9
Antimalarial Drugs and Drug Resistance

This chapter describes antimalarial drugs currently in use, with an emphasis on the artemisinins. It also reviews the way drug resistance develops and spreads, methods used to assess the presence and level of drug resistance, and the extent to which chloroquine and sulfadoxine/pyrimethamine (SP)—the two most widely used antimalarial drugs in the world today—have now lost efficacy.

CLINICAL MALARIA AND THE AIMS OF ANTIMALARIAL DRUG TREATMENT

Malaria sickens and kills people through several pathological mechanisms, understood to varying degrees. In addition to first- and second-line antimalarial drug treatments, adjunctive and supportive care measures (e.g., intravenous fluids, blood transfusions, supplemental oxygen, antiseizure medications) may be needed for severe manifestations. The aims of treatment are to prevent death or long-term deficits from malaria, to cut short the morbidity of an acute episode of illness, and to clear the infection entirely so that it does not recur.

Fever, sweating, and chills (or, in some cases, merely fever) triggered by the release of plasmodia into the bloodstream from mature blood schizonts, are the most common symptoms heralding the onset of a clinical case of uncomplicated falciparum malaria (see Chapter 6 for a description of the evolution of clinical symptoms). Without treatment—or an active immune



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Saving Lives, Buying Time: Economics of Malaria Drugs in an Age of Resistance 9 Antimalarial Drugs and Drug Resistance This chapter describes antimalarial drugs currently in use, with an emphasis on the artemisinins. It also reviews the way drug resistance develops and spreads, methods used to assess the presence and level of drug resistance, and the extent to which chloroquine and sulfadoxine/pyrimethamine (SP)—the two most widely used antimalarial drugs in the world today—have now lost efficacy. CLINICAL MALARIA AND THE AIMS OF ANTIMALARIAL DRUG TREATMENT Malaria sickens and kills people through several pathological mechanisms, understood to varying degrees. In addition to first- and second-line antimalarial drug treatments, adjunctive and supportive care measures (e.g., intravenous fluids, blood transfusions, supplemental oxygen, antiseizure medications) may be needed for severe manifestations. The aims of treatment are to prevent death or long-term deficits from malaria, to cut short the morbidity of an acute episode of illness, and to clear the infection entirely so that it does not recur. Fever, sweating, and chills (or, in some cases, merely fever) triggered by the release of plasmodia into the bloodstream from mature blood schizonts, are the most common symptoms heralding the onset of a clinical case of uncomplicated falciparum malaria (see Chapter 6 for a description of the evolution of clinical symptoms). Without treatment—or an active immune

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Saving Lives, Buying Time: Economics of Malaria Drugs in an Age of Resistance response primed by repeated previous malaria infections—the number of parasites will increase with every 2-day cycle of reproduction. A mature infection may involve up to 1012 circulating plasmodia. At any time after the infection is established, the vast majority of plasmodia will be in some stage of asexual maturation leading to another round of multiplication within the patient’s bloodstream. However, a few parasites will have transformed into sexual stages (gametocytes) that, once ingested by mosquitoes, can perpetuate the transmission cycle. Because each stage of the malarial life cycle exhibits distinct biochemical and other characteristics (i.e., it expresses different proteins or locates in different sites within the body), a drug may kill one stage but have little effect on another. In other words, in each life-cycle stage the parasite manifests unique biological properties that can offer a target for the action of one or more antimalarial drugs. ANTIMALARIAL DRUG CLASSES Currently available antimalarials fall into three broad categories according to their chemical structure and mode of action (Appendix 9-A): Aryl aminoalcohol compounds: quinine, quinidine, chloroquine, amodiaquine, mefloquine, halofantrine, lumefantrine, piperaquine, tafenoquine Antifolate compounds (“antifols”): pyrimethamine, proguanil, chlorproguanil, trimethoprim Artemisinin compounds (artemisinin, dihydroartemisinin, artemether, artesunate) Atovaquone is an antimalarial in its own class with a unique mode of action; combined with proguanil it is sold under the trade name Malarone®. Several antibacterial drugs (e.g., tetracycline, clindamycin) also have antiplasmodial activity, although in general their action is slow for malaria treatment (as opposed to prophylaxis); they are recommended only in combination with other antimalarial drugs. Drugs active against Plasmodium falciparum also are active against the other three malaria species that affect humans—P. vivax, P. malariae, and P. ovale—with the exception of antifols, which work poorly against P. vivax. Current treatment protocols for uncomplicated malaria and severe malaria are given in Tables 9-1 and 9-2.

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Saving Lives, Buying Time: Economics of Malaria Drugs in an Age of Resistance TABLE 9-1 Treatment of Uncomplicated Malariaa Malaria Drug Treatment P. vivax, P. malariae, P. ovale, known chloroquine-sensitive P. falciparuma Chloroquine 10 mg base/kg stat. Followed by: 5 mg/kg at 12, 24 and 36 h; or 10 mg/kg at 24 h, 5 mg/kg at 48 h or Amodiaquine 10 mg base/kg/day for 3 days1 Chloroquine-resistant P. falciparuma known to be sensitive to sulfadoxinepyrimethamine (SP) Pyrimethamine 1.25 mg/kg + sulfadoxine 25 mg/kg (single dose; 3 tablets in an adult) or Amodiaquine 10 mg base/kg/day for 3 days Chloroquine-resistant P. vivaxb and multidrug resistant P. falciparuma   Oral Artesunate 4 mg/kg daily for 3 days + mefloquine 25 mg base/kg (15 mg/kg on day 2, 10 mg/kg on day 3) Artemether-lumefantrine 1.5/9 mg/kg twice daily for 3 days with food Quinine 10 mg salt/kg three times daily plus tetracycline 4 mg/kg four times daily or doxycycline 3 mg/kg once daily or clindamycin 10 mg/kg twice daily for 7 days2 aFor acute treatment of falciparum malaria combinations containing an artemisinin-derivative are preferred. Artesunate (4 mg/kg/day for 3 days) has been combined successfully with chloroquine, amodiaquine, SP, mefloquine, and atovaquone-proguanil. bThis refers to truly resistant P. vivax infections, which are a significant problem only in Oceania and Indonesia and should not be confused with relapses. Amodiaquine is more effective than chloroquine for resistant P. vivax. Basic Properties of Antimalarials: Pharmacokinetics and Pharmacodynamics Pharmacokinetics The interactions of drugs with people who take them—how the compounds are absorbed, metabolized, distributed, and excreted—is referred to as pharmacokinetics. Antimalarial drugs differ considerably in their pharmacokinetics, which affect how well they work, how they are dosed, and how long they must be taken. People also vary in how they respond to drugs. Some of these responses are genetically determined, others by health status, others by dietary factors. In general, the pharmacokinetic properties of the antimalarials are similar in children and adults, although the metabo-

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Saving Lives, Buying Time: Economics of Malaria Drugs in an Age of Resistance General points A. There are now few places in the world where chloroquine can be relied upon for falciparum malaria, and SP resistance is spreading rapidly—so recent information on drug susceptibility is required if these drugs are used. Amodiaquine is more effective than chloroquine against chloroquine-resistant P. falciparum, but highly amodiaquine-resistant parasites are prevalent in East Asia. B. Pregnancy: There are insufficient data on the safety of most antimalarial drugs in pregnancy. Artemisinin and its derivatives should not be given in the first trimester. Halofantrine, primaquine, and tetracycline should not be used at any time in pregnancy. There are theoretical concerns over inducing kernicterus when long-acting sulfonamides are used near term, but no evidence that this is a significant problem in practice. There are uncertainties over the safety of mefloquine in pregnancy. Quinine, chloroquine, proguanil, SP, and clindamycin are regarded as safe in the first trimester. Quinine may cause hypoglycemia, particularly in late pregnancy. C. Vomiting is less likely if the patient’s temperature is lowered before oral drug administration. D. Where possible, artesunate or quinine should be combined with a tetracycline or clindamycin. Short courses for artesunate or quinine (< 7 days) alone are not recommended. E. In renal failure. the dose of quinine should be reduced by one-third to one-half after 48 hours, and doxycycline but not tetracycline should be prescribed. F. The doses of all drugs are unchanged in children: however, several drugs including atovaquone, proguanil and artesunate have significantly altered kinetics in pregnancy. Specific points 1. Patients with P. vivax and P. ovale infections also should be given primaquine 0.25 mg base/kg daily (0.375-0.5 mg base/kg in Oceania) for 14 days to prevent relapse. In mild G6PD deficiency 0.75 mg base/kg should be given once weekly for 6 weeks. In severe G6PD deficiency, primaquine should not be used. 2. None of the tetracyclines should be given to pregnant women or children under 8 years of age. lism of several drugs is altered in pregnancy (e.g., atovaquone, mefloquine, cycloguanil). A key pharmacokinetic property of antimalarials is how long they remain in the body. Artemisinin and its derivatives are absorbed and eliminated the most rapidly (half-life = 1 hour or less). Quinine also is absorbed and eliminated within one parasite life cycle (11 hours in healthy subjects to 18 hours in those with severe malaria). Other antimalarials are eliminated very slowly, remaining in significant concentrations for several days (pyrimethamine, halofantrine, lumefantrine, atovaquone), or even weeks (mefloquine, chloroquine, and piperaquine). In general, rapidly eliminated drugs (artemisinin, and quinine) must be taken over four asexual cycles (7 days) to ensure cure in nonimmune patients. In contrast, drugs that are

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Saving Lives, Buying Time: Economics of Malaria Drugs in an Age of Resistance TABLE 9-2 Treatment of Severe Malaria   Health Clinic:     Hospital Intensive Care Unit (Icu) No Intravenous Infusions Possible Rural Health Clinic: No Injection Facilities Chloroquine-resistant P. falciparum Quinine Quinine dihydrochloride 7 mg salt/kg infused over 30 minutes followed by immediately 10 mg/kg over 4 hours; or 20 mg salt/kg infused over 4 hours. Maintenance dose: 10 mg salt/kg infused over 2-8 hours at 8-hour intervalsa Quinine dihydrochloride 20 mg salt/kg diluted 1:2 with sterile water given by split injection into both anterior thighs. Maintenance dose: 10 mg/kg 8-hourlya     Quindine 10 mg base/kg infused over 1-2 hours followed by 1.2 mg base/kg per hourb Electrocardiographic monitoring advisable    

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Saving Lives, Buying Time: Economics of Malaria Drugs in an Age of Resistance   Artemisinin derivatives Artemether 3.2 mg/kg stat. by i.m. injection followed by 1.6 mg/kg daily: Artesunate 2.4 mg/kg stat. by i.v. injection followed by 1.2 mg/kd daily As for hospital ICU: artesunate can also be given by i.m. injection Artesunate rectocap: 10 mg/kg daily Artemisinin suppository 20 mg/kg at 0 and 4 hrs. then daily Known chloroquine-sensitive P. falciparum Chloroquine 10 mg base/kg infused intravenously at constant rate over 8 hours followed by 15 mg base/kg over 24 hours Chloroquine 3.5 mg base/kg 6-hourly or 2.5 mg base/kg 4-hourly by i.m. or s.c. injection. Total dose 25 mg base/kg 10 mg/kg daily or nasogastric chloroquine as for oral regimen aThe preferred dosage interval for parenteral quinine in African children is 12 hours. bSome authorities recommend a lower dose of 6.2 mg base/kg initially over 1 hour followed by 0.012 mg base/kg per hour. There are insufficient data for confident dosage recommendations. General points A. If in doubt, consider the infection as chloroquine-resistant. There are very few places where chloroquine can now be relied upon. B. Infusions can be given in 0.9% saline, 5% or 10% dextrose/water. C. Infusion rates for the quinoline antimlarials should be carefully controlled. D. Oral treatment should start as soon as patient can swallow reliably enough to complete a full course of treatment.

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Saving Lives, Buying Time: Economics of Malaria Drugs in an Age of Resistance eliminated slowly require fewer doses over shorter periods because they remain active in the body. Halofantrine, lumefantrine, atovaquone and, to a much lesser extent, mefloquine, are hydrophobic and lipophilic (i.e., insoluble in water and capable of dissolving in fat); as a result, their absorption also varies according to the amount of dietary fat consumed. For this reason, blood concentrations of these drugs may vary considerably from one individual to another following the same dose. Pharmacodynamics The way drugs act on their target—in this case, plasmodia—is called pharmacodynamics. The principal effect of antimalarial drugs in uncomplicated malaria is to inhibit parasite multiplication by killing parasites. If an untreated infection progressed at maximum efficiency, with each life cycle, the total body parasite load would increase by a multiplication factor approximating the average number of viable parasites in a mature schizont (18-36) (White, 1997). Proliferation of parasites in nonimmune individuals often proceeds at multiplication rates of 6 to 20 per 2-day cycle (30-80 percent efficiency). Antimalarial drugs exerting maximum effect (Emax), on the other hand, reduce total parasite numbers 10- to 10,000-fold per cycle. Individual antimalarial drugs differ in their Emax (i.e., the proportion of total plasmodia killed per treatment); for example, artemisinins often yield a 10,000-fold reduction per asexual cycle, whereas antimalarial antibiotics such as tetracycline or clindamycin may only achieve a 10-fold parasite reduction per cycle. The lowest blood or plasma concentration of an antimalarial drug that results in Emax can be considered a “minimum parasiticidal concentration” (MPC). Parasite reduction appears to be a first-order process throughout (Day et al., 1996), which means that a fixed fraction of the infecting malaria parasite population is removed with each successive cycle as long as the MPC is exceeded. Clinical Pharmacodynamics Patients with acute malaria may have up to 1012 parasites circulating in their blood. Even with killing rates of 99.99 percent per cycle, complete eradication of the parasite load requires at least three life cycles (6 days); therefore, therapeutic drug concentrations should be present for 4 cycles to effect a cure (White, 1997, 1998). Simply put, patients taking rapidly eliminated drugs must continue treatment for a full week. Treatment responses are always better in patients with some immunity (York and Macfie, 1924) because the immune response kills parasites in much the same way that a

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Saving Lives, Buying Time: Economics of Malaria Drugs in an Age of Resistance drug does. In endemic areas, the worst treatment results are seen in young children who have little immunity. In contrast, although their degree of immune protection cannot be quantitated or assumed, older children or adults in high-transmission areas may do surprisingly well with failing drugs because much of their therapeutic response stems from immunity rather than antimalarial drug action. In severe falciparum malaria, the stage at which an antimalarial drug acts is especially important since the ultimate goal of treatment is to halt parasite maturation to late-stage, cytoadherent parasites (i.e., mature schizonts that attach to endothelial cells lining small blood vessels), which are primarily responsible for life-threatening complications. The artemisinin derivatives are advantageous because they prevent parasites from maturing to these more pathological stages, whereas quinine and quinidine do not affect parasites until they have already cytoadhered. The antifols act even later in the cycle, and are not recommended for severe malaria (Yayon et al., 1983; ter Kuile et al., 1993). None of the drugs will prevent rupture of infected erythrocytes and reinvasion once a schizont has formed. Young ring forms (i.e., early asexual parasites) also are relatively drug resistant, especially to quinine and pyrimethamine. Artemesinin derivatives offer the broadest antimalarial action against the range of developmental stages, and the most rapid in vivo activity (ter Kuile et al., 1993; White, 1997). These compounds (and, to a lesser extent, chloroquine) prevent ring stages from maturing, hastening their clearance, and preventing end-organ pathology that would otherwise occur if cytoadherence progressed unchecked (Chotivanich et al., 2000). MECHANISMS OF ACTION AND DRUG RESISTANCE Antifolate Drugs Pyrimethamine, and biguanides such as cycloguanil interfere with folic acid synthesis, inhibiting the parasite enzyme known as dihydrofolate reductase-thymidilate synthase (DHFR). Sulfonamides act at the previous step in the folic acid pathway, inhibiting the parasite enzyme dihydropteroate synthase (DHPS). There is marked synergy between these two classes of drugs when they are taken together. However, resistance to pyrimethamine in P. falciparum developed within a few years of its introduction (Peters, 1987) due to point mutations in the DHFR gene, which cause 100- to 1,000-fold reduced affinity of the enzyme complex to the drug. Progressive mutations in the DHFR gene of P. falciparum further decreased efficacy. Triple mutant infections are relatively resistant to antifolate treatment; with a fourth mutation within the malaria parasite, antifolate drugs become completely ineffective.

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Saving Lives, Buying Time: Economics of Malaria Drugs in an Age of Resistance Quadruple mutant P. falciparum strains are now prevalent in parts of Southeast Asia, and South America (Imwong et al., 2001). Resistance to partner antifols sulfonamide and sulfone results from progressive acquisition of mutations in the P. falciparum gene encoding the target enzyme DHPS. Chloroquine One of chloroquine’s most dramatic characteristics is its ability to concentrate itself from nanomolar (10-9) levels outside the parasite to levels one million times higher (millimolar levels, 10-3) in the acid food vacuole of the parasite inside a red blood cell (Krogstad and Schlesinger, 1987). This action in itself does not explain chloroquine’s antimalarial activity, however. Chloroquine works by interfering with heme dimerization, the detoxifying biochemical process within the malaria parasite that normally yields malaria pigment (hemozoin). Reduced intracellular drug concentrations accompany chloroquine resistance because resistant parasites expel chloroquine from their acid food vacuoles 40-50 times faster than do drug-sensitive parasites (Bray et al., 1998). Such accumulation deficits were once attributed to changes in pH gradient, or to altered membrane permeability, or both (Le Bras and Durand, 2003). However, chloroquine resistance was then found to be reversible by verapamil, a drug which also modulates resistance in multidrug resistant (MDR) mammalian cancer cells. This discovery led to the identification of the protein Pgh1 (an analog to overexpressed glycoproteins that expel cytotoxic drugs in cancer cells) in the digestive vacuole membrane of P. falciparum. Genes encoding MDR proteins have been identified in P. falciparum (pfmdr1); amplification of these “wild type” MDR genes has recently been shown to cause mefloquine resistance (Price et al., 1999b). Point mutations in the gene encoding a food vacuole transporter protein (pfcrt) have been linked to chloroquine resistance (Durand et al., 2001; Warhurst, 2001) and correlate with reduced in vivo chloroquine efficacy (Djimde et al., 2001). In the presence of pfcrt mutations, mutations in the second transport genes (Pfmdr1) further modulate resistance in vitro although the role of Pfmdr1 mutations in determining in vivo responses to chloroquine treatment is still unclear. Additional unlinked mutations are probably involved in the development of chloroquine resistance, some of which have not yet been discovered. In the laboratory, the efflux mechanism seen in chloroquine-resistant P. falciparum parasites can be inhibited by several unrelated drugs (calcium channel blockers such as verapamil as well as tricyclic antidepressants, phenothiazines, and antihistamines), whereas mefloquine resistance can be

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Saving Lives, Buying Time: Economics of Malaria Drugs in an Age of Resistance reversed by penfluridol (Martin et al., 1987; Oduola et al., 1993). Clinical applications of these findings are few to date, although chloroquine plus high doses of chlorpheniramine (an antihistamine) did show improved efficacy against chloroquine-resistant P. falciparum in Nigerian children (Sowunmi et al., 1997). Whether general use of resistance reversers will be safe and feasible in the future remains an open question (Personal communication, N. White, Mahidol University, March 2004). Other Antimalarial Drugs In general, antimalarial drug resistance to mefloquine, quinine, lumefantrine, and halofantrine is linked, whereas chloroquine, and mefloquine resistance are not. Cross-resistance between antimalarials is related to common aspects of their modes of action as well as their resistance mechanisms. Parasites with high-level chloroquine resistance (present in Southeast Asia), are generally resistant to amodiaquine as well; in residents of Southeast Asia, amodiaquine may thus fail as a back-up treatment (Le Bras and Durand, 2003). The same relationship holds true for halofantrine, and mefloquine. On the other hand, there may be an inverse correlation between chloroquine and mefloquine sensitivity: in Africa, for example, chloroquine-sensitive strains are substantially less sensitive to mefloquine or halofantrine, and vice versa (Oduola et al., 1987; Simon et al., 1988). Atovaquone is a component of Malarone®, a new combination drug (consisting of atovaquone and proguanil) used for treatment and prevention of chloroquine-resistant P. falciparum. Atovaquone interferes with mitochondrial electron transport, and also blocks cellular respiration (Srivastava et al., 1997). High levels of atovaquone resistance result from single-point mutations in a gene encoding cytochrome b found on a small, extrachromosomal DNA-containing element in the parasite (Korsinczky et al., 2000). ARTEMISININS Of the available antimalarials, the artemisinins are effective at killing the broadest range of asexual stages of the parasite, ranging from medium-sized rings to early schizonts; they also produce the most rapid therapeutic responses by accelerating clearance of circulating ring-stage parasites (ter Kuile et al., 1993). Qinghaosu, or artemisinin, is a sesquiterpene lactone peroxide extracted from the leaves of the shrub Artemisia annua (qinghao). Three derivatives are widely used: the oil-soluble methyl ether, artemether (artemotil [arteether] is a closely related compound); the water soluble hemi-succinate derivative, artesunate; and dihydroartemisinin (DHA).

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Saving Lives, Buying Time: Economics of Malaria Drugs in an Age of Resistance Artesunate, artemether, and arteether are all synthesized from DHA, and they are converted back to it within the body. Artemisinin itself is available in a few countries in Asia. It is 5-10 times less active than the derivatives, and it is not metabolized to DHA. Artemisinin is available as capsules of powder, or as suppositories. Artemether is formulated in peanut oil, and arteether in sesame seed oil, for intramuscular injection, and in capsules or tablets for oral use. Artesunate is formulated either as tablets, in a gel enclosed in gelatin for rectal administration (called a rectocap™), or as dry powder of artesunic acid for injection, supplied with an ampoule of 5 percent sodium bicarbonate. The powder is dissolved in the sodium bicarbonate to form sodium artesunate, and then diluted in 5 percent dextrose or normal saline for intravenous or intramuscular injection. Artelinic acid is a water-soluble second-generation compound under long-term development. It has not yet been used in treatment. The majority of clinical data pertain to the most widely used derivative, artesunate. Botanical Properties Artemisinin was first isolated from the stems, leaves, and flowers of Artemisia annua by Chinese scientists (Anonymous, 1982; Klayman et al., 1984), but details of the process were not released. Researchers at the Walter Reed Army Institute of Medical Research (WRAIR) successfully isolated artemisinin derivatives from air-dried parts of plants growing in the wild near Washington, D.C., using petroleum ether extraction (Klayman, 1985). The plant grows easily in temperate areas, and has become naturalized in many countries. It can attain a height of two meters or more, appearing as an erect specimen with a woody stem. Artemisinin accumulates in all parts of A. annua except for the roots (Abdin et al., 2003). Artemisinin content in flowers is 4-5 times higher than in leaves. Plant age correlates with artemisinin yield, presumably due to a progressive increase in leaf yield and artemisinin content with plant growth. In agricultural settings in Asia, artesunate production has varied from 5 kg/hectare to 50 kg/hectare (Personal communication, J-M. Kindermans, Médecins Sans Frontières, February 2004). Mechanism of Action Artemisinin’s chemical structure is unlike any other known antimalarial. It includes an endoperoxide bridge necessary for its antimalarial action (Brossi et al., 1988). Artemisinin treatment of membranes, especially in the presence of heme, causes lipid peroxidation (Scott et al., 1989;

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Saving Lives, Buying Time: Economics of Malaria Drugs in an Age of Resistance Sowunmi A, Oduola AM, Ogundahunsi OA, Falade CO, Gbotosho GO, Salako LA. 1997. Enhanced efficacy of chloroquine-chlorpheniramine combination in acute uncomplicated falciparum malaria in children. Transactions of the Royal Society of Tropical Medicine and Hygiene 91(1):63-67. Srivastava IK, Rottenberg H, Vaidya AB. 1997. Atovaquone, a broad spectrum antiparasitic drug, collapses mitochondrial membrane potential in a malarial parasite. Journal of Biological Chemistry 272(7):3961-3966. Steketee RW, Wirima JJ, Slutsker L, Khoromana CO, Breman JG, Heymann DL. 1996. Objectives and methodology in a study of malaria treatment and prevention in pregnancy in rural Malawi: The Mangochi Malaria Research Project. American Journal of Tropical Medicine and Hygiene 55(1 Suppl):8-16. Stepniewska K, Taylor WRJ, Mayxay M, Smithuis F, Guthmann J-P, Barnes K, Myint H, Price R, Olliaro P, Pukrittayakamee S, Hien TT, Farrar J, Nosten F, Day NPJ, White NJ. In press. The in vivo assessment of antimalarial drug efficacy in falciparum malaria; the duration of follow-up. Antimicrobial Agents and Chemotherapy Sutherland CJ, Alloueche A, Curtis J, Drakeley CJ, Ord R, Durasingh M, Greenwood BM, Pinder M, Warhurst D, Targett GAI. 2002. Gambian children successfully treated with chloroquine can harbor and transmit Plasmodium falciparum gametocytes carrying resistance genes. American Journal of Tropical Medicine and Hygiene 67:578-585. Talisuna AO, Kyosiimire-Lugemwa J, Langi P, Mutabingwa TK, Watkins W, Van Marck E, Egwang T, D’Alessandro U. 2002a. Role of the pfcrt codon 76 mutation as a molecular marker for population-based surveillance of chloroquine (Cq)-resistant Plasmodium falciparum malaria in Ugandan sentinel sites with high Cq resistance. Transactions of the Royal Society of Tropical Medicine and Hygiene 96(5):551-556. Talisuna AO, Langi P, Bakyaita N, Egwang T, Mutabingwa TK, Watkins W, Van Marck E, D’Alessandro U. 2002b. Intensity of malaria transmission, antimalarial-drug use and resistance in Uganda: What is the relationship between these three factors? Transactions of the Royal Society of Tropical Medicine and Hygiene 96(3):310-317. Talisuna AO, Bloland P, D’Alessandro U. 2004. History, dynamics, and public health importance of malaria parasite resistance. Clinical Microbiology Reviews 17:235-254. Targett G, Drakeley C, Jawara M, von Seidlein L, Coleman R, Deen J, Pinder M, Doherty T, Sutherland C, Walraven G, Milligan P. 2001. Artesunate reduces but does not prevent posttreatment transmission of Plasmodium falciparum to Anopheles gambiae. Journal of Infectious Diseases 183(8):1254-1259. Taylor WRJ, White NJ. 2004. Antimalarial drug toxicity: A review. Drug Safety 27(1):25-61. ter Kuile FO, Luxemburger C, Nosten F, Thai KL, Chongsuphajaisiddhi T, White NJ. 1995. Predictors of mefloquine treatment failure: A prospective study of 1590 patients with uncomplicated falciparum malaria. Transactions of the Royal Society of Tropical Medicine and Hygiene 89(6):660-664. ter Kuile F, White NJ, Holloway P, Pasvol G, Krishna S. 1993. Plasmodium falciparum: In vitro studies of the pharmacodynamic properties of drugs used for the treatment of severe malaria. Experimental Parasitology 76(1):85-95. Toovey S, Jamieson A. 2004. Audiotometric changes associated with the treatment of uncomplicated falciparum malaria with co-artemether. Transactions of the Royal Society of Tropical Medicine and Hygiene 98(5):261-267 [discussion 268-269]. Tran TH, Day NP, Nguyen HP, Nguyen TH, Tran TH, Pham PL, Dinh XS, Ly VC, Ha V, Waller D, Peto TE, White NJ. 1996. A controlled trial of artemether or quinine in Vietnamese adults with severe falciparum malaria. New England Journal of Medicine 335(2):76-83.

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Saving Lives, Buying Time: Economics of Malaria Drugs in an Age of Resistance Van Vugt M, Brockman A, Gemperli B, Luxemburger C, Gathmann I, Royce C, Slight T, Looareesuwan S, White NJ, Nosten F. 1998. Randomized comparison of artemether-benflumetol and artesunate-mefloquine in treatment of multidrug-resistant falciparum malaria. Antimicrobial Agents and Chemotherapy 42(1):135-139. Van Vugt M, Ezzet F, Nosten F, Gathmann I, Wilairatana P, Looareesuwan S, White NJ. 1999. No evidence of cardiotoxicity during antimalarial treatment with artemether-lumefantrine. American Journal of Tropical Medicine and Hygiene 61(6):964-967. Van Vugt M, Angus BJ, Price RN, Mann C, Simpson JA, Poletto C, Htoo SE, Looareesuwan S , White NJ, Nosten F. 2000. A case-control auditory evaluation of patients treated with artemisinin derivatives for multidrug-resistant Plasmodium falciparum malaria. American Journal of Tropical Medicine and Hygiene 62(1):65-69. Vieira PP, das Gracas Alecrim M, da Silva LH, Gonzalez-Jimenez I, Zalis MG. 2001. Analysis of the pfcrt K76t mutation in Plasmodium falciparum isolates from the Amazon region of Brazil. Journal of Infectious Diseases 183(12):1832-1833. von Seidlein L, Duraisingh MT, Drakeley CJ, Bailey R, Greenwood BM, Pinder M. 1997. Polymorphism of the pfmdr1 gene and chloroquine resistance in Plasmodium falciparum in the Gambia. Transactions of the Royal Society of Tropical Medicine and Hygiene 91(4):450-453. von Seidlein L, Milligan P, Pinder M, Bojang K, Anyalebechi C, Gosling R, Coleman R, Ude JI, Sadiq A, Duraisingh M, Warhurst D, Alloueche A, Targett G, McAdam K, Greenwood B, Walraven G, Olliaro P, Doherty T. 2000. Efficacy of artesunate plus pyrimethamine-sulphadoxine for uncomplicated malaria in Gambian children: A double-blind, randomised, controlled trial. Lancet 355(9201):352-357. Wang P, Brooks DR, Sims PF, Hyde JE. 1995. A mutation-specific PCR system to detect sequence variation in the dihydropteroate synthetase gene of Plasmodium falciparum. Molecular and Biochemical Parasitology 71(1):115-125. Wang P, Lee CS, Bayoumi R, Djimde A, Doumbo O, Swedberg G, Dao LD, Mshinda H, Tanner M, Watkins WM, Sims PF, Hyde JE. 1997. Resistance to antifolates in Plasmodium falciparum monitored by sequence analysis of dihydropteroate synthetase and dihydrofolate reductase alleles in a large number of field samples of diverse origins. Molecular and Biochemical Parasitology 89(2):161-177. Warhurst DC. 2001. A molecular marker for chloroquine-resistant falciparum malaria. New England Journal of Medicine 344(4):299-302. Watkins WM, Mosobo M. 1993. Treatment of plasmodium falciparum malaria with pyrimethamine-sulfadoxine: Selective pressure for resistance is a function of long elimination half-life. Transactions of the Royal Society of Tropical Medicine and Hygiene 87(1):75-78. Wei N, Sadrzadeh SM. 1994. Enhancement of hemin-induced membrane damage by artemisinin. Biochemical Pharmacology 48(4):737-741. Wellems TE, Walker-Jonah A, Panton LJ. 1991. Genetic mapping of the chloroquine-resistance locus on Plasmodium falciparum chromosome 7. Proceedings of the National Academy of Sciences of the United States of America 88(8):3382-3386. Wernsdorfer WH, Noedl H. 2003. Molecular markers for drug resistance in malaria: Use in treatment, diagnosis and epidemiology. Current Opinion in Infectious Diseases 16(6):553-558. White NJ. 1997. Assessment of the pharmacodynamic properties of antimalarial drugs in vivo. Antimicrobial Agents and Chemotherapy 41(7):1413-1422. White NJ. 1998. Why is it that antimalarial drug treatments do not always work? Annals of Tropical Medicine and Parasitology 92(4):449-458. White NJ. 1999. Delaying antimalarial drug resistance with combination chemotherapy. Parassitologia 41(1-3):301-308.

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Saving Lives, Buying Time: Economics of Malaria Drugs in an Age of Resistance White NJ, Olliaro P. 1998. Artemisinin and derivatives in the treatment of uncomplicated malaria. Medecine Tropicale 58(3 Suppl):54-56. White NJ, Pongtavornpinyo W. 2003. The de novo selection of drug-resistant malaria parasites. Proceedings of the Royal Society of London—Series B: Biological Sciences 270(1514):545-554. WHO. 1996. Assessment of Therapeutic Efficacy of Antimalarial Drugs for Uncomplicated Falciparum Malaria in Areas With Intense Transmission. Geneva: World Health Organization. WHO. 2000. Severe falciparum malaria. Transactions of the Royal Society of Tropical Medicine and Hygiene 94(Suppl 1):S1-S90. WHO. 2001. Presentation at the meeting of the Antimalarial Drug Combination Therapy: Report of a WHO Technical Consultation. Geneva: World Health Organization. WHO. 2003. Assessment and Monitoring of Antimalarial Drug Efficacy for the Treatment of Uncomplicated Falciparum Malaria. Geneva: World Health Organization. WHO/HTM/ RBM/2003.50. WHO/RBM/UNDP/World Bank. 2003. Assessment of the Safety of Artemisinin Compounds in Pregnancy. Report of the two informal consultations convened by WHO in 2002. Geneva: World Health Organization. Wongsrichanalai C, Wimonwattrawatee T, Sookto P, Laoboonchai A, Heppner DG, Kyle DE, Wernsdorfer WH. 1999. In vitro sensitivity of Plasmodium falciparum to artesunate in Thailand. Bulletin of the World Health Organization 77(5):392-398. Wongsrichanalai C, Pickard AL, Wernsdorfer WH, Meshnick SR. 2002. Epidemiology of drug-resistant malaria. The Lancet Infectious Diseases 2(4):209-218. Yayon A, Vande Waa JA, Yayon M, Geary TG, Jensen JB. 1983. Stage-dependent effects of chloroquine on Plasmodium falciparum in vitro. Journal of Protozoology 30(4):642-647. York W, Macfie JWS. 1924. Observations on malaria made during treatment of general paralysis. Transactions of the Royal Society of Tropical Medicine and Hygiene 18(1&2):12-44. Zalis MG, Pang L, Silveira MS, Milhous WK, Wirth DF. 1998. Characterization of Plasmodium falciparum isolated from the Amazon region of Brazil: Evidence for quinine resistance. American Journal of Tropical Medicine and Hygiene 58(5):630-637.

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Saving Lives, Buying Time: Economics of Malaria Drugs in an Age of Resistance APPENDIX 9-A Descriptions of Specific Antimalarial Drugs1 QUININE, first isolated from cinchona bark in 1820, remains a fundamental tool for treating malaria, especially severe disease. Quinine acts rapidly, targeting the bloodborne asexual stages of all malaria species. It is available in oral and injectable preparations and can be used in infants and pregnant women. Side effects—nausea, mood change, blurred vision, and ringing in the ears—are common but typically resolve after treatment ends. Since P. falciparum parasites from most areas of the world respond well to quinine, short courses of the drug are often sufficient when paired with a second drug. In Southeast Asia, however, full course quinine treatment is necessary, usually given in combination with a second drug such as tetracycline. CHLOROQUINE is a 4-aminoquinoline derivative of quinine first synthesized in 1934. It is safe in infants and pregnant women, and was the historical drug of choice for treatment of nonsevere or uncomplicated malaria and to prevent malaria in travelers. Chloroquine acts primarily against bloodborne asexual stages, although it also works against the bloodstream stage infective to mosquitoes. Because of widespread resistance to this drug, its usefulness is increasingly limited. Side effects are uncommon and generally mild. AMODIAQUINE, which is closely related to chloroquine, fell out of favor because it caused adverse effects on bone marrow and liver when used for prophylaxis. Amodiaquine is currently being reevaluated as a co-formulation partner with artesunate. Concerns over toxicity remain. ANTIFOL COMBINATION DRUGS include various combinations of dihydrofolate reductase inhibitors (proguanil, chlorproguanil, pyrimethamine, and trimethoprim) and sulfa drugs (dapsone, sulfalene, sulfamethoxazole, sulfadoxine, and others). The partner drugs in antifol combinations have similar mechanisms of action; consequently, they do not protect each other from resistance to the same degree as unrelated drugs. Current combinations include sulfadoxine-pyrimethamine (SP; Fansidar), sulfalene/pyrimethamine (Metakelfin), and sulfamethoxazole/trimethoprim (cotrimoxazole). Proguanil has also been used in combination with chloroquine for prophylaxis in areas of moderate chloroquine resistance, although it confers only minimal added benefit, especially with prolonged exposure 1   Adapted from Bloland and Williams (2003).

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Saving Lives, Buying Time: Economics of Malaria Drugs in an Age of Resistance (Steffen et al., 1993). When used for prophylaxis, Fansidar can produce severe allergic reactions: in American travelers, Fansidar was linked to severe skin reactions (1 per 5,000 to 8,000 users) and mortality (1 per 11,000 to 25,000 users) (Miller et al., 1986). These adverse outcomes are not as frequent when a single dose of Fansidar is used for treatment. Concerns about sulfa drug use during pregnancy are outweighed by the known risks to mother and fetus of untreated malaria. The latest antifol combination is chlorproguanil and dapsone, also known as Lapdap. This particular combination is inherently more effective than Fansidar (even in areas where resistance is present) and has a far shorter elimination time, which may decrease the likelihood of resistance (Watkins et al., 1997; Mutabingwa et al., 2001). On the other hand, its shorter half-life requires that Lapdap be given over 3 days rather than as SP’s one single dose. TETRACYCLINE and derivatives such as doxycycline may be paired with other drugs for treatment or used as single agents for prophylaxis. In areas where quinine efficacy is diminished, tetracyclines are often added to quinine to improve cure rates. Tetracyclines are also used with shortened courses of quinine to decrease quinine-associated side effects. Tetracyclines are contraindicated in pregnant or breastfeeding women, or in children under age 8. Common side effects include nausea, vomiting, diarrhea, secondary yeast infections, and photosensitivity. PRIMAQUINE, an 8-aminoquinoline, acts against malaria parasites in the liver, thereby reducing the likelihood of P. vivax or P. ovale relapse. Primaquine is also reasonably efficacious (74% efficacy against P. falciparum; 90 percent efficacy against P. vivax) when used for prophylaxis (Baird et al., 1995). Although it also has activity against blood-stage asexual parasites, drug concentrations that kill fully mature blood parasites are toxic. Primaquine is also a potent gametocidal drug, i.e., it kills the sexual stage of the malaria parasite infective to mosquitoes. Primaquine can produce severe and potentially fatal hemolytic anemia in people with glucose-6-phosphate dehydrogenase (G6PD) enzyme deficiencies. The most severe Mediterranean B variant and related Asian variants of G6PD deficiency occur at high rates among several groups and regions: Kurdish Jews (62 percent), Saudia Arabia (13 percent), Burma (20 percent), and southern China (6 percent) and have now spread through migration and intermarriage. Primaquine should not be used in pregnancy. TAFENOQUINE, a synthetic analog of primaquine, is currently being tested. It is highly effective against both liver and blood stages of malaria. Because of its long half-life (14 days versus 6 hours for primaquine),

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Saving Lives, Buying Time: Economics of Malaria Drugs in an Age of Resistance tafenoquine may prove to be a valuable chemoprophylactic drug (Lell et al., 2000). As with primaquine, tafenoquine can produce acute hemolytic anemia in patients with G6PD deficiency. MEFLOQUINE is a quinoline-methanol derivative of quinine that can be used for treatment or prevention in most areas with multidrug resistant malaria. Resistance to mefloquine occurs frequently in parts of Southeast Asia, however, and sporadic resistance has been reported in areas of Africa and South America. Mefloquine causes a relatively high incidence of neuropsychiatric side effects when used at treatment doses and to a lesser degree when used for prophylaxis. In one large study in Asia, mefloquine was associated with stillbirth when given in pregnancy (Nosten et al., 1999). HALOFANTRINE is a phenanthrene-methanol compound with activity against the bloodborne stages of the malaria parasite. It is especially useful in areas where multidrug-resistant falciparum malaria is present. Cardiac conduction abnormalities (specifically, prolongation of the PR and QT intervals on a standard electrocardiogram) are halofantrine’s major drawback (Nosten et al., 1993). Taking halofantrine immediately following mefloquine or quinine therapy also increases the risk of cardiac complications. Halofantrine and mefloquine may exhibit clinical cross-resistance (Wongsrichanalai et al., 1992; ter Kuile et al., 1993). CLINDAMYCIN is an antibiotic with weak antimalarial activity. It should only be used in combination with a fast-acting schizonticide, such as quinine, especially when treating patients with little or no immunity to malaria (Pukrittayakamee et al., 2000b; Parola et al., 2001). Clindamycin is considered safe for use in pregnant women and very young children (Pukrittayakamee et al., 2000a). ARTEMISININ COMPOUNDS include the compounds artesunate, artemether, arteether, and dihydroartemisinin derived from the sesquiterpene lactone principle (artemisinin) of the plant Artemisia annua. In severe malaria, artemisinin compounds produce faster parasite clearance and resolution of fever than quinine. Artemisinins also reverse coma more quickly than quinine (Taylor et al., 1993; Salako et al., 1994). However, used alone for periods under 5 to 7 days, recrudescence rates are high. For nonsevere malaria, artemisinins are most successful when used in combination with a second drug (Nosten et al., 1994). The best documented combination is mefloquine plus 3 days of artesunate. The safety of artemisinins in early pregnancy is of particular concern since the drugs have produced fetal resorption in experimental animals. Despite reassuring clinical data on over 600 carefully followed pregnancies

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Saving Lives, Buying Time: Economics of Malaria Drugs in an Age of Resistance treated with artemisinins in the second and third trimesters of pregnancy, there are unresolved concerns about their effects in early human gestation. A fixed-dose preparation of lumefantrine and artemether is commercially sold under the trade name of Coartem or Riamet. Lumefantrine (previously known as benflumetol) is an aryl-amino alcohol antimalarial compound. Although chemically related, lumefantrine does not appear to have the same cardiac effects as halofantrine (van Vugt et al., 1999). Coartem is marketed in two packages: a six-dose (24-tablet) package intended for nonimmune patients and a four-dose (16-tablet) package for use by semi-immune patients. Until studies show conclusive efficacy of the four-dose regimen in semi-immune populations, all patients should receive the six-dose regimen (van Vugt et al., 2000). Until further safety data become available, lumefantrine is not recommended for treatment of pregnant women. ATOVAQUONE PLUS PROGUANIL (MALARONE) is a fixed-dose combination containing 250 mg of atovaquone (a hydroxynaphthoquinone) and 100 mg of proguanil in a single adult-sized pill taken daily for prophylaxis. An adult treatment course of Malarone is 1,000 mg of atovaquone and 400 mg of proguanil daily for 3 days. Malarone has also been combined with artesunate for treatment of uncomplicated multidrug-resistant falciparum malaria (van Vugt et al., 2002). Malarone is also thought to be effective against bloodborne forms of P. vivax (Looareesuwan et al., 1996a). PYRONARIDINE has been used in China for over 20 years. While it was reportedly 100 percent effective in a single trial in Cameroon, the drug was only 63 to 88 percent effective in Thailand (Ringwald et al., 1996; Looareesuwan et al., 1996b). Further testing is required before pyronaridine can be recommended for widespread use. PIPERAQUINE is an orally active bisquinoline discovered in the early 1960s and developed for clinical use in China in 1973. In vitro testing in several laboratories has shown that piperaquine approximates chloroquine’s effects against sensitive parasites and is significantly more effective than chloroquine in treating resistant P. falciparum. In China, Vietnam and Cambodia, piperaquine is now available as a fixed combination with dihydroartemisinin (it has also been combined with trimethoprim and primaquine). Prospective clinical trial data are pending.

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Saving Lives, Buying Time: Economics of Malaria Drugs in an Age of Resistance Appendix 9-A References Baird JK, Fryauff DJ, Basri H, Bangs MJ, Subianto B, Wiady I, Purnomo, Leksana B, Masbar S, Richie TL, Jones TR, Tjitra E, Wignall FS, Hoffman SL. 1995. Primaquine for prophylaxis against malaria among nonimmune transmigrants in Irian Jaya, Indonesia. American Journal of Tropical Medicine and Hygiene 52(6):479-484. Bloland PB, Williams H. 2002. Malaria Control During Mass Population Movements and Disasters. Committee on Population. National Research Council of the National Academies, Roundtable on the Demography of Forced Migration. Washington, DC: The National Academies Press. Bloland PB, Ettling M, Meek S. 2000. Combination therapy for malaria in Africa: Hype or hope? Bulletin of the World Health Organization 78:1378-1388. Doherty JF, Sadiq AD, Bayo L, Alloueche A, Olliaro P, Milligan P, von Seidlin L, Pinder M. 1999. A randomized safety and efficacy trial of artesunate plus sulfadoxine-pyrimethamine vs. sulfadoxine-pyrimethamine alone for the treatment of uncomplicated malaria in Gambian children. Transactions of the Royal Society of Tropical Medicine and Hygiene 93(5):543-546. Greenberg AE, Ntumbanzondo M, Ntula N, Mawa L, Howell J, Davachi F. 1989. Hospital-based surveillance of malaria-related paediatric morbidity and mortality in Kinshasa, Zaire. Bulletin of the World Health Organization 67:189-196. Greenwood BM. 1987. Asymptomatic malaria infections. Do they matter? Parasitology Today 3:206-214. Kachur SP, Abdulla S, Barnes K, Mshinda H, Durrheim D, Kitua A, Bloland P. 2001. Letter to the editors. Tropical Medicine and International Health 6:324-325. Kazadi WM, Vong S, Makina BN, Mantshumba JC, Kabuya W, Kebela BI, Ngimbi NP. 2003. Assessing the Efficacy of chloroquine and sulfadoxine-pyrimethamine for treatment of uncomplicated Plasmodium falciparum malaria in the Democratic Republic of Congo. Tropical Medicine and International Health 8(10):868-75. Lell G, Faucher J-F, Missinou MN, Bormann S, Dangelmaier O, Horton J, Kremsner PG. 2000. Malaria chemoprophylaxis with tafenoquine: A randomized study. Lancet 255:2041-2045. Looareesuwan S, Viravan C, Webster HK, Kyle DE, Hutchinson DB, Canfield CJ. 1996a. Clinical studies of atovaquone, alone or in combination with other antimalarial drugs for the treatment of acute uncomplicated malaria in Thailand. American Journal of Tropical Medicine and Hygiene 54(1):62-66. Looareesuwan S, Olliaro P, Kyle D, Werndorfer W. 1996b. Pyronaridine. Lancet 347:1189-1190. Miller KD, Lobl HO, Satrial RF, Kuritsky JN, Stern R, Campbell CC. 1986. Severe cutaneous reactions among American travelers using pyrimethamine-sulfadoxine (fansidar) for malaria prophylaxis. American Journal of Tropical Medicine and Hygiene 35:451-458. Molyneux ME, Taylor TE, Wirima JJ, Borgstein J. 1989. Clinical features and prognostic indicators in paediatric cerebral malaria: A study of 131 comatose Malawian children. Quarterly Journal of Medicine 71:441-459. Mutabingwa T, Nzila A, Mberu E, Nduati E, Winstanley P, Hills E, Watkins W. 2001. Chlorproguanil-dapsone for treatment of drug-resistant malaria in Tanzania. Lancet 358:1218-1223. Nosten F, ter Kuile FO, Luxemburger D, Woodrow C, Kyle DE, Chongsuphajaisiddhi T, White NJ. 1993. Cardiac effects of antimalarial treatment with haolfantrine. Lancet 341 (8852):1054-1056. Nosten F, Luxemburger C, ter Kuile FO, Woodrow C, Eh JP, White NJ. 1994. Treatment of multidrug-resistant Plasmodium falciparum malaria with 3-day artesunate-mefloquine combination. Journal of Infectious Diseases 170:971-977.

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Saving Lives, Buying Time: Economics of Malaria Drugs in an Age of Resistance Nosten F, Vincenti M, Simpson J, Yei P, Kyaw Lay Thwai, De Vries A, Chongsuphajaisiddhi T, White NJ. 1999. The effects of mefloquine treatment in pregnancy. Clinical Infectious Diseases 28(4):808-815. Nosten F, van Vugt M, Price R, Luxemburger C, Thway KI, Brockman A, McGready R, ter Kuile F, Loosareesuwan S, White NJ. 2000. Effects of artesunate-mefloquine combination on incidence of Plasmodium falciparum malaria in western Thailand: A prospective study. Lancet 356(9226):297-302. Parola P, Ranque S, Badiaga S, Niang M, Blin O, Charbit JJ, Delmont J, Brousqui P. 2001. Controlled trial of 3-day quinine-clindamycin treatment versus 7-day quinine treatment for adult travelers with uncomplicated falciparum malaria imported from the tropics. Antimicrobial Agents and Chemotherapy 45:932-935. Price RN, Nosten F, Luxemburger C, van Vugt M, Phaipun I, Chongasuphajaisiddi T, White NJ. 1997. Artesunate/mefloquine treatment of multi-drug resistant falciparum malaria. Transactions of the Royal Society of Tropical Medicine and Hygiene 91:574-577. Pukrittyakamee S, Chantra A, Simpson JA, Vanijanonta S, Clemens R, Loosareesuwan S, White NJ. 2000a. Therapeutic responses to different antimalarial drugs in vivax malaria. Antimicrobial Agents and Chemotherapy 44:1680-1685. Pukrittayakamee S, Chantra A, Vanijanonta S, Clemens R, Loosareesuwan S, White NJ. 2000b. Therapeutic responses to quinine and clindamycin in multidrug-resistant falciparum malaria. Antimicrobial Agents and Chemotherapy 44:2395-2398. Radloff PD, Phillipps J, Nkeyi M, Hutchinson D, Kremsner PG. 1996. Atovaquone and proguanil for Plasmodium falciparum malaria. Lancet 347:1511-1513. Ringwald P, Bickii J, Basco L. 1996. Randomised trial of pyronaridine versus chloroquine for acute uncomplicated falciparum malaria in Africa. Lancet 347:24-27. Salako LA, Walker O, Sowunmi A, Omokhodion SJ, Adio R, Oduola AM. 1994. Artemether in moderately severe and cerebral malaria in Nigerian children. Transactions of the Royal Society of Tropical Medicine and Hygiene 88(Suppl 1):S13-S15. Steffen R, Fuchs E, Schildknecht J, Naef U, Funk M, Schlagenhauf P, Phillips-Howard P, Nevill C, Stürchler D. 1993. Mefloquine compared with other malaria chemoprophylactic regimens in tourists visiting East Africa. Lancet 341:1299-1303. Talisuna AO, Bloland P, D’Alessandro U. 2004. History, dynamics, and public health importance of malaria parasite resistance. Clinical Microbiology Reviews 17:235-254. Taylor TE, Wills BA, Kazembe P, Chisale M, Wirima JJ, Ratsma EY, Molyneux ME. 1993. Rapid coma resolution with artemether in Malawian children with cerebral malaria. Lancet 341(8846):661-662. Ter Kuile FO, Dolan G, Nosten F, Edstein MD, Luxemburger C, Phaipun L, Chongsuphajaisiddhi T, Webster HK, White NJ. 1993. Halofantrine versus mefloquine in treatment of multidrug-resistant falciparum malaria. Lancet 341(8852):1044-1049. Van Hensbroek MB, Morris-Jones S, Meisner S, Jaffar S, Bayo L, Dackour R, Phillips C, Greenwood BM. 1995. Iron, but not folic acid, combined with effective antimalarial therapy promotes haematological recovery in African children after acute falciparum malaria. Transactions of the Royal Society of Tropical Medicine and Hygiene 89(6):672-676. van Vugt M, Ezzet F, Nosten F, Gathmann I, Wilairatana P, Looareesuwan S, White NJ. 1999. No evidence of cardiotoxicity during antimalarial treatment with artemether-lumefantrine. American Journal of Tropical Medicine and Hygiene 61(6):964-967. van Vugt M, Angus BJ, Price RN, Mann C, Simpson JA, Poletto C, Htoo SE, Looareesuwan S, White NJ, Nosten F. 2000. A case-control auditory evaluation of patients treated with artemisinin derivatives for multidrug-resistant Plasmodium falciparum malaria. American Journal of Tropical Medicine and Hygiene 62(1):65-69.

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Saving Lives, Buying Time: Economics of Malaria Drugs in an Age of Resistance van Vugt M, Leonardi E, Phaipun L, Slight T, Thway KL, McGready R, Brockman A, Villegas L, Looareesuwan S, White NJ, Nosten F. 2002. Treatment of uncomplicated multidrug-resistant falciparum malaria with artesunate-atovaquone-proguanil. Clinical Infectious Diseases 35:1498-1504. Von Seidlen L, Milligan P, Pinder M, Bojang K, Anyalebeschi C, Gosling R, Coleman R, Ude JL, Sadiq A, Duraisingh M, Warhurst D, Alloueche A, Targett G, McAdam K, Greenwood B, Walraven G, Olliaro P, Doherty T. 2000. Efficacy of artesunate plus pyrimethamine-sulphadoxine for uncomplicated malaria in Gambian children: A double-blind, randomized controlled trial. Lancet 355(9220):352-357. Watkins WM, Mberu EK, Winstanley PA, Plowe CV. 1997. The efficacy of antifolate antimalarial combinations in Africa: A predictive model based on pharmacodynamic and pharmacokinetic analyses. Parasitology Today 13:459-464. White N. 1999. Antimalarial drug resistance and mortality in falciparum malaria. Tropical Medicine and International Health 4:469-470. WHO. 2003. Assessment and monitoring of antimalarial drug efficacy for the treatment of uncomplicated falciparum malaria Geneva: World Health Organization. WHO/HTM/ RBM/2003.50. Wongsrichanalai C, Webster HK, Wimonwattrawatee T, Sookto P, Chuanak N, Thimasarn K, Wernsdorfer WH. 1992. Emergence of multidrug-resistant Plasmodium falciparum in Thailand: In vitro tracking. American Journal of Tropical Medicine and Hygiene 47(1):112-116.

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