Sustaining Antimalarial Drug Development

Review TRENDS in Parasitology Vol.22 No.7 July 2006

Medicines for Malaria Venture: sustaining antimalarial drug development

Ian Bathurst and Chris Hentschel

Medicines for Malaria Venture (MMV), International Center Cointrin (ICC) Building, 20 rte de Pre´ -Bois, 1215 Geneva 15, Switzerland

The Medicines for Malaria Venture (MMV) is committed Between 75% and 90% of malaria cases are currently to discovering, developing and delivering new drugs for found in sub-Saharan Africa but global warming and malaria. Founded in 1999 as a nonprofit organization demographic changes could change this. Both warming bringing private sector management methods to bear and increased flooding are conditions that favor the spread on a global public health problem, MMV is today of the mosquito species that transmits malaria, thus recognized as a leader among the public–private increasing the possibility that malaria will return to partnerships working on diseases for the developing parts of Europe and the USA [5,6]. world. Together with its many partners, MMV manages PPPs have rapidly evolved as the preferred way to the world’s largest malaria research and development ensure that progress can be made in addressing health- portfolio, covering the innovation spectrum from basic care issues that neither the public nor the private sector drug discovery to late-stage development. can solve on their own. MMV, incorporated as a Swiss foundation and officially launched on 3 November 1999, Introduction to MMV was among the first PPPs established to tackle the drug The Medicines for Malaria Venture (MMV; www.mmv.org) innovation gap of a major global neglected disease. The is a not-for-profit Swiss foundation that was created to synergistic combination of pharmaceutical industry discover, develop and deliver new affordable antimalarial knowledge and expertise in drug discovery and develop- drugs through effective public–private partnerships ment, and the public sector with its depth of expertise in (PPPs). After five years of operation, MMV, together basic biology, clinical medicine and malaria control with its many partners, manages the world’s largest experience, constituted the underlying rationale for its malaria research and development portfolio from basic chosen PPP formation. drug target discovery and validation projects through to The organizational structure of MMV (Figure 1) advanced formulations of existing drugs. All MMV enables flexibility in governance and management, development projects are executed to international Good making it possible for objectives to be met efficiently and Clinical Practices standards, as defined, for example, by rapidly. MMV is today governed by a board of up to 12 the US Food and Drug Administration or the European members chosen for their scientific, medical and public- Agency for the Evaluation of Medicinal Products. Equally, health expertise in malaria and related fields, their all drugs are manufactured to quality standards, as research and management competence, and their experi- promulgated under European Directive 2003/94/EC or ence in business, finance and fundraising. MMV uses an equivalent. Several drugs are currently in advanced Expert Scientific Advisory Committee (ESAC) to advise on development and MMV expects to launch several the selection and review of projects for funding by MMV important new antimalarial drugs before 2010. and to provide more general advice and information on appropriate technical strategies for the Foundation to achieve its goals. The members of the ESAC come from The extent of the challenge both industry and academia and cover the full range of Malaria kills between one and two million people annually, expertise required to assess projects in the extremely the majority of those affected being children under five complex process of drug research and development. years of age and pregnant women [1]. Each year, 300–500 Current and former members of the ESAC also participate million new clinical cases of malaria are reported in official in the MMV–ESAC Mentor Program. statistics. Although preventable through vector control or insecticide-treated bed nets, at present only drugs can be The need for continued drug innovation used to cure this life-threatening infection [2]. The true Although malaria control programs, malaria product number of clinical cases is not accurately known, and research and, indeed, the number of malariologists recent estimates suggest that actual numbers might be themselves decreased after the eradication era in the much larger than the official statistics suggest [3,4]. 1950–1960s, resistance to antimalarial drugs and to

Corresponding author: Bathurst, I. ([email protected]). insecticides has increased [7]. The world’s poorest people Available online 6 June 2006 in endemic regions do not beneﬁt from drugs developed for www.sciencedirect.com 1471-4922/$ - see front matter Q 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.pt.2006.05.011 302 Review TRENDS in Parasitology Vol.22 No.7 July 2006

Key committees

Stakeholders Outsourced support Remuneration Legal

Audit Board of directors Fundraising

President and I.T. Nominations Chief Executive Officer

C.R.O. Expert Scientific Advisory Direction Reporting Committee (ESAC) Consultants: science

MMV Communications Geographic spread management team

MMV Geneva

MMV Europe

Project teams & New Delhi support staff support office TRENDS in Parasitology

Figure 1. The organizational structure of MMV. The reporting system and key committees that are involved in the operation of MMV are shown. Abbreviations: C.R.O., contract research organization; I.T., information technology. the specialized travelers’ market in wealthy countries times that used to treat malaria [10,11].Theyare because these drugs are expensive and largely designed specifically contraindicated in early pregnancy [12,13]. for prophylaxis rather than therapy. Although the Moreover, because these agents are extracted from travelers’ market in industrialized countries totals, plants, their production time is lengthy and costly. perhaps, some US$300 million per year, this is still well Although usually purchased through global donations below the amount required to generate commercial for the public sector in developing countries, the research and development from the research-based underlying cost is still 10–30 times more than the pharmaceutical industry. Furthermore, the potential market for innovative new antimalarial drugs is ham- pered by competing counterfeit and substandard drugs, Table 1. The effectiveness of antimalarial drugs can be limited owing to a poor regulatory and enforcement infrastructure by resistance and safetya,b in many disease-endemic countries (http://www.cdc.gov/ Antimalarial drug Year Year resist- Other malaria/travel/counterfeit_drugs.htm). The net result has introduced ance found limitations been a lack of innovation and diversity that has led to Quinine 19th century 1910 Compliance, increasing drug resistance. The old, affordable first-line safety drug treatments such as chloroquine and sulfadoxine– Chloroquine 1945 1957 None pyrimethamine are today virtually useless in many parts Proguanil 1948 1949 None Primaquine 1950 No resistance Safety of Africa and Asia [8,9] (Table 1). Sulfadoxine– 1967 1967 None pyrimethamine Amodiaquine 1975 No resistance Safety, Artemisinin combination therapies possibly The Chinese initiated the development of the fast-acting resistance artemisinin drugs during the Vietnam War (1966–1971) Mefloquine 1977 1982 Cost, safety and have continued working on them as combinations Artemisinins 1970s No resistance Compliance, with slower-acting partner drugs. Artemisinin com- cost, possibly bination therapies (ACTs) are by far the best class of safety antimalarial drugs available today, both in terms of Halofantrine 1988 1992 Cost, safety efficacy and prospective longevity. However, ACT drugs Atovaquone 1996 1996 Cost are still not ideal in terms of safety, with potential Lapdap 2003 No resistance Resistance neurotoxicity and neuronal degeneration observed in potential aSource: MMV, World Health Organization. animals, and cell culture conditions that use artemisinin bTable reproduced, with permission, from Ref. [27]. q (2005) American Chemical or artemisinin derivatives at concentrations several Society. www.sciencedirect.com Review TRENDS in Parasitology Vol.22 No.7 July 2006 303 traditional first-line drug treatments. Scale-up requires a uncomplicated malaria. Artekine has been widely used considerable quantity of agricultural land and dedicated in Southeast Asia but has not yet been developed to extraction plants that can pose environmental risks. international registration or quality standards. The active Because of the time lag between needs forecasts, pharmaceutical ingredients in Eurartekine (the new fully procurement and delivery times, which are also affected international standard drug) were initially manufactured by lengthy planting and growing seasons, shortages at by Sigma-Tau in Italy for the clinical trials, and this the point of use of this plant-based drug are common. expertise is being transferred back to our Chinese Furthermore, use of artemisinin-based monotherapy, partners, Holley Pharmaceuticals. Because of extensive which threatens much of the rationale of the combination human experience, the nonclinical development plan drugs by risking the generation of resistance, continues (toxicology and pharmacokinetics) is being performed virtually unabated. concurrently with the clinical development plan, which Ideally, the Global Malaria Programme would like to includes three pharmacokinetic and two confirmatory have an effective and affordable first- and second-line Phase III studies [14,15]. drug specifically suited for each country or region. Because no drug will fit the needs of every country, at Chlorproguanil–dapsone (Lapdape)–artesunate: least three or four good options should ideally be Phase III available (the most current World Health Organization Chlorproguanil–dapsone–artesunate is a fixed-ratio treatment guidelines are published elsewhere [9]). MMV three-drug combination (Lapdape with artesunate) that and its partners are currently developing several lower- is being developed to treat uncomplicated Plasmodium cost ACTs (e.g. chlorproguanil–dapsone–artesunate and falciparum malaria. The Phase II dose-ranging study in Eurartekine), targeted to be approved within the next adults and children with uncomplicated malaria has been three years. However, the longer-term and unique completed and the optimum ratio of artesunate to the fixed contribution of MMV (Figure 2) to the antimalarial combination of chlorproguanil and dapsone has been arsenal will be the development of newer antimalarial established. A Phase III clinical development program combination therapies such as the synthetic peroxides, will involve multiple sites in Central, East and which do not rely on artemisinin as the sole fast-acting West Africa. drug class (see later). Pediatric Coarteme Developing drugs up close: clinical development Based on the data obtained with various trial pediatric projects formulations, a user-friendly pediatric dispersible tablet is Artekine (dihydroartemisinin–piperaquine): Phase I, II in development. The efficacy and safety of the Coarteme and III dispersible tablet will be compared with the conventional Dihydroartemisinin–piperaquine (Artekine) is a fixed- crushed Coarteme tablet in an investigator-blinded, ratio drug combination being developed to treat multicenter Phase III study in infants and children (in

Exploratory Discovery Preclinical Clinical development

Lead Lead Transition Phase I Phase II Phase III identification optimization

Dihydrofolate OZ (synthetic PSAC Novel reductase peroxide) antagonist macrolides (DHFR) RBx11160 / OZ 277

Pf enoyl-ACP New Chlorproguanil- 4(1H)-pyridones AQ-13 new reductase dicationic 4(1H)-pyridones aminoquinoline dapsone (Lapdapª) (Fab I) molecules back-ups -artesunate (CDA)

Next Falcipains Isoquine Cyclofarnesyl Pyronaridine- generation (cysteine (an improved sequiterpenes artesunate OZ proteases) aminoquinoline)

Entantioselective Pediatric 8-aminoquinolines Coartemª

Novel imidazolidine Artekinª (dihydroartemisinin-piperaquine) -diones

Projects in the GSK/MMV mini-portfolio TRENDS in Parasitology

Figure 2. The project portfolio of MMV. Projects in the MMV pipeline are categorized according to stages from exploratory to clinical trials and then towards product registration. Abbreviation: PSAC, plasmodial surface anion channel. www.sciencedirect.com 304 Review TRENDS in Parasitology Vol.22 No.7 July 2006 the weight range 5–35 kg) suffering from malaria. Six leishmaniasis and early-stage African trypanosomiasis centers in Africa were selected for this study and the trial (sleeping sickness), and has also been tested in a Phase II began in early 2006. proof-of-concept study to treat malaria. Its low toxicity and demonstrated activity in humans is an encouraging Pyronaridine–artesunate: Phase II proof of concept for improved-activity dicationic A fixed combination of pyronaridine and artesunate is molecules. These molecules concentrate selectively in being assessed as a once-daily oral treatment in both P. falciparum-infected red blood cells, where they enter adults and children suffering from acute uncomplicated and kill the parasites. The exact mechanism of action of P. falciparum and Plasmodium vivax malaria. A multi- these compounds is not understood but, along with DNA objective Phase I study was completed in 2005 and a study intercalation [17], they are also believed to interfere with to assess the tolerability, safety and pharmacokinetics in the heme degradation pathway. Recent work has demon- children is being initiated in Gabon in 2006. Following this strated that superior compounds with excellent selective study, the Phase III program is planned to be conducted in activity against malaria can be designed, and these 2006 both in Africa and Southeast Asia, in child and compounds are currently being evaluated in the Aotus adult patients. monkey model of P. falciparum to select the best candidate. Synthetic peroxide RBx11160/OZ 277: Phase II and partner drug selection Enantioselective 8-aminoquinolines RBx11160/OZ 277 [16] completed Phase I clinical trials in Over the past few years, there has been increasing 2004. A Phase I–II pharmacodynamic study in adult concern that morbidities resulting from P. vivax malaria patients in Thailand completed enrolment in 2005 and have been underestimated and that chloroquine resist- trial data are currently being analyzed. Additional Phase I ance is spreading [18,19]. The need for a new, safe, studies and a Phase II dose-ranging study are to be started efficacious and affordable treatment for both the acute and in 2006. Development of both a pediatric formulation and relapse phases of P. vivax malaria is pressing. To date, an intravenous formulation are underway, together with 8-aminoquinolines are the only compounds that have been piperaquine as the first partner. Preclinical studies are shown to be efficacious as anti-relapse therapy; ongoing with the combination and a Phase I clinical trial is NPC1161B is the (K) enantiomer of 8-aminoquinoline. planned for 2006. Although it retains potent pharmacological activities both in vivo and in vitro, it was shown to be significantly less Preclinical development projects toxic than the (C) enantiomer or the racemic mixture in Isoquine (an improved aminoquinoline) the models tested so far. Isoquine is being developed in partnership with Glaxo- SmithKline and the University of Liverpool, where it was Discovery projects – exploratory and lead identification discovered. It is a second-generation aminoquinoline, P. falciparum enoyl-acyl carrier protein reductase (Fab I) which retains the ease of synthesis of amodiaquine and Fab I is the only known enoyl-acyl carrier protein promises a new generation of affordable, well-tolerated reductase in P. falciparum. Phylogenetically, this enzyme and effective antimalarial drugs that are devoid of any is in the same group as the plant and bacterial enoyl cross-resistance to the chemically related chloroquine and reductases, and is different from the FAS I system present amodiaquine. In 2005, the N-tert-butyl form passed in animals. In bacteria, Fab I has been shown to be candidate selection criteria and, with the preclinical essential for fatty acid synthesis and is the molecular phase completed, is scheduled to be first tested in humans target for several antimicrobial drugs, including isoniazid in 2006. and triclosan. P. falciparum (Pf) is sensitive to triclosan, and Pf Fab I has been validated pharmacologically with Discovery projects – lead optimization triclosan. The Pf Fab I enzyme assay and enzyme 3D 4(1H)-pyridones structure are being used to guide hit-to-lead chemistry to In 2004, the 4(1H)-pyridone derivative GW844520 progress current inhibitors to the lead declaration progressed from discovery to development. The preclinical decision point. program revealed problems that made it unlikely for this specific molecule to progress further. A pyridone back-up Second-generation ozonide (synthetic peroxide) lead optimization program was then initiated and several This project was conceived to identify a second-generation promising drug candidates have now been generated with ozonide that will provide single-dose oral cures for increased solubility and enhanced oral bioavailability. patients with uncomplicated P. falciparum malaria. The After an exploratory animal toxicology program, a new screening and selection strategy has focused on optimizing candidate with improved properties was selected in early the pharmacokinetic–pharmacodynamic relationship of 2006. The rapid success in the back-up program is a part of these ozonides to provide single-dose cures with out- the strategic portfolio approach built into the Glaxo- standing prophylactic potential, optimized bioavailability SmithKline and MMV collaboration. and low cost of goods. Specifically, current studies are focused on identifying compounds with an increased half- New dicationic molecules life after oral administration to enable extended exposure Pentamidine, a dicationic molecule, has been used to treat following a single dose. The lead ozonide has a 100% cure Pneumocystis carinii pneumonia, antimony-resistant rate when administered as a single dose at 30 mg per kg www.sciencedirect.com Review TRENDS in Parasitology Vol.22 No.7 July 2006 305 body weight in a murine malaria model, and is as effective insights and contributions to the success of the MMV as mefloquine as a prophylactic agent, with a faster mode pipeline are invaluable. Finally, our rapid advances are of action. It has an extended half-life in rats relative to the made possible by the partners of MMV in academic original OZ 277 and has high oral bioavailability. research institutes and industry, of which there are nearly 40 in total. Currently, there are w300 scientists and Dihydrofolate reductase clinicians around the world working on antimalarial Drugs that inhibit the folate pathway have been widely projects supported by MMV (Figure 3). used for the treatment of malaria but their use is declining During the past five years, MMV has focused on owing to the emergence of drug resistance developed developing drugs that would be used primarily to treat through mutations in the dihydrofolate reductase (DHFR) uncomplicated P. falciparum malaria but there are other enzyme. However, the folate pathway remains a good malaria indications that need new drugs. Intermittent target for chemotherapy because the enzyme is limited in preventive treatment in pregnancy is one such indication its mutational capability. The availability of the crystal [23]. Developing drugs for pregnant women is difficult in structures of wild and mutant DHFR, both individually that the drugs must be safe and effective for the mother and complexed with inhibitors, has meant that it has been without causing damage to the developing fetus. Artemi- possible to design and synthesize compounds that inhibit sinin-based drugs have clear early embryo toxicity in the mutant enzymes. These new DHFR inhibitors are animal studies, although accidental human exposure shed inexpensive, active against multidrug-resistant strains little light on the potential safety in humans. and cure malaria within three days. The chemistry Intermittent preventive treatment in early infancy is program, guided by the enzyme structure, pharmaco- also needed because the majority of victims of malaria are kinetics, metabolism and in vitro and in vivo activity African children less than five years of age. During the studies, is aimed at overcoming the issue of first months after birth, the child gradually loses maternal oral bioavailability. protection and is susceptible to severe malaria. Inter- mittent preventive treatment in early infancy has been Falcipain (cysteine protease) found to be successful in preventing severe malaria and Inhibitors of cysteine proteases block hemoglobin decreasing the morbidity and mortality rates in young degradation and parasite development in malaria children, even when apparently less-effective drugs have parasites in vitro [20]. A proof-of-concept study using been used. This suggests that intermittent preventive azepanone compounds in a severe combined immuno- treatment can help to protect children from malaria while deficiency mouse model of P. falciparum was successful. they develop immunity [24]. The lead compound has demonstrated potent activity A malaria epidemic can have disastrous consequences against falcipains and against cultured malaria parasites, for a population with low or no natural immunity. In with good pharmacokinetic and metabolic properties and emergency situations, such as natural disasters and in low potential cost of goods, and can eradicate malaria refugee camps where health infrastructure is poor and infections in P. falciparum-infected mice. Future plans the potential for an epidemic is high, a single-dose include the selection of an orally active lead candidate for preclinical studies by the end of 2006, resolution of the antimalarial cure would be particularly relevant. structures of falcipains with candidate inhibitors, and Although P. vivax does not normally cause death, it is continued synthesis and study of related compounds as still a significant health problem in many parts of the back-up falcipain inhibitors. world. Treatment of acute blood-stage P. vivax malaria can still be achieved with chloroquine followed by a 14-day P. falciparum protein farnesyltransferase course of primaquine but relapses often occur because of In 2000, the project team showed that farnesyltransferase failure to complete the full course of treatment [25]. A new, inhibitors display potent anti-P. falciparum properties effective, radical cure that is significantly more easily in vitro [21]. This led to the possibility of ‘piggy-backing’ on tolerated is urgently needed. The MMV enantioselective farnesyltransferase inhibitors being developed by several 8-aminoquinoline project is working towards this goal. pharmaceutical companies. Protein farnesyltransferase Ultimately, severe cerebral malaria due to P. falci- was validated as the target for P. falciparum growth parum is the main cause of malaria-related death. Prompt inhibition with the tetrahydroquinoline class of inhibitors treatment of uncomplicated malaria at an early stage from Bristol-Myers Squibb. The evidence suggested that should prevent most patients from progressing to severe P. falciparum protein farnesyltransferase is a viable malaria. However, patients often present after the disease target for antimalarial drug development [22]. Several has already progressed to a stage where they cannot take tetrahydroquinoline molecules have good activity against oral drugs and need to be treated with intravenous or the target and the parasite but the challenge still remains intramuscular drugs. Intravenous forms of pyronaridine– to turn these into compounds that can be developed artesunate and the synthetic peroxide are the two drugs in as drugs. theportfoliothatarebeingdevelopedtotreat severe malaria. Looking to the future An ideal antimalarial drug will kill not only the The projects of MMV are evaluated continuously by the parasite but also the gametocytes, thus blocking trans- project management teams against set milestones. Once a mission as well as treating the infection. Artemisinins and year, the entire portfolio is assessed by the ESAC. Their synthetic peroxides seem to be transmission-blocking www.sciencedirect.com 306 Review TRENDS in Parasitology Vol.22 No.7 July 2006

Liverpool School of Tropical Medicine University of Liverpool University of California, San Francisco Oxford University University of Washington GlaxoSmithKline LSHTM Immtech International STI Korea Shin Poong Pharm. Inc. GlaxoSmithKline F. Hoffmann-La Roche University of Iowa Novartis Pharma WHO/(TDR) Yale University Sigma-Tau Industrie Farmaceutiche Riunite Albert Einstein Holleykin Pharmaceutical Company GlaxoSmithKline Ranbaxy Laboratories Limited College of Medicine Tres Cantos Texas A&M National Institutes of Health (NIH) University of North Carolina Chapel Hill BIOTEC University of Mississippi University of Nebraska Medical Center Mahidol University

= Pharmaceutical partner = University/institute = National research institute Monash University = Clinical trial site ( = under review) = International agency

TRENDS in Parasitology

Figure 3. The collaborations of MMV. MMV stakeholders, pharmaceutical partners, university and institutional partners, and existing and proposed clinical sites are shown. agents but new partner drugs should also be developed Cooperation, Rockefeller Foundation, Roll Back Malaria Partnership, with this activity. Swiss Agency for Development and Cooperation, UK Department for Although most of the 11 discovery projects in the MMV International Development (DFID), United States Agency for Inter- national Development (USAID), Wellcome Trust, World Bank, World portfolio have had successes in achieving their goals, Health Organization; Roll Back Malaria Department, Special Programme others are struggling to meet their milestones, as might be for Research and Training in Tropical Diseases (TDR). expected based on standard pharmaceutical attrition rates. To achieve the longer-term goals of MMV – to provide new, improved drugs that can replace the older References ones – the number of discovery projects is less than 1 Snow, R.W. et al. (2005) The global distribution of clinical episodes of optimal; MMV therefore plans to increase the number of Plasmodium falciparum malaria. Nature 434, 214–217 discovery projects in 2006. This will be done by: (i) adding 2 The Wellcome Trust. The parasite: the malaria medicine chest (http:// www.wellcome.ac.uk/en/malaria/TheParasite/pbdrug1.html) more projects to the portfolio, achieved through a focused 3 Rogers, D.J. et al. (2002) Satellite imagery in the study and forecast of Call for Proposals; and (ii) by seeking to build more malaria. Nature 415, 710–715 portfolio-based partnerships with industry. 4 Hay, S.I. et al. (2004) The global distribution and population at risk of The potential of malaria drug research, both within and malaria: past, present and future. Lancet Infect. Dis. 4, 327–336 outside of the MMV pipeline, is promising. There are no 5 Sutherst, R.W. (2004) Global change and human vulnerability to vector-borne diseases. Clin. Microbiol. Rev. 17, 136–173 technical reasons why research cannot deliver more than 6 Rogers, D.J. and Randolp, S.E. (2000) The global spread of malaria in a the ACT drugs that are today’s standard of care. A balance future warmer world. Science 289, 1763–1766 between continuous innovation and evidence-based use of 7 WHO/UNICEF (2003) Africa Malaria Report 2003 (http://www.rbm. malaria control and treatment measures provides the only who.int/amd2003/amr2003/amr_toc.htm) rational way forward to achieving the vision of MMV. It is 8 Greenwood, B. (2004) Between hope and a hard place. Nature 430, 926–927 now crucial that the well-documented mistakes of the 9 WHO (2006) Guidelines for the treatment of malaria. WHO/HTM/- failed eradication era in the 1950–1960s are not repeated MAL/2006.1108 (http://www.who.int/malaria/docs/TreatmentGuide- by thinking that all that is needed is already at hand [26]. lines2006.pdf) 10 Brewer, T.G. et al. (1994) Fatal neurotoxicity of arteether and artemether. Am. J. Trop. Med. Hyg. 51, 251–259 Acknowledgements 11 Schmuck, G. et al. (2002) Neurotoxic mode of action of artemisinin. MMV has received funding and support from the following organizations: Antimicrob. Agents Chemother. 46, 821–827 BHP Billiton, Bill and Melinda Gates Foundation, ExxonMobil, Global 12 WHO (2003) Assessment of the safety of artemisinin compounds in Forum for Health Research, International Federation of Pharmaceutical pregnancy. WHO/CDS/MAL/2003.1094 (http://www.who.int/malaria/ Manufacturers and Associations, Netherlands Minister for Development cmc_upload/0/000/016/323/artemisinin_pregnancy.pdf) www.sciencedirect.com Review TRENDS in Parasitology Vol.22 No.7 July 2006 307

13 Lono, M. et al. (2005) Use of antimalarial drugs in pregnancy: 21 Gelb, M.H. et al. (2003) Protein farnesyl and N-myristoyl transferases: assessment of the effects of artemisinin compounds on reproduction. piggy-back medicinal chemistry targets for the development of Parassitologia (Suppl. 1), 48 antitrypanosomatid and antimalarial therapeutics. Mol. Biochem. 14 Lau, C.X. et al. (1989) In vitro sensitivity of Plasmodium falciparum to Parasitol. 126, 155–163 piperaquine phosphate assayed in Linshui and Baisha counties, 22 Wiesner, J. et al. (2003) New antimalarial drugs. Angew. Chem. Int. Hainan Province. Zhongguo Ji Sheng Chong Xue Yu Ji Sheng Chong Ed. 42, 5274–5293 Bing Za Zhi 7, 163–165 23 Mubyazi, G. et al. (2005) Intermittent preventive treatment of malaria 15 Gou, X.B. (1993) Randomised comparison on the treatment of during pregnancy: a dualitative study of knowledge, attitudes and falciparum malaria with dihydro artemisinin and piperaquine. practices of district health managers, antenatal care staff and Zhonghua Yi Xue Za Zhi 73, 602–604 pregnant women in Korogwe District, North-Eastern Tanzania. 16 Vennerstrom, J.L. et al. (2004) Identification of an antimalarial Malaria Journal 4, 31 (DOI:10.1186/1475-2875-4-31) synthetic trioxolane drug development candidate. Nature 430, 900 24 O’Meara, W.P. et al. (2005) The promise and potential challenges of 17 Arafa, R.K. et al. (2005) Synthesis, DNA affinity, and antiprotozoal intermittent preventive treatment for malaria in infants (IPTi) activity of fused ring dicationic compounds and their prodrugs. J. Med. Malaria Journal 4, 33 (DOI: 10.1186/1475-2875-4-33) Chem. 48, 5480–5488 25 Looareesuwan, S. et al. (1999) Chloroquine sensitivity of Plasmodium 18 Mendis, K. et al. (2001) The neglected burden of Plasmodium vivax vivax in Thailand. Ann. Trop. Med. Parasitol. 93, 225–230 malaria. Am. J. Trop. Med. Hyg. 64, 97–106 26 Lang, T. et al. (2006) Beyond registration – measuring the public- 19 Rodriguez-Morales, et al. (2006) Impact of imported malaria on the burden of disease in northeastern Venezuela. J. Travel Med. 13, health potential of new treatments for malaria in Africa. Lancet Infect. 15–20 Dis. 6, 46–52 20 Shenai, B.R. et al. (2002) Stage-specific anti-malarial activity of 27 Thayer, A.M. (2005) Fighting malaria. Chemical and Engineering News cysteine protease inhibitors. Biol. Chem. 383, 843–847 83, 69–82 (http://pubs.acs.org/cen/coverstory/83/8343malaria.html)

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