned that anticircumsporozoite antibodies could be demonstrated in 11% of the personnel. Future options for Dutch troops will concentrate on atovaquone/proguanil and tafenoquine. Furthermore some kind of individualisation will be accepted. In conclusion malaria in Dutch troops has remained a manageable problem but vigilance remains necessary.

    PMID: 11584661 [PubMed - indexed for MEDLINE]

  63. Med Trop (Mars). 2001;61(1):56-8.

    Malaria prophylaxis/radical cure: recent experiences of the Australian Defence Force.

    Edstein MD(1), Walsh DS, Eamsila C, Sasiprapha T, Nasveld PE, Kitchener S, Rieckmann KH.

    Author information: (1)Australian Army Malaria Institute, Gallipoli Barracks, Enogerra, QLD, 4052 Australia.

    Since the eighties, the Australian Defence Force has deployed soldiers in malaria-endemic areas: Cambodia, Somalia, Rwanda, Bougainville, and East Timor. Currently, doxycycline is used as first line prophylactic drug and mefloquine is recommended for those who cannot tolerate the antibiotic. In 1998, the Australian Defence Force participated in the evaluation of tafenoquine for prophylaxis of both falciparum and vivax malaria in Thai soldiers. At the completion of this six-month study, 29 of 205 soldiers had come down with malaria including eight with falciparum malaria, 20 with vivax malaria, and one with mixed infection. A total of 28 of the 101 soldiers in the placebo group were infected with malaria as compared with only one of the 104 soldiers in the tafenoquine group. In 1999, another study was started on the island of Bougainville to compare the effectiveness a 3-day course of tafenoquine and a 14-day course of primaquine for radical cure of vivax malaria. At the present time, 411 soldiers have completed the study including 201 in tafenoquine arm and 210 in primaquine arm. Seven soldiers in each arm developed vivax malaria after returning to Australia. These results indicate that tafenoquine is not superior to primaquine in preventing vivax malaria. However study participants preferred the shorter course using tafenoquine and operationally it was found to be more suitable than primaquine.

    PMID: 11584657 [PubMed - indexed for MEDLINE]

  64. Med Trop (Mars). 2001;61(1):48-50.

    Development of new drugs for chemoprophylaxis of malaria.

    Milhous WK(1).

    Author information: (1)Division of Experimental Therapeutics Division, Walter Reed Army Institute of Research, Silver Spring, MD 20910, USA.

    When U.S. troops first encountered drug resistant malaria during the Vietnam war, the United States Army responded by establishing a malaria drug research program. In 1988, the Walter Reed Army Institute of Research developed mefloquine (WR 149240) and halofantrine (WR 171669). Actually, in association with SmithKline Beecham, the WRAIR is developing tafenoquine (WR 238605), an analog of primaquine, which is expected to be effective in both preventing and treating malaria in deployed military personnel. Final phase III studies leading to U.S. Food and Drug Administration approval are planned for 2000. Applied research is also carried out with the association atovaquone-proguanil (Malarone) or with azithromycin, but also with primaquine, the associations paludrine-dapsone or lapudrine-dapsone, analogs of floxacrine (WR 243251), and a guanylhydrazone (WR 182393). The future scientific directions must focus on basic and applied research for a better understanding of the modes of action and mechanisms of resistance to standard and developmental drugs. Using new techniques, the design and synthesis of new drugs would hopefully result in the development of drugs that circumvent the malaria parasites elusive mechanisms of drug resistance.

    PMID: 11584654 [PubMed - indexed for MEDLINE]

  65. Clin Infect Dis. 2001 Aug 1;33(3):381-5. Epub 2001 Jul 5.

    Malaria chemoprophylaxis in the age of drug resistance. II. Drugs that may be available in the future.

    Shanks GD(1), Kain KC, Keystone JS.

    Author information: (1)US Army Medical Component of the Armed Forces Research Institute of Medical Sciences, 315/6 Rajvithi Road, Bangkok 10400, Thailand.

    All current regimens of malaria chemoprophylaxis have serious drawbacks as a result of either suboptimal efficacy, difficulty with medication compliance, or adverse events. Two 8-aminoquinolines may be approaching registration, with primaquine having completed its prophylactic field testing and tafenoquine having begun advanced field testing at the end of 2000. Primaquine has long been used for management of relapses of malaria, but in the past decade, it has been reexamined for use in malaria prevention in order to stop infection in the liver. In field trials performed in Indonesia and Colombia, the efficacy of primaquine for malaria prevention was approximately 90%, compared with that of placebo. Because of its short half-life, primaquine requires daily administration. For adults, the prevention regimen is 30 mg base daily (0.5 mg base/kg/day), and it can probably be discontinued soon after departure from an area where malaria is endemic. To kill parasites that already exist in the liver, terminal prophylaxis is given after exposure to relapses of malaria infection; for adults, such prophylaxis usually consists of 15 mg base (0.3 mg base/kg/day) given daily for 2 weeks. Primaquine-induced gastrointestinal disturbances can be minimized if the drug is taken with food. Neither primaquine nor tafenoquine should be given to persons with glucose-6-phosphate dehydrogenase deficiency, to avoid the development of potentially severe drug-induced hemolysis. Tafenoquine is an analogue of primaquine that is more potent than the parent drug. Field trials in Kenya, Ghana, Gabon, and Southeast Asia have demonstrated an efficacy rate of approximately 90% for tafenoquine. Its long half-life allows for infrequent dosing (currently tested at 200 mg base/week), and its effect on parasites at the liver stage may allow for drug discontinuation at the time of departure from the area of endemicity.

    PMID: 11438908 [PubMed - indexed for MEDLINE]

  66. Clin Infect Dis. 2001 Jul 15;33(2):226-34. Epub 2001 Jun 14.

    Malaria chemoprophylaxis in the age of drug resistance. I. Currently recommended drug regimens.

    Kain KC(1), Shanks GD, Keystone JS.

    Author information: (1)Centre for Travel and Tropical Medicine, Division of Infectious Diseases, Department of Medicine, Toronto General Hospital and University of Toronto, Toronto, Ontario, Canada.

    As international travel becomes increasingly common and resistance to antimalarial drugs escalates, a growing number of travelers are at risk for contracting malaria. Parasite resistance to chloroquine and proguanil and real or perceived intolerance among patients to standard prophylactic agents such as mefloquine have highlighted the need for new antimalarial drugs. Promising new regimens include atovaquone and proguanil, in combination; primaquine; and a related 8-aminoquinoline, tafenoquine. These agents are active against the liver stage of the malaria parasite and therefore can be discontinued shortly after the traveler leaves an area where malaria is endemic, which encourages adherence to the treatment regimen. Part 1 of this series reviews currently recommended chemoprophylactic drug regimens, and part 2 will focus on 8-aminoquinoline drugs.

    PMID: 11418883 [PubMed - indexed for MEDLINE]

  67. Presse Med. 2001 Apr 21;30(15):767-71.

    [Plasmodium vivax: therapy update].

    [Article in French]

    Nicolas X(1), Granier H, Laborde JP, Talarmin F, Klotz F.

    Author information: (1)Service de Médecine interne, HIA Clermont-tonnerre, F 29240 Brest Naval.

    IMPACT OF PLASMODIUM VIVAX WORLDWIDE: Plasmodium vivax is the most widespread malanal agent in the world. Unlike Plasmodium falciparum, P. vivax can cause early or late recurrence and is not fatal (benign tertian malaria). EMERGENCE OF RESISTANT STRAINS: P. vivax strains resistant to chloroquine, then primaquine, have emerged over the last decade, creating the need for a new therapeutic strategy. TREATMENT OF PRIMARY DISEASE: Generally, chloroquine is the first intention treatment, excepting patients who also have P. falciparum infection or a strain with suspected resistance to chloroquine. Mefloquine, quinine and halofantrine are also logical alternatives. TREATMENT OF RECURRENT DISEASE: A schizonticidal agent should be given followed by a hypnozoitocidal agent, primaquine. Primaquine dosage should now be raised or adjusted to the patient's weight.THERAPEUTIC PERSPECTIVES: Tafenoquine, delayed-release amino-8-quinoleine, is a potential alternative for primaquine for the treatment of recurrences. Studies are also in progress to evaluate the role of primaquine as a prophylaxic agent.

    PMID: 11360746 [PubMed - indexed for MEDLINE]

  68. Curr Infect Dis Rep. 2001 Feb;3(1):68-76.

    Recent Advances in the Prophylaxis and Treatment of Malaria.

    Labbé AC(1), Loutfy MR, Kain KC.

    Author information: (1)Department of Medicine, Tropical Disease Unit, University Health Network, University of Toronto, 200 Elizabeth Street, EN G 224, Toronto, ON, Canada, M5G 2C4.

    Increases in international travel and escalating drug resistance are putting put a growing number of travelers at risk of contracting malaria. Resistance to chloroquine and proguanil and real and perceived intolerance to standard agents, such as mefloquine, has highlighted the need for new antimalarials to prevent and treat malaria. Promising new agents to prevent malaria include the combination of atovaquone and proguanil, primaquine, and a related 8-aminoquinoline, tafenoquine. These agents are active against the liver stage of the malaria parasite, and therefore can be discontinued shortly after the traveler leaves the malaria-endemic area; this offers a clear advantage, in terms of adherence to a treatment regimen. For treatment of multidrug-resistant Plasmodium falciparum malaria, the combination of artemisinin derivatives plus mefloquine, or atovaquone plus proguanil, are the most active drug regimens.

    PMID: 11177733 [PubMed - as supplied by publisher]

  69. MMW Fortschr Med. 2000 Sep 21;142(38):13.

    [New preventive antimalaria drug. 3 tables, 2 months of protection. Interview by Petra Eiden].

    [Article in German]

    Kremsner P.

    PMID: 11050883 [PubMed - indexed for MEDLINE]

  70. Lancet. 2000 Jun 10;355(9220):2041-5.

    Malaria chemoprophylaxis with tafenoquine: a randomised study.

    Lell B(1), Faucher JF, Missinou MA, Borrmann S, Dangelmaier O, Horton J, Kremsner PG.

    Author information: (1)Research Unit, Albert Schweitzer Hospital, Lambaréné, Gabon.

    BACKGROUND: Tafenoquine is an analogue of primaquine with an improved therapeutic and safety profile. It has a long half-life and activity against liver-stage malaria parasites, so may be useful for chemoprophylaxis. In this randomised, double-blind study we assessed the efficacy and safety of tafenoquine in different doses. METHODS: 2144 individuals aged 12-20 years living in Lambaréné, Gabon, an endemic area for Plasmodium falciparum malaria, were invited to take part. 535 attended, and 426 eligible participants were randomly assigned tafenoquine (250 mg, 125 mg, 62.5 mg, or 31.25 mg) or placebo daily for 3 days. 417 received initial curative treatment with halofantrine, and 410 completed the assigned prophylaxis regimen. During follow-up of 70 days, adverse events were recorded and thick blood smears were examined weekly. The primary and secondary endpoints were the number of individuals with positive blood smears by day 56 and day 77, respectively. Analyses were per-protocol. FINDINGS: Eight positive blood smears were recorded by day 56 (four/82 participants in the placebo group; four/79 tafenoquine 31.25 mg group). By day 77, 34 positive blood smears had been recorded (14/82 placebo; 16/79 tafenoquine 31.25 mg; three/86 tafenoquine 62.5 mg; one/79 tafenoquine 125 mg; none/84 tafenoquine 250 mg). Numbers of adverse events did not differ significantly between the treatment groups. INTERPRETATION: Tafenoquine is effective and well tolerated. It has the potential to replace currently used drugs for malaria chemoprophylaxis.

    PMID: 10885356 [PubMed - indexed for MEDLINE]

  71. Ther Drug Monit. 2000 Apr;22(2):184-9.

    Measurement of tafenoquine (WR 238605) in human plasma and venous and capillary blood by high-pressure liquid chromatography.

    Kocisko DA(1), Walsh DS, Eamsila C, Edstein MD.

    Author information: (1)Department of Pharmacology, Australian Army Malaria Institute, Enoggera, QLD.

    A simple, rapid, and accurate high-pressure liquid chromatographic method with fluorescence detection is described for the measurement of tafenoquine (TQ) (also known as WR 238605) from human plasma and venous and capillary blood. Tafenoquine was measured in plasma and venous blood following protein precipitation. Chromatographic separation was achieved using a Waters S5P Spherisorb phenyl analytical cartridge (150 mm x 4.6 mm I.D., 5 microm particle size) (Waters, Milford, MA, USA) and a mobile phase of 22 mM ammonium acetate, pH 4:acetonitrile (45:55, vol/vol). The flow rate was 1.5 mL/min and the retention times were approximately 3.5 min for WR VIIIAc (internal standard) and approximately 7.8 min for TQ. The interday and intraday coefficients of variation of TQ over a concentration range of 20-1000 ng/mL in plasma were < or =8.4% and in venous blood were < or =9.6%. The mean percent difference between added concentration and obtained concentration was 7.3% in plasma and 8.5% in venous blood over the corresponding concentration range. The limit of quantitation for both fluids was 10 ng/mL. Tafenoquine concentrations were comparable between capillary and venous blood with no significant difference between measurement in both biological fluids. The clinical application of the method was demonstrated by measuring plasma and whole blood concentrations of TQ from participants in a chemosuppression trial of the drug against malaria infections in Thailand.

    PMID: 10774631 [PubMed - indexed for MEDLINE]

  72. J R Soc Med. 1999 Jul;92(7):345-52.

    The evolution of tafenoquine--antimalarial for a new millennium?

    Peters W(1).

    Author information: (1)CABI Bioscience, St Albans, Herts, UK.

    PMCID: PMC1297286 PMID: 10615272 [PubMed - indexed for MEDLINE]

  73. J Infect Dis. 1999 Oct;180(4):1282-7.

    Randomized dose-ranging study of the safety and efficacy of WR 238605 (Tafenoquine) in the prevention of relapse of Plasmodium vivax malaria in Thailand.

    Walsh DS(1), Looareesuwan S, Wilairatana P, Heppner DG Jr, Tang DB, Brewer TG, Chokejindachai W, Viriyavejakul P, Kyle DE, Milhous WK, Schuster BG, Horton J, Braitman DJ, Brueckner RP.

    Author information: (1)Department of Immunology, US Army Medical Component, Armed Forces Research Institute of Medical Sciences, Bangkok, Thailand.

    WR 238605 is an 8-aminoquinoline developed for the radical cure of Plasmodium vivax. Forty-four P. vivax-infected patients were randomly assigned to 1 of 4 treatment regimens: 3 groups received a blood schizonticidal dose of chloroquine followed by WR 238605: group A (n=15) received 300 mg daily for 7 days; group B (n=11), 500 mg daily for 3 days, repeated 1 week after the initial dose; group C (n=9), 1 dose of 500 mg. A fourth group (D; n=9) received chloroquine only. Among patients who completed 2-6 months of follow-up (n=23), there was 1 relapse in group B (day 120) and 1 in group C (day 112). Among patients treated with chloroquine only, there were 4 relapses (days 40, 43, 49, and 84). WR 238605 was safe, well tolerated, and effective in preventing P. vivax relapse.

    PMID: 10479159 [PubMed - indexed for MEDLINE]

  74. J Travel Med. 1999 May;6 Suppl 1:S31-2.

    Possible options for malaria chemoprophylaxis on the horizon.

    Shanks GD(1).

    Author information: (1)US Army Medical Research Unit-Kenya, Nairobi, Kenya.

    PMID: 23573551 [PubMed - indexed for MEDLINE]

  75. Am J Trop Med Hyg. 1998 May;58(5):645-9.

    First-time-in-humans safety and pharmacokinetics of WR 238605, a new antimalarial.

    Brueckner RP(1), Lasseter KC, Lin ET, Schuster BG.

    Author information: (1)Division of Experimental Therapeutics, Walter Reed Army Institute of Research, Washington, District of Columbia 20307-5100, USA.

    WR 238605 is an 8-aminoquinoline drug currently under development for prophylaxis and treatment of malaria. Preclinical studies have demonstrated that it has greater efficacy and less toxicity compared with primaquine. In this first-time-in-human randomized, double-blind, placebo-controlled study designed to evaluate the safety, tolerance and pharmacokinetics, WR 238605 was administered to 48 men in single oral doses ranging from four to 600 mg (base). It was well tolerated, with gastrointestinal disturbances as possible side effects. Linear kinetics were demonstrated at these doses. WR 238605 has a long absorption phase and is slowly metabolized, with a tmax of 12 hr and an elimination half-life of 14 days. These safety, efficacy and pharmacokinetic properties make this drug an excellent candidate for further testing as a prophylactic, radical curative, and terminal eradication drug.

    PMID: 9598455 [PubMed - indexed for MEDLINE]

  76. Antimicrob Agents Chemother. 1998 May;42(5):1293-4.

    Prophylaxis of Plasmodium falciparum infection in a human challenge model with WR 238605, a new 8-aminoquinoline antimalarial.

    Brueckner RP(1), Coster T, Wesche DL, Shmuklarsky M, Schuster BG.

    Author information: (1)Division of Experimental Therapeutics, Walter Reed Army Institute of Research, Washington, DC 20307-5100, USA. LTC_Ralf_Brueckner@WRSMTP-ccMail.Army.Mil

    The prophylactic efficacy of WR 238605, a primaquine analog, was studied with a human Plasmodium falciparum challenge model. A single oral dose of 600 mg, administered 1 day prior to challenge, successfully protected three of four subjects. The fourth subject developed mild, oligosymptomatic malaria on day 31, with drug concentrations one-half of those in the protected individuals. WR 238605 appears to be a promising prophylactic drug for P. falciparum malaria.

    PMCID: PMC105811 PMID: 9593172 [PubMed - indexed for MEDLINE]

  77. Am J Trop Med Hyg. 1997 May;56(5):508-10.

    WR 238605, chloroquine, and their combinations as blood schizonticides against a chloroquine-resistant strain of Plasmodium vivax in Aotus monkeys.

    Obaldia N 3rd(1), Rossan RN, Cooper RD, Kyle DE, Nuzum EO, Rieckmann KH, Shanks GD.

    Author information: (1)Promed Trading SA, Panama City, Panama.

    The compound WR 238605 is a primaquine analog being developed by the U.S. Army as an antimalarial drug. Currently, there is no established treatment for Plasmodium vivax parasitemias that are not cured by chloroquine. This study tested WR 238605, chloroquine, and their combinations against a chloroquine-resistant strain of P. vivax (AMRU 1) in Aotus monkeys. A total dose of 3 mg/kg of WR 238605 given at a dosage of 1 mg/kg/day for three days cleared patent parasites in all eight monkeys but recrudescence of parasitemia occurred 15-25 days after initiation of treatment. A total dose of 9 mg/kg of WR 238605 over a three-day period cured all three monkeys of their infections. A total dose of 30 mg/kg of chloroquine did not clear patent infections in three monkeys, whereas a total dose of 60 mg/kg generally (two of three) cleared patent parasitemia but did not cure. Whereas total doses of 30 mg/kg of chloroquine or 3 mg/kg of WR 238605 given alone failed to cure, both drugs given in combination at these dosages cured two of three infections. These results indicate that WR 238605 may be an alternative treatment for chloroquine-resistant vivax malaria.

    PMID: 9180599 [PubMed - indexed for MEDLINE]

  78. Ann Trop Med Parasitol. 1997 Jan;91(1):33-9.

    The chemotherapy of rodent malaria. LIV. Combinations of 'Fenozan B07' (Fenozan-50F), a difluorinated 3,3'-spirocyclopentane 1,2,4-trioxane, with other drugs against drug-sensitive and drug-resistant parasites.

    Fleck SL(1), Robinson BL, Peters W.

    Author information: (1)International Institute of Parasitology, St Albans, U.K.

    Fenozan B07, a 1,2,4-trioxane endoperoxide with potent blood schizontocidal activity against drug-sensitive and drug-resistant rodent malaria parasites, exerted a modest potentiating action when administered with chloroquine (CQ) to mice infected with parasites of the CQ-resistant P. yoelii ssp. NS, but not when given to mice infected with the CQ-sensitive P. berghei N strain. The reason why this potentiation may be of particular value in the treatment of severe falciparum malaria is discussed. Mefloquine and halofantrine displayed a similar level of potentiation with Fenozan B07 against the CQ-resistant parasites. However, antagonism was shown by combinations of Fenozan B07 with pyronaridine or the 8-aminoquinoline WR 238 605 when used against CQ-resistant parasites. Mefloquine with Fenozan B07 is also antagonistic against a highly mefloquine-resistant line of P. yoelii ssp. NS. The reasons behind such antagonism are not known. The importance is stressed of using carefully selected drug combinations of novel antimalarials, rather than single drugs, in order to impede the selection of drug-resistant parasites, but only after adequate, preclinical, toxicity testing.

    PMID: 9093427 [PubMed - indexed for MEDLINE]

  79. Antimicrob Agents Chemother. 1997 Jan;41(1):91-4.

    Evaluation of selected antiprotozoal drugs in the Babesia microti-hamster model.

    Marley SE(1), Eberhard ML, Steurer FJ, Ellis WL, McGreevy PB, Ruebush TK 2nd.

    Author information: (1)Division of Parasitic Diseases, Centers for Disease Control and prevention, Department of Health and Human Services, Atlanta, Georgia 30341, USA.

    The presently used therapy for Babesia microti infections, a combination of quinine and clindamycin, does not always result in parasitologic cures. To identify possible alternative chemotherapeutic agents for such infections, we screened, in the hamster-B. microti system, 12 antiprotozoal drugs that have either recently been released for human use or were in experimental stages of development at the Walter Reed Army Institute of Research for the treatment of malaria and leishmaniasis. Several well-recognized antimalarial drugs, such as mefloquine, halofantrine, artesunate, and artelenic acid, exhibited little or no effect on parasitemia. Two 8-aminoquinolines, WR006026 [8-(6-diethylaminohexylamino)-6-methoxy-4-methylquinoline dihydrochloride] and WR238605 [8-[(4-amino-1-methylbutyl)amino]-2,6-dimethoxy-4-methyl-5 -(3-trifluoromethylphenoxy-7) quinoline succinate], produced clearance of patent parasitemia. Furthermore, blood from infected hamsters treated with WR238605 via an intramuscular injection failed to infect naive hamsters on subpassage, thus producing a parasitologic cure. These two compounds merit further screening in other systems and may prove useful in treating human babesiosis.

    PMCID: PMC163666 PMID: 8980761 [PubMed - indexed for MEDLINE]

  80. Trans R Soc Trop Med Hyg. 1994 Nov-Dec;88(6):691-2.

    The efficacy of WR238605 against the blood stages of a chloroquine resistant strain of Plasmodium vivax.

    Cooper RD(1), Milhous WK, Rieckmann KH.

    Author information: (1)Army Malaria Research Unit, Liverpool Military Area, NSW, Australia.

    PMID: 7886774 [PubMed - indexed for MEDLINE]

  81. Ann Trop Med Parasitol. 1993 Dec;87(6):547-52.

    The chemotherapy of rodent malaria. LI. Studies on a new 8-aminoquinoline, WR 238,605.

    Peters W(1), Robinson BL, Milhous WK.

    Author information: (1)CAB International Institute of Parasitology, St. Albans, U.K.

    WR 238,605, a novel 3-phenoxy-substituted 8-aminoquinoline, possesses causal prophylactic, blood schizontocidal and gametocytocidal activity against rodent malaria parasites. Against the asexual, intra-erythrocytic stages of drug-sensitive Plasmodium berghei N strain, it is about nine times as active as primaquine (PQ). It is from four to 100 times as active as PQ against lines of P. berghei or P. yoelii that are resistant to currently used antimalarials. WR 238,605 is three times as active as PQ against the pre-erythrocytic stages of P. y. nigeriensis but it has very poor gametocytocidal action and no sporontocidal activity against this parasite. In combination with chloroquine (CQ), WR 238,605 and PQ display a synergistic or 'resistance-reversing' action against CQ-resistant P. yoelii NS parasites. No such effects are seen when WR 238,605 is deployed with mefloquine against a mefloquine-resistant line or with artemisinin against an artemisinin-resistant line and it appears to be antagonistic to halofantrine against a halofantrine-resistant parasite. It is suggested that WR 238,605 is a good candidate compound for clinical trials against polyresistant P. falciparum, possibly in combination with CQ.

    PMID: 8122915 [PubMed - indexed for MEDLINE]

  82. Acta Leiden. 1991;60(1):147-56.

    Drug use and design in the nineties.

    Trigg PI(1).

    Author information: (1)Malaria Unit, World Health Organization, Geneva, Switzerland.

    PMID: 1820704 [PubMed - indexed for MEDLINE]

  83. Am J Trop Med Hyg. 1990 Mar;42(3):196-205.

    Sporontocidal activity of the antimalarial WR-238605 against Plasmodium berghei ANKA in Anopheles stephensi.

    Coleman RE(1).

    Author information: (1)Walter Reed Army Institute of Research, Washington, DC.

    The influence of WR-238605 (8-[(4-amino-1-methyl-butyl) amino]-2,6-dimethoxy-4-methyl-5-[3-tri-fluoromethylphenoxyl] quinoline succinate) on the sporogonic development of a Plasmodium berghei ANKA clone was determined. Anopheles stephensi were fed on P. berghei infected mice treated 90 min earlier with 25 or 50 mg WR-238605/kg body weight. Mosquitoes engorging on drug-treated mice produced the same number of ookinetes as did those fed on controls; drug-fed mosquitoes produced fewer oocysts/mosquito than did controls. These oocytes developed more slowly than did those in control-fed mosquitoes. Sporozoites did not invade the salivary glands of drug-fed mosquitoes, nor did these mosquitoes transmit P. berghei to mice. Uptake of WR-238605 6 or 12 days after mosquitoes were infected with P. berghei had no effect on the percentage of mosquitoes with oocysts or the mean number of oocysts produced per mosquito. Oocyst development was significantly retarded in mosquitoes ingesting drug on day 6 postinfection. Subsequent salivary gland sporozoite infections were lighter in mosquitoes drug-fed on day 6 or day 12 than in control mosquitoes or mosquitoes drug-fed on day 18. These data indicate that WR-238605 has significant sporontocidal activity.

    PMID: 2180334 [PubMed - indexed for MEDLINE]

  84. J R Soc Med. 1989;82 Suppl 17:63-6; discussion 66-8.

    Antimalarial drugs currently in development.

    Gutteridge WE(1).

    Author information: (1)Wellcome Research Laboratories, Beckenham, Kent.

    PMCID: PMC1291944 PMID: 2693729 [PubMed - indexed for MEDLINE]

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