Annu. Rev. Med. 1999. 50:17992Copyright 1999 by Annual Reviews. All rights reservedMALARIA: New Developments inTreatment and PreventionPaul Newton, BM, DPhil, MRCP andNicholas White, DSc, MD, FRCPFaculty of Tropical Medicine, Mahidol University, 420/6 Rajvithi Road, Bangkok10400, Thailand; e-mail: fnnjw@diamond.mahidol.ac.thKEY WORDS: Plasmodium, falciparum, therapy, prophylaxisABSTRACTMalaria still kills some 0.52.5 million people per year in the tropics. Resis-tancetothecheap,mostcommonlyusedantimalarialscontinuestospreadalarminglyandcouldoutpacedrugdevelopment. Theartemisininderiva-tives have had an important clinical impact both on the treatment of resistantfalciparummalariaandontheincidenceofdiseaseinlow-transmissionar-eas. A few promising new antimalarials are being tested clinically but thereis an imperative need for cheap, well-tolerated drugs that can be used in shortcourses, and for strategies to delay the onset of drug resistance. Bed nets havebeen shown to reduce the incidence of severe malaria in many areas but aneffective vaccine is urgently needed.INTRODUCTIONAfterhedescribedthelifecycleofthemalariaparasite102yearsago,Rosswrote a poem in which he described malaria as the million-murdering Death(1). It remainsso, affecting200millionpeopleat anyonetimeandkillingsome 0.52.5 million people each year (1a). Malaria is transmitted by the in-oculation of sporozoites during the bite of a female anopheline mosquito. Theparasites invade and develop within hepatocytes, which later burst, releasingthousandsofmerozoites. Thesequicklyinvadeerythrocytesandgrowfromrings to trophozoites and then schizonts before themselves bursting, releasingmerozoitesthatinvadefurthererythrocytes. Theinfectionexpandsapproxi-matelytenfoldperasexualcycle. Someintra-erythrocyticparasitesdevelopinto gametocytes that are taken up by the mosquito vector, in which they un-0066-4219/99/0201-0179$08.00179Annu. Rev. Med. 1999.50:179-192. Downloaded from arjournals.annualreviews.orgby INFLIBNET Master on 04/18/09. For personal use only.dergo sexual multiplication and then transmit the infection to another humanhost.Ofthefourhumanmalariaparasites,Plasmodiumfalciparumistheover-whelming cause of serious disease and death. It is characterized by the seques-tration of erythrocytes that are parasitized by trophozoites and schizonts in themicrovasculatureofvitalorgans. Infectionwiththeotherspeciesofhumanmalariaparasite, P. vivax, P. malariae, andP. ovale, althoughrarelyfatal,causes considerable morbidity.The failure of mosquito eradication programs, the evolution of drug resis-tance outpacing antimalarial development, and continued overwhelming pov-erty have combined to create a severe and intractable problem.EPIDEMIOLOGY OF DRUG RESISTANCEWorldmapsthatdepictcountriesashavingornothavingdrug-resistantma-laria are potentially misleading, as there is great heterogeneity within countriesand across political boundaries. Local knowledge is of paramount importance.Chloroquine-resistant strains of P. falciparum are prevalent in most of themalarious world. They evolved independently nearly 40 years ago in southeastAsiaandSouthAmerica, inpartbecauseoftheselectivepressurefromthewidespread distribution of chloroquine-medicated salt (2, 3). Falciparum ma-lariaparasitesremainfullysensitivetochloroquineonlyinCentralAmericanorth of the Panama Canal, in Haiti and Egypt, and in scattered parts of AsiaandSouthAmerica(4). ChloroquinehasbeenreplacedbyFansidar(pyri-methamine andsulfadoxine) as first-line therapyinKenya, Malawi, Bot-swana, and South Africa (4). There is some evidence that chloroquine sensitiv-ity may have increased slightly as its use has declined in China and Thailand(5). Despitethehighprevalenceofchloroquine-resistant P. falciparuminsub-Saharan Africa, chloroquine is still a useful drug in areas with low-graderesistanceasitischeap,easilyavailable,andmayremainlifesavingforthesemi-immunechildwithseveremalaria. Eveninsoutheast Asiatherearepockets where chloroquine remains effective, such as in Laos, the Philippines,and Malaysia.P. falciparumparasitesresistant tomefloquineandpartiallyresistant toquinine are prevalent in Thailand, Myanmar, and Cambodia (6, 7). Some WestAfricanstrainsareintrinsicallyresistanttomefloquine. Resistancebetweenquinolineantimalarialsislinkedwithcross-resistancebetweenmefloquine,quinine,lumefantrine,andhalofantrine.Surprisingly,thereappearstobeaninverserelationshipbetweenmefloquineandchloroquineresistance.Meflo-quine and quinine resistance may have driven each other in Thailand (8).Fansidarresistance developed rapidly in southeast Asia and South Amer-ica and, like chloroquine, may have been fuelled initially by the distribution ofpyrimethamine-medicated salt. Resistance to Fansidaris not yet considered a180 NEWTON & WHITEAnnu. Rev. Med. 1999.50:179-192. Downloaded from arjournals.annualreviews.orgby INFLIBNET Master on 04/18/09. For personal use only.clinical problem in India (although there are few data from this enormous at-risk population) but is likely to become one soon in sub-Saharan Africa. Thereis alreadyincreasingresistanceinMalawi, Zaire, Tanzania, SouthAfrica,Kenya, and Nigeria (4, 7). Fortunately, significant resistance to the artemisininderivatives and the antimalarial antibiotics has not yet been recorded. Chloro-quine-resistant strains of P. vivax have recently been reported fromPapua NewGuinea, Sumatra, Irian Jaya, Burma, Vanuatu, and India (4, 9), but clinicallyimportant drug resistance in P. ovale and P. malariae has not been described.Human falciparum malaria infections are often polyclonal, and drug resis-tance arises through the selection of spontaneous mutations with reduced drugsensitivity.Drug-resistantparasitesaremorelikelytobeselectedifparasitepopulationsareexposedtosub-therapeuticdrugconcentrationsthrough(a)blanketdruguse, suchasinmedicatedsalt; (b)theuseoflonghalf-lifedrugs,suchaschloroquine(half-life12months),mefloquine(23weeks),sulfadoxine (1 week), and pyrimethamine (3 days); and (c) use of inadequatetreatment regimens (10).Remarkably, the incidence of falciparummalaria has declined in some partsof southeast Asia, such as southern Vietnam and the western border of Thai-land. This is thought to result from the gametocytocidal action of artemisininderivatives interrupting transmission (11).CURRENT DRUG THERAPY AND MECHANISMS OFRESISTANCEThe drugs currently used to treat malaria are the aryl aminoalcohols, folate an-tagonists, antibiotics, and the new artemisinin derivatives (1a, 12). Assumingno access difficulties, the best choice will depend on the patients level of im-munity, the drugs side effect profile and cost, and the site where the infectionwas acquired (i.e. likely pattern of resistance).The 4-AminoquinolinesDespite significant resistance, chloroquine remains the first-line antimalarialdruginmuchofsub-SaharanAfrica,theMiddleEast,andpartsofAsiaandSouth America. The quinolines and related compounds kill malaria parasitesby inhibiting the polymerization of heme, which is toxic to the parasite (13).Thisinhibitionisnonenzymatic. Mechanismsofresistancetothequinolineantimalarials are incompletely understood. Chloroquine resistance is linked topolymorphisms in genes encoding the membrane proteins cg1 and cg2 (3), andthe drug fails to accumulate in the parasites food vacuole because of increasedefflux and reduced influx (8). In vivo, this efflux can be reversed by a diversearray of compounds including calcium-channel blockers, tricyclic antidepres-sants, antihistamines, and phenothiazines.MALARIA TREATMENT AND PREVENTION 181Annu. Rev. Med. 1999.50:179-192. Downloaded from arjournals.annualreviews.orgby INFLIBNET Master on 04/18/09. For personal use only.Becausechloroquineischeapandreadilyavailable,strategieshavebeendevised to try to continue using it in low-grade resistance areas. Examples in-cludeco-administrationwiththeantibioticclindamycin(14) andwiththeresistance-reversing antihistamines chlorpheniramine (15) or promethazine.Althoughthereis somecross-resistancewithchloroquine, amodiaquineismore active than chloroquine against moderately resistant P. falciparum para-sites and is used in some African countries and in Oceania.Quinine and QuinidineIntravenous or intramuscular quinine remains the first-line drug for severe ma-laria. When given intravenously it must be by careful, rate-controlled infusion,neverbyinjection, andit shouldbesupplementedorallywithtetracycline,clindamycin,orFansidarwhenthepatientrecovers(16).Oralquininemayalso be combined with an antibiotic to treat uncomplicated malaria in areas ofmulti-drug resistance (4, 17). However, there is poor compliance with oral qui-ninebecauseofitsbittertasteandconsistent adverseeffects(cinchonism),comprising nausea, dysphoria, tinnitus, and high-tone deafness. The main dan-gerousadverseeffectofquinineishypoglycemia,especiallyinchildrenandpregnant women. Quinimax, a combination of four cinchona alkaloids includ-ing quinine, can be substituted. Quinidine, the stereoisomer of quinine, is usedin the United States; it has greater efficacy but also greater toxicity (4).MefloquineMefloquineisstructurallyrelatedtoquinineandisusedbothinprophylaxisandoral treatment of uncomplicatedmalaria. Itslongterminal half-lifeof1421 days probably contributed to the rapid evolution and spread of meflo-quineresistanceinsoutheast Asia. However, thecombinationofartesunateand mefloquine in Thailand has slowed the further development of mefloquineresistance (11). Mefloquine resistance is associated with amplification of themulti-drug resistance (mdr) genes that encode for Plasmodium P-glycoproteinpumps, which reduce drug concentrations within the parasites.There has been considerable controversy over the true incidence of neuro-psychiatric side effects of mefloquine used for both treatment and prophylaxis(seebelow). Thefrequencyofthesesideeffectsrangesbetween1:200and1:1200whenmefloquineisusedinthetreatmentofuncomplicatedmalaria,butrisesto1:20followingseveremalaria(4,18).Mefloquineshouldnotbeused in patients with severe malaria, in those who have had mefloquine in theprevioustwomonths,inthefirsttrimesterofpregnancy,orinpatientswithpre-existing neurological or psychiatric disease (4, 18, 19). The incidence ofothercommonsideeffects,suchasvomiting,anorexia,anddizziness,isre-duced if the dose is split (19).182 NEWTON & WHITEAnnu. Rev. Med. 1999.50:179-192. Downloaded from arjournals.annualreviews.orgby INFLIBNET Master on 04/18/09. For personal use only.HalofantrineHalofantrine, a structural relative of mefloquine, is better tolerated and alsoeffectiveinthetreatmentofchloroquine-resistantfalciparummalaria.How-ever, the development of cross-resistance with mefloquine and the finding ofan association with sudden death, probably linked to prolongation of the elec-trocardiographic QTc interval (7, 20), have raised doubts about the safety andutility of halofantrine.Antifolate DrugsPyrimethamine, a dihydrofolate reductase (DHFR) inhibitor, is used in syner-gistic combination with the dihydropteroate synthase inhibitor sulfadoxine asFansidaror with sulfalene as Metakelphin. Proguanil, a pro-drug metabo-lized to the antimalarial DHFR inhibitor cycloguanil, is used only in combi-nationwithchloroquineoratovaquone.Geneticpolymorphismsinthecyto-chrome P450 (2C19) mixed-function oxidases mean that about 20% of Orien-tals and 3%of Caucasians or Africans do not convert proguanil to cycloguanil.However, proguanil itself has some in vitro antimalarial action (probably unre-latedtoDHFRinhibition), andit issynergisticincombinationwithatova-quone.Unlikeresistancetothequinolineantimalarials,resistancetotheDHFRinhibitorsanddihydropteroatesynthaseinhibitorsariseswhensinglepointmutationsoccurinthegenesencodingtheseparasiteenzymes.Henceresis-tance develops very quickly when the drugs are used alone.Artemisinin and DerivativesArtemisininanditsderivativesaresesquiterpenelactoneperoxidesderivedfrom the leaves of wormwood (Artemisia annua L.). Developed in China, theyare used increasingly in Asia and Africa but are not licensed for use in NorthAmericaor Europe. Theykill all stagesof themalariaparasite, includingyoung rings, by interacting with heme to produce carbon-centered free radi-cals that alkylate protein and damage the parasites microorganelles and mem-branes (21).To prevent the high recrudescence rates that result when artemisinin or oneof its derivatives is used alone, and to combat the development of resistance,they should always be combined with another unrelated antimalarial, such asmefloquineordoxycycline(21, 22). Artesunateiswater-solubleandisdis-pensedforintravenous,intramuscular,oral(tablet),orrectaladministration.Artemether and arteether are oil-soluble and available in tablet, capsule, or in-tramuscular injection form (21).Several trialsinvolving >1500adultsandchildrenhavecomparedintra-muscular artemether with intramuscular quinine in the treatment of severe ma-MALARIA TREATMENT AND PREVENTION 183Annu. Rev. Med. 1999.50:179-192. Downloaded from arjournals.annualreviews.orgby INFLIBNET Master on 04/18/09. For personal use only.laria(20). Artemethergavefasterparasiteclearancebut unexpectedlypro-longed coma recovery. There was no significant mortality benefit. Equivalentstudies have not been conducted with artesunate. In comparison with quinine,artemisinin derivatives also have the advantages of once-daily administration,absence of cinchonismor local toxicity, and significantly reduced incidence ofhypoglycemia. Rectaladministrationofartemisinin, artemether, andartesu-nate enables effective treatment of severe malaria before hospitalization in therural tropics.The large clinical trials with these drugs have been notable for the absenceof serious side effects. However, the experimental administration of intramus-culararteetherorartemethertorodents, dogs, andnonhumanprimateshasdemonstratedanunusualandselectiveinjurytocertainbrain-stemnuclei,particularlythoseinvolvedinauditorylocalization. Thedosesthat causednervoussystemdamagewerehigherthanthoseusedclinically(23),andtheclinical significance of these findings remains uncertain. There have been noreportsofneurotoxicityinhumansdespitethetreatmentofovertwomillionpatients.AntibioticsOral tetracycline and doxycycline probably act by damaging P. falciparummi-tochondria(24).Theyactslowlyandshouldalwaysbeusedincombinationwith another antimalarial, such as in a 7-day course to supplement the faster-acting drugs quinine and artesunate (17). Tetracyclines should not be used inchildrenor pregnant women, but clindamycinissafe(14). Oral fluoroqui-nolones are not effective clinically (4, 25). Co-trimoxazole is effective in areaswhere sensitivity to pyrimethamine-sulfadoxine is retained.PrimaquineP. vivax and P. ovale, but not P. falciparum or P. malariae, characteristicallyleave dormant parasites within hepatocytes (hypnozoites), which give rise tofuture relapses. Primaquine, an 8-aminoquinoline, kills these hypnozoites. It isalso used as a single dose to eradicateP.falciparum gametocytes. However,whether this treatment effectively reduces malaria transmission in endemic ar-eas has never been demonstrated, and it carries the potential risk of hemeolysisin patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency.Etaquine, a more active and slowly eliminated successor to primaquine, is cur-rently undergoing clinical trials.Adjunctive TherapyIn the treatment of severe malaria, supportive therapy is vital, including judi-ciouscareinavoidingoverhydration,hypoglycemia,andconvulsions.Low-184 NEWTON & WHITEAnnu. Rev. Med. 1999.50:179-192. Downloaded from arjournals.annualreviews.orgby INFLIBNET Master on 04/18/09. For personal use only.doseintramuscularphenobarbitonereducedthefrequencyofconvulsionsinadults with cerebral malaria (26) but the optimum anticonvulsant prophylaxisin children remains to be determined. Despite much research, no additional ad-junctivetherapyhasconvincinglydemonstratedpracticalvalue(1a, 20, 27,28). Exchange transfusion combined with quinine may reduce mortality com-pared with quinine alone (29), but no randomized controlled comparisons havebeen conducted, and the risk-benefit assessment remains very imprecise. Anyputative benefit should be weighed against the cost and the risks of fluid over-load, hypovolemia, and transmission of blood-borne pathogens.Tumor necrosis factor (TNF) has been implicated in the production of ma-larial fever and in the pathogenesis of severe disease (30). In African childrenwithcerebral malaria, murineanti-TNFantibodyreducedfever (31), andpentoxifylline (a TNF antagonist) shortened coma duration (32); neither, how-ever, reduced mortality. In a more recent study in Thai adults, pentoxifyllineprovided no benefit (33). One trial found that the iron chelator desferrioxamineshortened coma duration and parasite clearance time (34), but a later double-blindcomparisonfromthesameinvestigatorsshowednobenefit.Thiscom-monsequence,inwhichaninitialtrialshowsevidenceofbenefitthatisnotconfirmedbyasecond,usuallylarger,investigation,emphasizestheimpor-tance of conducting very large and carefully controlled studies before adoptingnew treatment strategies in severe malaria.Elevated venous and cerebrospinal fluid lactate are important poor-prognostic factors in severe malaria. Dichloroacetate (DCA), which stimulatesthe utilization of lactate, significantly reduced venous lactate in adult patientswithseveremalaria(35).Alargedouble-blindrandomizedstudyofDCAiscurrently under way in Africa.CURRENT TREATMENTTable 1 summarizes the treatment of falciparum malaria (1a, 4, 16, 20, 36). P.vivax, P. malariae, and P. ovale may all be treated with chloroquine. If reinfec-tion is unlikely, primaquine is required to kill P. vivax and P. ovale hypnozoi-tes (Table 1). In the face of mild G6PD deficiency, 45 mg weekly for 6 weeksis appropriate. In those few areas with vivax malaria resistant to chloroquine,chloroquine plus primaquine, quinine, or mefloquine may be used (9).Inpregnant patients, quinine, quinidine, chloroquine, andFansidarareconsidered safe, although there is a theoretical risk of kernicterus if the latterisused near term. Although preliminary evidence suggested that mefloquinewas probably safe in pregnancy after 20 weeks gestation (37), more data arenecessary to be sure. The safety of artemisinin derivatives in pregnancy is un-certainbutthebenefitsprobablyoutweightherisksinpatientswithmeflo-quine-resistant falciparum malaria.MALARIA TREATMENT AND PREVENTION 185Annu. Rev. Med. 1999.50:179-192. Downloaded from arjournals.annualreviews.orgby INFLIBNET Master on 04/18/09. For personal use only.186 NEWTON & WHITETable 1 Antimalarial drugs: recommended doses for the treatment of adults and childrenUncomplicated malariaoral Severe malariaparenteralaChloroquine-sensitive malariabChloroquinec10 mg base/kg followed eitherby 10 mg/kg at 24 h and 5mg/kgat 48 h or 5 mg/kg at 12, 24, and36 h. Total dose 25mg base/kg.For P. vivax or P. ovale, addprimaquined0.25mg base/kgdaily for 14 days for radical cure10 mg base/kg by infusion over 8 hfollowed by 15mg/kg over 24 hor 3.5 mg base/kg by intramus-cular or subcutaneous injectionevery 6 h. Total dose 25mgbase/kgSulfadoxine-pyrimethamine20 mg/1 mg/kg single oral dose.1 tablet = 500 mg/25 mgUsual adult dose = 3 tabletsChloroquine-resistant malariaMefloquineeFor semi-immunes, 15 mg base/kgsingle dose only. For non-im-munes or in mefloquine-resistantareas, give second dose (10 mg/kg)824 h later. In US 1 tablet = 228mg base, elsewhere 1 tablet = 250mg baseQuinine 10 mg salt/kg 8 hourly for 7 dayscombined with tetracycline4 mg/kg four times a day ordoxycyclinef3 mg/kg once a dayfor 7 days or clindamycin 10mg/kg twice a day for 37 daysh20 mg of dihydrochloride salt/kggby intravenous infusion over 4 hfollowed by 10 mg/kg infusedover 28 h every 8 hQuinidine 10 mg base/kg infused over 12 hfollowed by 0.02 mg/kg/minwith electrocardiographic moni-toringHalofantrinei,j8 mg/kg at 0, 6 and 12 h. Repeat thedose one week later in non-immunesArtesunateiIn combination with 25 mg/kg mef-loquine, give 1012 mg/kg individed doses over 35 days (e.g.4 mg/kg for 3 days or 4 mg/kgfollowed by 1.5 mg/kg/day for 4days). If used alone, divide thesame dose over 7 days (usually4 mg/kg initially followed by2 mg/kg on day 2 and 3 followedby 1 mg/kg on days 47). 1 tablet= 50 mg2.4 mg/kg i.v. or i.m. stat, followedby 1.2 mg/kg at 12, 24 h thendaily. Artesunic acid (60 mg) isdissolved in 0.6 mL of 5% so-dium bicarbonate and diluted to35 mL with 5% dextrose fori.v. bolus or i.m. injectionArtemetheriSame dose regime as artesunate.1 capsule = 40 mg3.2 mg/kg i.m. stat followed by 1.6mg/kg daily. Not for i.v. admini-stration. 1 ampoule = 80 mgAnnu. Rev. Med. 1999.50:179-192. Downloaded from arjournals.annualreviews.orgby INFLIBNET Master on 04/18/09. For personal use only.POTENTIAL FUTURE DRUGSThemainneedis for cheap, well-toleratedoral drugs efficacious inshortcourses to replace pyrimethamine-sulfadoxine as resistance spreads in Africa.Advances in adjunctive therapy for severe malaria are hampered by continuedignorance of how malaria parasites actually harm people (38).Most of the antimalarial activity of artemisinin derivatives (but not artem-isininitself)isduetothemetabolitedihydroartemisinin(DHA). OralDHAtreatment, already in use in China and some African countries, produces curerates and parasite-clearance times equivalent to historical controls treated withoralartesunate.Thismaybeimportant,asDHAcanbemanufacturedmorecheaply (39). Artelinic acid, currently under development, is a water-solubleartemisinin derivative that is more stable in solution than artesunate (21). Tri-oxanes, simplified analogues of artemisinin retaining the crucial endoperoxidebridge, are being developed but have not yet entered clinical trials.Atovaquone acts by inhibiting the parasites mitochondrial respiratorychain. Because resistance is conferred by a single point mutation in the cyto-chromebgene, it arisesrapidlywhenatovaquoneisusedasmonotherapy.When combined with proguanil, the drug is highly effective and well tolerated(40). However, thepotentialforresistancestillremainsandwoulddeveloprapidly if the drug were deployed widely.MALARIA TREATMENT AND PREVENTION 187aOral treatment should be substituted as soon as the patient can take tablets by mouth. i.m. = in-tramuscular, i.v. = intravenous.bIf there is any doubt concerning drug sensitivity, then the infection should be considered re-sistant.Antimalarialdosesaregenerallyrecommendedintermsofbasebutoftendispensedinweights of salt. This often gives rise to confusion and prescribers should make clear to nurses andpharmacists which they mean.cChloroquine phosphate (250 mg salt = 156 mg base) or chloroquine sulfate (200 mg salt = 147mg base) may be used. If chloroquine is not available, hydroxychloroquine (200 mg salt = 155 mgbase) may be used.dPrimaquine phosphate (26.3 mg salt = 15mg base). In Oceania and southeast Asia the doseshould be 0.330.5 mg base/kg.eSee text for contraindications.fTetracycline or doxycycline should not be given to pregnant women or to children8 years oldor younger.gAlternatively, 7 mg salt/kg can be infused over 30 min followed by 10 mg salt/kg over 4 h.h3-day combination regimes have proved effective in endemic areas, but in general at least 5days treatment should be given for patients with background immunity, and 7 days treatmentmust be given to non-immunes.iNot available in the United States.jHalofantrine should not be taken with fatty foods. It should not be given to patients with pre-existingcardiacconductiondefectsoralongECGQTcinterval,orwhohavereceivedmeflo-quine within 28 days, or who are taking drugs known to prolong the QTc interval (e.g. quinine,quinidine, chloroquine, tricyclic antidepressants, neuroleptics, terfenadine, astemizole).Annu. Rev. Med. 1999.50:179-192. Downloaded from arjournals.annualreviews.orgby INFLIBNET Master on 04/18/09. For personal use only.Lumefantrine (benflumetol) is structurally related to quinine but with phar-macokinetics similar to those of halofantrine. In a comparison of oral combi-nationsofartemether-lumefantrineandartesunate-mefloquineinuncompli-catedfalciparummalaria, theformergaveslightlylowercureratesbutwasbettertolerated(41). Recentworkinthesamepopulationhasdemonstratedthat a higher-dose regime of artemether-lumefantrine is as effective asartesunate-mefloquine and better tolerated.Pyronaridine,aMannichbasesynthesizedbyChinesescientists,iseffec-tive in chloroquine-resistant P. falciparum. In Thailand, 28-day follow-up af-ter a 5-day pyronaridine course demonstrated a 12% recrudescence rate, sug-gestingthatitshouldpreferablybeusedincombinationwithanartemisininderivative (42). Formulation and dose optimization studies are in progress.Two new potent 8-aminoquinolones, etaquine and CDRI 80/53, are under-goingclinicaltrials. Otherpotentialapproachesunderdevelopmentincludephosphatidyl choline and orotic acid analogues and inhibitors of aspartate andcysteine proteases (43).The future significance of these newdrugs will depend as much on prevent-ing or delaying resistance as on their efficacy and tolerability. Drug combina-tion treatment designed to delay resistance, as used in tuberculosis therapy, hasbeen neglected in malaria but needs to be developed (44). Current importantcombination regimes include (a) mefloquine with artesunate or artemether and(b) quinine with tetracycline, doxycycline, or clindamycin. It has been recom-mended recently that an artemisinin derivative should be combined with all an-timalarial drugs to delay resistance. Single-drug therapy for malaria may be athing of the past.It is unclear whether drugs that remove sequestered parasites from the vas-culatureof vital organswouldbebeneficial inseverefalciparummalaria.However, a peptide modeled from the band-3 protein and soluble chondroitinsulfate A both released sequestered P. falciparum parasites into the peripheralcirculation of nonhuman primates, which suggests that this strategy is techni-cally feasible (45, 46).PROPHYLAXISMalarial chemoprophylaxis is important in two circumstances: first and mostimportant, to prevent severe maternal and fetal disease during pregnancy; sec-ond, to protect travelers from non-malarious countries who visit malarious ar-eas. The global importance of the latter, with some 20 people dying per year inthe United States and United Kingdom, should be contrasted with the millionsdying in the tropics.Malariaprophylaxisinpregnancyiscontroversial but most studieshavedemonstrateditsefficacy. Chloroquineandproguanil, Maloprim(dapsone188 NEWTON & WHITEAnnu. Rev. Med. 1999.50:179-192. Downloaded from arjournals.annualreviews.orgby INFLIBNET Master on 04/18/09. For personal use only.and pyrimethamine), intermittent Fansidar, and, in the second half of preg-nancy, mefloquine have all been used (37). Concern that prophylaxis in semi-immunepopulationscouldleadtoalossofimmunity,withagreatersubse-quent susceptibility, is not supported by data fromThe Gambia (47). However,most pregnant residents of malarious areas do not receive prophylaxis becauseof economic constraints.Current prophylaxis guidelines for travelers include chloroquine andproguanil, mefloquine, doxycycline, or Maloprim(36, 48). The diversity ofnational malaria-prophylaxis guidelines for travelers demonstrates the uncer-tainty about the risks and benefits of different drugs in different areas. Localknowledgeofmalariaepidemiologyanddrugresistanceareofkeyimpor-tance. With considerable diversity of resistance patterns, patient exposure, andabilitytotoleratesideeffects,theprimaryaimshouldbetopreventseveredisease. Forexample, chloroquinewithproguanilmaybemoreappropriateprophylaxis than mefloquine in an area of low-level chloroquine resistance de-spite inferior efficacy, if mefloquine side effects lead to abandonment of pro-phylaxis. At least chloroquine and proguanil might prevent severe disease (8).However, there is a considerable disparity between the media reports of meflo-quineadverseeffectsandthegenerallygoodtolerabilityprofilesfrompro-spective trials.When used in prophylaxis, the frequency of serious neuropsychiatric re-actions to mefloquine (1:10,000) is similar to that for chloroquine. Accordingto some studies but not others (4), such symptoms as dizziness and depressionhave been more frequent among those taking mefloquine. Mefloquine remainsvaluablefor peoplewithout contraindicationstravelinginareasof chloro-quine-resistant malaria who are at high risk of exposure. Contraindications in-cludepre-existingneurological orpsychiatricdisease, thefirst trimesterofpregnancy, or the need for a clear sensorium and fine coordination (e.g. in pi-lotingaircraft). Inanareaof severechloroquineresistance, mefloquineordoxycycline have proved highly efficacious and well-tolerated in nonimmunesoldiers (49). In a recent study of nonimmune volunteers (50), primaquine hasbeen shown to be an effective and well-tolerated prophylactic against falcipa-rum and vivax malaria in Indonesia. The artemisinin derivatives quinine andamodiaquine should not be used for prophylaxis. Stand-by antimalarial treat-ment should also be considered for those visiting locations remote from medi-cal help (4).Trials in Africa and southeast Asia (12, 51) indicate that insecticide-treatedbed nets reduce childhood mortality by 1750%. However, analogous to che-moprophylaxis in pregnancy, some concerns have been raised that bed net useinareasof hightransmissionwill shift theburdenof diseasetoolder agegroups and hence increase mortality from cerebral malaria (52). There are alsoconsiderable logistic problems in implementing bed-net programs.MALARIA TREATMENT AND PREVENTION 189Annu. Rev. Med. 1999.50:179-192. Downloaded from arjournals.annualreviews.orgby INFLIBNET Master on 04/18/09. For personal use only.Whetheroralironsupplementationincreasestheriskofmalariahasbeencontroversial; it appears not to, and is additive with antimalarial treatment inpreventing severe anemia in endemic areas (53).VACCINESDespite considerable research, an effective vaccine is an unpredictablenumber of years away (7, 12, 54). The stumbling blocks have been the greatgeneticdiversityofP.falciparumparasites,thecomplexandinefficienthu-manimmuneresponse,andthelackofHLAantigenexpressiononhostredcells. There are three main current strategies, classified by their target stages.Pre-erythrocytic vaccines are designed to destroy sporozoites and infectedhepatocytes, preventing erythrocyte infection or at least reducing disease se-verity. The RTS,S vaccine gave sterile protection in volunteers, and field stud-ies are in progress in The Gambia (55).Blood-stage vaccines are designed to attack merozoites or intra-erythrocyticparasitestolimitorpreventparasitemultiplication. TheSPf66vaccine (which combines sporozoite and blood-stage antigens), in large clini-cal trials, showed some evidence of protection in South America and Tanzaniabut none in The Gambia or on the Thai/Burma border (7).Transmission-blockingvaccinesgenerateantibodiesthatarecarriedwiththe gametocytes in the blood meal into the mosquito gut, where they preventfertilizationordevelopment.Hence,theydonotimmediatelybenefitthepa-tient but aim to reduce transmission to the community (54).The difficulties of vaccine development suggest that it may be more practi-caltodevelopavaccinetoreducesymptoms(anti-disease)ratherthantoprevent infection. Multi-stage DNA vaccines are the most likely candidates toenter clinical practice.Visit the Annual Reviews home page athttp://www.AnnualReviews.org.190 NEWTON & WHITELiterature Cited1. Ross R. 1931. In In Exile, p. 73. London:John Murray. 77 pp.1a.White NJ. 1996. Malaria. In MansonsTropical Diseases, ed. G Cook, pp.1087164. London: Saunders2. Payne D. 1988. Did medicated salt hastenthe spread of chloroquine resistance inPlasmodiumfalciparum? Parasitol. To-day 4:112153. SuX,KirkmanLA,FujiokaH,WellemsTE. 1997. Complex polymorphisms in an~330kDa proteinare linkedtochloro-quine-resistant P. falciparumin South-east Asia and Africa. Cell 91: 5936034. WHO. 1997. Management of uncom-plicatedmalariaandtheuseofantima-larial drugsfor theprotectionof travel-lers. WHO/MAL/96.1075Rev1. WorldHealth Organ., Geneva5. LiuDQ, LiuRJ, RenDX, et al. 1995.Annu. Rev. Med. 1999.50:179-192. Downloaded from arjournals.annualreviews.orgby INFLIBNET Master on 04/18/09. For personal use only.MALARIA TREATMENT AND PREVENTION 191Changes in the resistance of Plasmodiumfalciparum to chloroquine in Hainan,China. Bull. World Health Organ. 73:483866. Pukrittayakamee S, Supanaranond W,LooareesuwanS, etal. 1994. Quinineinsevere falciparummalaria: evidence ofdecliningefficacyinThailand.Trans.R.Soc. Trop. Med. Hyg. 88:324277. NostenF, vanVugt M. 1996. Malaria:still no vaccine and very few drugs. Curr.Opin. Infect. Dis. 9:429348. WhiteNJ.1992.Antimalarialdrugresis-tance: thepacequickens. J. Antimicrob.Chemother. 30:571859. WhitbyM.1997.DrugresistantPlasmo-diumvivax malaria. J. Antimicrob. Chemo-ther. 40: 7495210. White NJ. 1997. Assessment of the phar-macodynamicproperties of antimalarialdrugs in vivo. Antimicrob. Agents Chemo-ther. 41:14132211. PriceRN, NostenF, LuxemburgerC, etal. 1996. Effects of artemisininderiva-tivesonmalariatransmissibility. Lancet347:16545812. Baird JK, Hoffman SL. 1996. Progress inprevention and treatment of malaria.Curr. Opin. Infect. Dis. 9:3192913. Slater F, Cerami A. 1992. Inhibitionbychloroquineofanovelhaempolymeraseenzymeactivityinmalariatrophozoites.Nature 355:1676914. KremsnerPG, RadloffP, MetzgerW, etal. 1994. Quinineplus clindamycinim-proves chemotherapy of severe malaria inchildren. Antimicrob. Agents Chemother.39:1603515. SowunmiA,OduolaAMJ,OgundahunsiOAT,SalakoLA.1998.Comparativeef-ficacy of chloroquine plus chlorpheni-ramine and pyrimethamine/sulfadoxinein acute uncomplicated falciparumma-lariainNigerianchildren.Trans.R.Soc.Trop. Med. Hyg. 92:778116. WHO. 1990. Severe and complicated ma-laria.Trans.R.Soc.Trop.Med.Hyg. 84:165 (Suppl.)17. Watt G, Loesuttivibool L, Shanks GD, etal. 1992. Quinine with tetracycline for thetreatment of drug-resistant falciparummalariainThailand. Am. J. Trop. Med.Hyg. 47:1081118. Mai NT, DayNP, HienTT, WhiteNJ.1996. Neurological sequelaeof cerebralmalaria. Lancet 348:16585919. NostenF, PriceRN. 1995. Newantima-larials. A risk-benefit analysis. Drug Saf.12:2647320. White NJ. 1996. The treatment of malaria.N. Engl. J. Med. 335:800621. Meshnik SR, Taylor TE, Kamchonwong-paisan S. 1996. Artemisinin and the anti-malarial endoperoxides: from herbal rem-edy to targeted chemotherapy. Microbiol.Rev. 60:3011522. Hien TT, White NJ. 1993. Qinghaosu.Lancet 341:603823. Petras JM, Kyle DE, Gettayacamin M, etal. 1997. Arteether: risks of two-week ad-ministrationinMacacamulatta. Am. J.Trop. Med. Hyg. 56:390624. KiatfuengfooR, Suthiphongchai T, Pra-punwttanaP, YuthavongY. 1989. Mito-chondriaasthesiteofactionoftetracy-cline on Plasmodiumfalciparum. Mol.Biochem. Parasitol. 34:10911625. Watt G, ShanksGD, EdsteinMD, et al.1991. Ciprofloxacin treatment of drug-resistant falciparummalaria. J. Infect.Dis. 164:602426. WhiteNJ,LooareesuwanS,PhillipsRE,et al. 1988. Singledosephenobarbitoneprevents convulsions in cerebral malaria.Lancet 2:646627. Warrell DA, Looareesuwan S, WarrellMJ, et al. 1982. Dexamethasoneprovesdeleterious in cerebral malaria: a double-blindtrial in100comatosepatients. N.Engl. J. Med. 306:3131928. Hemmer CJ, KernP, Holst FGE, et al.1991.Neitherheparinnoracetylsalicylicacidinfluencetheclinical courseinhu-manPlasmodiumfalciparummalaria: aprospective randomized study. Am. J.Trop. Med. Hyg. 45:6081229. Hoontrakoon S, Suputtamongkol Y. 1998.Exchange transfusion as an adjunct to thetreatment of severe falciparummalaria.Trop. Med. Int. Health 3:1566130. ClarkIA, Rockett KA. 1994. Thecyto-kine theoryof humancerebral malaria.Parasitol. Today 10:4101231. Kwiatkowski D, Molyneux ME, StephensS,etal.1993.Anti-TNFtherapyinhibitsfeverincerebralmalaria. Q. J. Med. 86:919832. Perri GD, Perri IGD, Monteiro GB, et al.1995. Pentoxifylline as a supportive agentin the treatment of cerebral malaria inchildren. J. Infect. Dis. 171:13172233. LooareesuwanS, WilairatanaP, Vanna-phanS, et al. 1998. PentoxifyllineasanancillarytreatmentforseverefalciparummalariainThailand. Am. J. Trop. Med.Hyg. 58:3485334. Gordeuk V, Thuma P, BrittenhamG, et al.1992.Effectofironchelationtherapyonrecovery from deep coma in children withcerebral malaria. N. Engl. J. Med. 327:14737735. KrishnaS, SupanaranondW, Pukrittay-Annu. Rev. Med. 1999.50:179-192. Downloaded from arjournals.annualreviews.orgby INFLIBNET Master on 04/18/09. For personal use only.192 NEWTON & WHITEakamee S, et al. 1994. Dichloroacetate forlacticacidosisinseveremalaria:aphar-macokinetic and pharmacodynamic as-sessment. Metabolism 43:9748136. MurphyGS,OldfieldEC.1996.Falcipa-rummalaria. Infect. Dis. Clin. No. Am.10:7477537. NostenF,terKuleF,MaelankriL,etal.1994. Mefloquine prophylaxis preventsmalaria during pregnancy: a double-blind, placebo-controlled study. J. Infect.Dis. 169:59560338. White NJ, Ho M. 1992. The pathophysiol-ogy of malaria. In Advances in Parasitol-ogy, ed. RM Baker, pp. 84175. London:Academic39. Looareesuwan S, Wilairatana P, Vanijan-onta S, et al. 1996. Treatment of acute, un-complicated, falciparummalaria with oraldihydroartemisinin. Ann. Trop. Med.Parasitol. 90:212840. Lell B, Luckner D, Ndjave M, et al. 1998.Randomisedplacebo-controlledstudyofatovaquone plus proguanil for malaria pro-phylaxis in children. Lancet 351:7091341. VanVugtM, BrockmanA, GemperliB,et al. 1998. Randomisedcomparisonofartemether-benflumetol and artesunate-mefloquineintreatmentofmultidrugre-sistant falciparummalaria. Antimicrob.Agents Chemother. 42:1353942. Looareesuwan S, Kyle DE, Viravan C, etal. 1996. Clinical studyof pyronaridineforthetreatmentofacuteuncomplicatedfalciparummalaria inThailand. Am. J.Trop. Med. Hyg. 54:205943. WhiteNJ, NostenF. 1993. Advancesinchemotherapy and prophylaxis of ma-laria. Curr. Opin. Infect. Dis. 6:3233044. White NJ, Olliaro PL. 1996. Strategies forthe prevention of antimalarial drug resis-tance: rationaleforcombinationchemo-therapy for malaria. Parasitol. Today 12:39940145. Crandall I, Collins WE, Gysin J, ShermanIW. 1993. Synthetic peptides based onmotifspresent inhumanband3proteininhibit cytoadherence/sequestration ofthe malaria parasite Plasmodium falcipa-rum. Proc. Natl. Acad. Sci. USA 90:4703746. Scherf A, PouvelleB, Hernandex-RivasR, et al. 1997. Sequestration of P. falcipa-ruminfectederythrocytestochondroitinsulphate A: desequestration by solubleCSAinvivoandcloningoftheparasitecounter-receptor. Proc. 2nd Global Meet.Parasitic Dis., Hyderabad, p. 8347. Greenwood AM, Menendez C, AlonsoPL, et al. 1994. Canmalariachemopro-phylaxis be restricted to first pregnan-cies?Trans. R. Soc. Trop. MedHyg.88:6818248. Bradley DJ, Warhurst DC. 1995. Malariaprophylaxis: guidelines for travellersfrom Britain. Br. Med. J. 310:7091349. Ohrt C, Richie TL, Widjaja H, et al. 1997.MefloquinecomparedwithdoxycyclinefortheprophylaxisofmalariainIndone-sian soldiers. Ann. Intern. Med. 126:9637250. Fryauff DJ, Baird JK, Basri H, et al. 1995.Randomised placebo-controlled trial ofprimaquine for prophylaxis of falciparumand vivax malaria. Lancet 346:11909351. Choi HW, Breman JG, Teutsch SM, et al.1995. The effectiveness of insecticide-impregnated bed nets in reducing cases ofmalaria infection: a meta-analysis of pub-lished results. Am. J. Trop. Med. Hyg.52:3778252. SnowRW, OmumboJA, LoweB, et al.1997. Relation between severe malariamorbidityinchildrenandlevel ofPlas-modiumfaciparumtransmission in Af-rica. Lancet 349:16505453. MenendezC, KahigwaE, Hirt R, et al.1997. Randomised placebo-controlledtrial of iron supplementation and malariaprophylaxis for prevention of severeanaemia and malaria in Tanzanian in-fants. Lancet 350:8445054. Kwiatowski D, Marsh K. 1997. Develop-ment of amalariavaccine. Lancet 350:1696170155. StouteJA, Slaoui M, Heppner G, et al.1997. Apreliminaryevaluationof are-combinant circumsporozoite protein vac-cine against Plasmodium falciparum ma-laria. N. Engl. J. Med. 336:8691Annu. Rev. Med. 1999.50:179-192. Downloaded from arjournals.annualreviews.orgby INFLIBNET Master on 04/18/09. For personal use only. Annual Review of MedicineVolume 50, 1999CONTENTSCyclosporine Treatment of Glomerular Diseases, Michael Klein, MD, Jai Radhakrishnan, MD, Gerald Appel, MD1Arrhythmogenic Right Ventricular Dysplasia, G. Fontaine, F. Fontaliran, J.L. Hbert, D. Chemla, O. Zenati, Y. Lecarpentier, R. Frank17Intestinal Pseudo-Obstruction, Bernard Coulie, MD, PhD, Michael Camilleri, MD37The Ubiquitin-Proteasome Pathway and Pathogenesis of Human Diseases, Alan L. Schwartz, PhD, MD, Aaron Ciechanover, MD, PhD57Concept and Evaluation of Hibernating Myocardium, Shahbudin H. Rahimtoola, MB, FRCP, MACP75Genetics of Hemochromatosis, L.M. Cullen, BSc, G.J. Anderson, PhD, G.A. Ramm, PhD, E.C. Jazwinska, PhD, L.W. Powell, MD, PhD, DUniv, FRCP, FRACP, FRCPT87How Can Physicians Keep Up-To-Date?, Christine Laine, MD, MPH, David S. Weinberg, MD, MSc99Mitochondrial Disorders: Clinical and Genetic Features, D.K. Simon, MD, PhD, D.R. Johns, MD111Heparin-Induced Thrombocytopenia: A Ten-Year Retrospective, Theodore E. Warkentin, MD129The Biology of Cystitis: Host and Bacterial Factors, M. Sussman, PhD, D. L. Gally, PhD149Idiopathic Ventricular Tachycardia, Gregory T. Altemose, MD, Alfred E. Buxton, MD159Malaria: New Developments in Treatment and Prevention,Paul Newton, BM, DPhil, MRCP, Nicholas White, DSc, MD, FRCP179Dialysis or Transplant:Fitting the Treatment to the Patient, Michael Berkoben, MD, Steve Schwab, MD193Screening for Prostate Cancer: The Roles of Science, Policy, and Opinion in Determining What is Best for Patients, Steven H. Woolf, MD, MPH, Stephen F. Rothemich, MD207Coagulase-Negative Staphylococci: Role as Pathogens, Johannes Huebner, MD, Donald A. Goldmann, MD223Biphosphonates in the Treatment of Malignant Bone Disease, James R. Berenson, MD, Allan Lipton, MD237Insights From the Study of Heart Rate Variability, P.K. Stein, PhD, R.E. Kleiger, MD249Hereditary Peripheral Neuropathies: Clinical Forms, Genetics, and Molecular Mechanisms, Laura E. Warner, Carlos A. Garcia, MD, James R. Lupski, MD, PhD263Applications of NMR Spectroscopy to Study Muscle Glycogen Metabolism in Man, M. Roden, MD, G. I. Shulman, MD, PhD277Immunologic Therapy of Multiple Sclerosis, Barry G. W. Arnason, MD 291Allergic Bronchopulmonary Aspergillosis, B. A. Cockrill, MD, C. A. Hales, MD303Postural Hypotension: Causes, Clinical Features, Investigation, and Management, Christopher J. Mathias, DPhil, DSc, FRCP, Jeffery R. Kimber, BSc, MB, BS, MRCP317Annu. Rev. Med. 1999.50:179-192. Downloaded from arjournals.annualreviews.orgby INFLIBNET Master on 04/18/09. For personal use only.New Transfusion Strategies: Red Cell Substitutes, Robert M. Winslow, MD337Escherichia coliO157:H7 Gastroenteritis and the Hemolytic Uremic Syndrome: An Emerging Infectious Disease, Richard E. Besser, MD, Patricia M. Griffin, MD, Laurence Slutsker, MD, MPH355The Graft-Versus-Leukemia Effects of Allogeneic Cell Therapy, David L. Porter, MD, Joseph H. Antin, MD369Sleep and Its Disorders, A. N. Vgontzas, MD, A. Kales, MD 387The Prognostic Significance of Altered Cyclin-Dependent Kinase Inhibitors in Human Cancer, J. Tsihlias, MD, FRCSC, L. Kapusta, MD, FRCPC, J. Slingerland, MD, FRCPC, PhD401Chemokines and Chemokine Receptors: Biology and Clinical Relevance in Inflammation and AIDS, Massimo Locati, MD, Philip M. Murphy, MD425Arrhythmias in the Athlete with Congenital Heart Disease: Guidelines For Participation, Richard R. Liberthson, MD441Natural History and Preventative Treatment of Recurrent Mood Disorders, Ellen Frank, PhD, Michael E. Thase, MD453Biology of Gastroesophageal Reflux Disease: Pathophysiology Relating to Medical and Surgical Treatment, Tom R. DeMeester, MD, Jeffrey H. Peters, MD, Cedric G. Bremner, MD, Parakh Chandrasoma, MD469Dendritic Cell Vaccines for Cancer Immunotherapy, John M. Timmerman, MD, Ronald Levy, MD507Spectrum of Hantavirus Infection: Hemorrhagic Fever with Renal Syndrome and Hantavirus Pulmonary Syndrome, C. J. Peters, MD, Gary L. Simpson, MD, PhD, MPH, H. Levy, MD, PhD531Annu. Rev. Med. 1999.50:179-192. Downloaded from arjournals.annualreviews.orgby INFLIBNET Master on 04/18/09. For personal use only.