treatment of malariatreatment o malaria 12. pe.sonal ,uf1or(s) hotman s,. 13a. type of report 13b....

,.-,,... REPORT DOCUMENTATION PAGEr ~ ~ llm I EOTSCRT L~J~tI b. RESTRICTIVE MARKINGS

- Unclassified IL Pr _____________________

2a. SECURITY CLASSIFICATION AUTHORITY 3. DISTRIBUTION/AVAILABILITY OF REPORT

# lk Approved for public release;2b. DECLASSIFICATION DOWNGRADING SCHEDULE distribution is unlimited

( 4. PERFORMING ORGANIZATION REPORT NUMBER(S) $. MONITORING ORGANIZATION REPORT NUMBER(S)

NMRI 86-115

6. NAME OF PERFORMING ORGANIZATION 6b OFFICE SYMBOL 7a. NAME OF MONITORING ORGANIZATIONNaval Medical Research (If applicable) Naval Medical Command

6c. ADDRESS (Cty, State, and ZIPCode) 7b. ADDRESS (City, State. and ZIP Code)

Bethesda, Maryland 20814-5055 Department of the NavyWashington, D.C. 20372-5120

Ba. NAME OF FUNDING ISPONSORING 8b. OFFICE SYMBOL 9. PROCUREMENT INSTRUMENT IDENTIFICATION NUMBERORGANIZATION Naval Medical O plcbeResearch and Development Command

Sc. ADDRESS (City, State, and ZIP Code) 10. SOURCE OF FUNDING NUMBERSBethesda, aryland 20814-5055 PROGRAM ' PROJECT TASK WRK UNIT"

ELEMENT NO. NO. NO. ACCE SIO N NO0.N.A.

11. TITLE (Include Se unty Classification)Treatment o malaria

12. PE.SONAL ,Uf1OR(S)Hotman s,.

13a. TYPE OF REPORT 13b. TIME COVERED 114. DATE OF REPORT (Year, Month, Day) S.PG 1UY

journal article FROM TO 1986 5 4. A AplT16. SUPPLEMENTARY NOTATIONcaMeiieadCmuial iesSV01()Ar -9B

Reprinted from: Clinics in Tropica MeiieadCmuncbeDsae. Vl112Apil194. pp. 171-224

17. COSATI CODES 18. SUBJECT TERMS (Continue on reverse if necessary and identif by block number)FIELD GROUP SUB-GROUP Malaria Chemotherapy Falciparnm

Plasmodiumt - Drug resistance

19. ABSTRACT (Continue on reverse if necessary and identify by block number)

DTICCLECTE

MAR 2 7 I

[D6

20. DISTRIBUTION /AVAILABILITY OF ABSTRACT 121. ABSTRACT SECURITY CLASSIFICATION

IMUNCLASSIFIED/UNLIMITEo 03 SAME AS RPT. D oTIC USERS Unclassified

22a. NAME OF RESPONSIBLE INDIVIDUAL 22b. TELEPHONE (Include Area Code) 22c. O FICE SYMBOL

Phyllis Blum, Information Services Division 202-295-2188 ISD /ADMINM1NJi.I

00 IORM 1473,84 MAR 83 APR eotion may Oe used until exhausted. zCURITY CLASSIFICATION OF THIS PAGE

All other editions are obsolete. UNCLASSIFIED

, [6

Treatment of Malaria

": STEPHEN L. HOFFMAN

Almost all patients with malaria can be successfully treated by non-physicianhealth care workers trained to select and administer antimalarials andantipyretics. These health care workers can also recognize patients who areat risk of developing, or who have developed, complicated malaria, but thetreatment of patients with severe malaria requires all the skills and resourcesavailable to the modern physician. All malaria infections can be cured with

Accesion For available antimalarials if the patient receives a complete course of appro-I priate therapy.NTIS .CRA&I r The principles of malari i therapy are:DTC TAB e 13 Recognize malaria infections as rapidly as possible.Unannounced .Initiate effective antimalarial therapy to reduce arid eliminate parasit-Justification .aemia as rapidly as possible.

v "* -: .. .... - -';: Anticipate and prevent cor~plications.By Treat complications and prevent deati.'Distribution 1 5. Prevent recrudescence and relapse:

6. Recognize and treat recrudescence' and relapse and prevent recurrence. J!

Availability Codes Reduce transmission.

Dist Special MALARIA TERMINOLOGY )Some terms relevant to treatment of malaria are defined as follows. Theprepatent period is the time from sporozoitc inoculation by a mosquito until

AC) -,/ Oasexual parasites are detectable in the blood. The incubation period is the (K-,time from sporozoite inoculation until onset of clinical symptoms. Recurrentparasitaemia occurs when parasites reappear in the blood after they havebeen undetectable by standard methods. Recurrent parasitaemia may bedue to either relapse or recrudescence. Relapse is the reappearance, aftereradication of the original blood stage infection, of asexual parasitaemiaresulting from delayed maturation of a hypnozoite (the slowly developing ordormant exocrythrocytic stage) in the liver. It only occurs with Plasmodiumvii'ax and 1). orale. Recrudescence is the reappearance of detectable asexualparasilaemia due to persistence of asexual L ryhroyic stages at undctcct-able (subpatent) levels. Subpatent parasitacmia can be documented only bysubinoculation of blood into susceptible volunteers. In the absence of re-infection, recrudescence is responsible for all recurrences of 1). falciparuon

('Uit itn Iro P al V otIf in, and 0 ,,min Itiah'l [)Nn i --II. . No I. Apr I [IQ8 1 71

• • . , I I I I I I I

172 S. L. HOFFMAN

.. -. ..- **and P. malariae infections. A blood schizonticide is a drug that destroys theIasexual erythrocytic stages of the parasite. It is used for treating acute

infections and recrudescences and for chemnoprophylaxis as a suppressiveprophylactic. A tissue schizonticide destroys the liver asexual stages includ-ing hypnozoites. It is used to prevent relapse and as a casual prophylactic toprevent blood stage infections. Gamietocyltocidal drugs destroy the sexualforms of the parasite and sporonticidal drugs inhibit the development ofoocysts on the stomach wall of the mosquito. They are both used to reducetransmission. Clinical cure refers to relief of symptoms of malaria withoutcomplete elimination of the infection. Radical cure refers to completeelimination of malaria parasites from the body so that recrudescences andrelapses cannot occur. A semni-immune individual is one who has hadmultiple malaria infections, has developed an acquired immune response tomalaria, is relatively resistant to infection and, if infected, is unlikely todevelop severe disease. A non-immune individual is one who has had littleor no recent exposure to malaria and has no effective acquired immuneresponse against malaria.

DRUG RESISTANCE

Drug resistance refers to the ability of a parasite strain to multiply or survivein the presence of concentrations of a drug that normally destroy or preventmultiplication of that species of parasite. Resistance may be relative(yielding to increased doses of the drug) or complete (withstanding themaximum tolerated doses of the drug).

Most drug resistance terminology refers to the response of P. falciparumto chloroquine and other 4-aminoquinolines. An in vivo grading systemdeveloped by the World Health Organization defines P. falciparu sensi-tivity to 4-aminoquinolines (World Health Organization, 1973; Lepes et al.1980). Parasites are sensitive to the antimalarial if they are cleared from thebloodstream within seven days of initiation of therapy and do not returnwithin 28 days. RI resistant organisms are cleared within seven days. butreappear (recrudesce) within 28 davs. With Ru resistant organisms. parasit-aemia levels fall by more than 75 c within 48 hours of initiation of therapy,but are not cleared within seven days. With RIII resistant organisms,parasitaenia levels fall by less than 75% within 48 hours and are not clearedwithin seven days. There is some controversy about the appropriateness ofthis system for classifying the response to longer act ng ntimalarials. such asmefloquine but it is still generally used. In vitro correlates of in vivoresistance have been established for some antimalarials. In vitro tests areuseful epidemiologically, but proof of drug resistance is dependent ondemonstrating in vivo resistance in patients shown to have received andabsorbed adequate amounts of antimalarials.

There has been little work on resistance of P. viaax to blood schizonticidesbecause: (1) the parasite has remained highly sensitive to chloroquine. (2) itis extremely difficult to distinguish between recrudescence because of drugresistance and relapse. and (3) the parasite cannot he grown in culture.

TREATMENT OF MALARIA 173

However, some strains of P. vivax display relative resistance to primaquine,the most commonly used tissue schizonticide (Bruce-Chwatt, 1981).

The mechanisms of development and spread of drug resistance are poorlyunderstood in human malaria. It is never clear whether initial resistantisolates are introduced to an area from outside or represent spontaneousmutations. It seems clear that continued drug pressure selects for resistantisolates which eventually become predominant. All investigations indicatethat resistance to chloroquine, sulphonamides, and pyrimethamine is trans-ferred by classical Mendelian inheritance during sexual reproduction of theparasite in the anopheline vector (Beale et al, 1978; Walliker, 1982; WorldHealth Organization, 1984).

HISTORY OF ANTIMALARIALS

The first and, until the twentieth century, the only blood schizonticideknown in the Americas and Europe was cinchona bark, which takes its name(given by Linnaeus in 1649) from the Countess of Chinchon, who may, ormay not, have been cured of malarial fever in 1630 in Peru by an oralinfusion of an extract of the bark (Wesselhoeft, 1914; Haggis, 1941). It wasintroduced to Europe from Peru in the 1630s or early 1640s by Jesuit priestsand during the next 200 years the 'Jesuit's' or 'Peruvian' bark becameincreasingly more important for treating malarial fevers (agues). Quinine,the principal alkaloid of cinchona bark, was isolated from cinchona in 1820and by the late nineteenth century quinine was widely used to treat malarialfevers which had been shown in 1880 to be caused by a protozoan. The firstsynthetic antimalarial, pamaquin, was introduced in the 1920s. Mepacrineand several 4-aminoquinolines were synthesized in the 1930s. Mepacrine(= atabrine = quinacrine) was the most commonly used antimalarial duringWorld War II. The 4-aminoquinolines, chloroquine and amodiaquine, andthe biguanide, proguanil, were developed during the war and the folic acidsynthesis inhibitor, pyrimethamine, in 1951. By the early 1950s, chloro-quine, which was easily administered in a short course and effective againstall human malarias, was the drug of choice for treatment of malaria and theuse of quinine fell out of favour. In the late 1950s and early 1960s, resistanceof P. falciparwn to chloroquine was documented in Colombia and Thailand(Harinasuta et al, 19o2; Peters. 1970). Since then chloroquine resistance hasspread to most of the malarious world. Although several excellent newantimalarials including mefloquine and halofantrine have been developedby the United States Army, in 1986 quinine is again the most important P.fuh( iparttm b !ool w ontic~i~e o!Itsidc of China. I-or nearly 2tMR) years qtighao (Artemnisia annua L., sweet wormwood, annual wormwood) was used inChina to treat fevers including malaria. In 1972 a sesquiterpene lactoneconstituent of qing hao was isolated and found to be active against malaria.It was named qinglaosu (active principle of qing hao) in Chincse andartemisinine in English. Reports from China indicate that it is an effective.rapidly acting blood schizonticide (Oinghaosu Antimalaria CoordinatingResearch Group. 1979; China Cooperative Research Group of Oinghaosu

174 S. L. HOFFMAN

...... ..... and its Derivatives as Antimalarials, 1982; Guoqiao et al, 1982; Jiang et al,1982a; Guoqiao. 1984; Li et al, 1984; Klayman, 1985).

DIAGNOSIS

Delay in treatment of malaria patients, especially those with P. falciparuminfections, can be disastrous and has been responsible for many unnecessarydeaths. Institution of antimalarial therapy requires rapid diagnosis. Indi-viduals with a febrile illness who have been in a malarious area within thepast 12 months should be evaluated for malaria infection regardless ofwhether or not they have taken malaria chemoprophylaxis. More than 95%of primary infections will become patent within four weeks of mosquitoinoculation of sporozoites of P. falciparum and P. ovale and within six weeksof inoculation of P. vivax and P. malariae (Kitchen, 1949; Miller 1975),Delayed primary attacks of P. vivax more than six months after exposurehave been described for Dutch, Korean, Pakistani, Chinese. and Hibernans(Russia) strains (Miller, 1975; Jiang et al, 1982b; G. Strickland. personalcommunication). Secondary or relapse infections with P. vivax and P. ovalecan occur from several months to, occasionally, three years after infection.Untreated or incompletely treated P. falciparum infections are usuallyeliminated by host immune response within one year of infection, but mayrarely persist for two to three years (Verdrager, 1964: Brooks and Barry.1969). P. malariae persists longer than the others and has been responsiblefor transfusion malaria 46 years after last exposure (Miller, 1975).

Even when parasitaemia is extremely low, parasites can generally befound if a thick blood film is prepared, stained, and read properly (seeChapter 5). Thin films (peripheral smears) in which parasites are visualizedwithin intact erythrocytes are used to distinguish between the four species ofhuman plasmodia. It is often difficult to detect low levels of parasitaemiawith a thin film. Parasites can sometimes be found in bone marrow aspiratesor in intradermal fluid when not found in thick blood films (Guo et al. 1984),P. vivax schizonts have a buoyant density similar to that of leukocytes.Smears made from buffy coats or the mononuclear cell la~cr of ficoll-Hypaque gradients are more sensitive than thick blood films for detecting P'.vivax infection (Bass and Johns. 1915; Le Bras and Payct. 1978). P. fillci-parum has a 48-hour life cycle. Merozoites which invade erythrocytesdevelop from early trophozoites to schizonts. The schizonts rupture andrelease merozoites which reinvade erythrocytes. Only the early trophozoites(rings) are generally seen in peripheral blood films. Late tiophozoitfc ,andschizonts are sequestetcd in the capillaries and postcapillary venules of thedeep organs. The rings are only present for 18-24 hours of the 48-hour lifecycle. Thus. a patient with a synchronous high level infection (all parasites atsame stage of development) could have a negative blood film xhen allparasites are sequestered and a heavy parasitaemia 6-24 hours later. Ifmalaria is suspected and the thick blood fihm is negative, the smear should berepeated every 6-12 hours for 24-36 hours.

In recent years radioimmnunoassa\vs ( Nackev et al. 1980: A\rahan et al.

TREATMEINT OF MALARIA 175

1982), enzyme-linked immunosorbent assays (Mackey et al, 1982) and DNA.' probes (Franzen et al, 1984; Pollack et al, 1985; Mucenski et al, 1986;

Walker et al, 1986) for P. falciparum antigen detection in blood have beendeveloped. None of these techniques have been validated or standardizedfor routine use. It is likely that they will prove useful for screening largenumbers of individuals for parasitaemia, but not be particularly importantfor diagnosis in individual patients (Chapter 5).

ANTIMALARIAL DRUGS

Rapid reduction and clearing of parasitaemia require blood schizonticidaldrugs, i.e. antimalarials which are effective against the erythrocytic.asexual, stage of the parasite. Treatment of P. falciparum infections fromsome areas of the world may require two blood schizonticides, the first torapidly reduce parasitaemia and the second, a more slowly acting drug. toachieve radical cure.

Choice of blood schizonticide

The choice of antimalarial depends on the species of Plasmodium with whichthe patient is infected, the expected drug sensitivity pattern of the parasite,the clinical condition of the patie-nt, the malaria immune status of the patientand the patient's tolerance of specific antimalarials. The route of administra-tion is dictated by the patient's condition and the availability of intravenousfluids. In general, the physician treating an individual patient out of amalarious area should treat all patients with uncomplicated P. viiax. P.malariae, or P. ovale infections with oral chloroquine, all patients withuncomplicated P. falciparum infections with an antimalarial other thanchloroquinc (pyrimcthamine-sulfadoxine, quinine, quinidine, mefloquine).and all patients with complicated malaria, regardless of the apparent speciesof Plasmodium. with intravenous quinine or quinidine. The physician in amalarious area who is confident of the response of local P. falciparum tochloroquitie or amodiaquine may use one of these 4-aminoquinolines insteadof the alternative drugs listed above.

Response to therapy is monitored by examining the patient and malariablood films daily. If parasitacmia is not reduced by >75(4 within 48 hours,the clinician should suspect high grade drug resistance.

Classes of antimalarials

There are a number of classes of antimalarials, each of which may have aneffect on a different stage of the parasite and different species:

I. Cinchona alkaloids (quinine. quinidine)2. 4-Aminoquinolincs (chloroquine, amodiaquine)3. Diaminopyrimidines (pyrimethamine)4. Sulphonamides and sulphones (sulfadoxine. sulfamctopyrazine

sulfalenc), dapsone)

176 S. L. HOFFMAN

5. Tetracyclines (tetracycline, doxycycline, minocycline)6. Quinoline methanols (mefloquine)7. Sesquiterpene lactones (artemisinine = qinghaosu)8. Phenanthrene methanols (halofantrine)9. 8-Aminoquinolines (primaquine)

10. Biguanides (proguanil, chlorproguanil, cycloguanil)11. Other antibiotics and antimalarials.

Cinchona alkaloids

Quinine and quinidine are the only cinchona alkaloids in frequent clinicaluse. They are both rapid-acting agents against the asexual stages of all fourspecies of plasmodia that infect humans. More experience has been gainedwith quinine than with quinidine, and since the use of quinidine is associatedwith more frequent electrocardiographic abnormalities (White et al, 1983a)quinine, when available, is still the cinchona alkaloid of choice for thetreatment of malaria. If quinine is not available, quinidine is an excellentsubstitute.

Quinine

Recommendations regarding the optimum dosage, route of administrationand length of treatment with quinine are controveisial. This has been due toincomplete pharmacokinetic studies, non-specific and non-uniformmethods of measuring blood levels of the drug, the inability until recently tomeasure the in vitro inhibitory concentrations of quinine against P. falci-parum, changing quinine sensitivity patterns of P. falciparun. lack of dataestablishing correlations between in vitro and in vivo parasite inhibitoryconcentrations of quinine and difficulty in distinguishing the hypotensive,life-threatening complications of P. falciparun infections from the seriousside-effects of quinine.

In a series of well-designed studies carried out since 1980, investigators inThailand have provided pharmacokinetic data for the rational use of quinine(White et al, 1982, 1983b) and quinidine (Phillips et al, 1985) in severemalaria. They have shown that, in severe malaria, high plasma levels ofquinine are common, safe, and well tolerated and that severely ill patientstreated with standard regimens often die before plasma levels of quinineadequate for in vitro parasite inhibition are achieved (White et al, 1982,1983b). Their conclusions regarding the requirement for a loading dose ofquinine or quinidine in order to rapidly achieve and maintain adequate drugconcentrations are well substantiated from a pharmacological perspectiveand are suggestive from a clinical and parasitological perspective. Therehave been no studies which have adequately compared the clinical efficaciesof intravenous loading dose, intravenous non-loading dose, and intra-muscular quinine regimens for the treatment of severe malaria.

Antimalarial activity. Quinine is active against asexual erythrocytic stages ofall four human malaria parasites. It has no effect on exoervthrocvtic forms.

al fou hua maai IIl l|

\ -


. Immature gametocytes of P. falciparum and all gametocytes of the otherspecies are sensitive to quinine. P. vivax infections may respond less rapidlythan P. falciparum infections.

Absorption and disposition. Quinine is well absorbed after oral administra-tion. Peak plasma concentrations occur within one to four hours after asingle dose. It is generally given as quinine sulphate which in some studieswas not as well absorbed as the dihydrochloride and bisulphate salts(Garnham et al, 1971). Plasma concentrations were 10-30% lower aftertablets and intramuscular injection than after intravenous infusion in adults(Hall et al, 1973, 1975a). In children there was no difference between levelsafter tablets or intravenous infusion (Sabchareon et al, 1983). When10mg/kg quinine dihydrochloride (8.3mg/kg base) was given by four-hourintravenous infusion every eight hours, steady state levels (10-15 mg/I) werenot reached for 48-72 hours. When a loading dose of 20mg/kg was givenduring four hours, levels of 93% ± 10 of steady state peak and 75% ± 14 ofsteady state trough were reached after the first dose (White et al, 1982.1983b). Erythrocyte concentrations of quinine are directly correlated withthe level of parasitaemia, but the ratio of red cells to plasma quinine levelsrarely exceeds one (White et al, 1983c). Cord blood and breast milk con-centrations of quinine are approximately one-third those of maternal plasmalevels (White, 1985). Plasma protein binding is higher in cerebral malaria(93%) than in uncomplicated malaria (90%) or in convalescence (89%)(Silmaut et al, 1985). This may explain the lack of apparent quinine toxicitydespite high plasma concentrations in severe falciparum malaria.Cerebrospinal fluid levels of quinine are 5-10% of plasma levels suggestingthat quinine does not freely cross the blood-brain barrier (White et al, 1982:Silmaut et al, 1985).

Metabolism and elimination. Quinine is cleared primarily by hepaticmetabolism and only 15-20% is excreted in the urine. Acidification of theurine increases excretion. There is little, if any, reduction in quinineclearance in patients with renal failure (White et al, 1982). Several studieshave shown that plasma and erythrocyte levels of quinine are higher inpatients with severe malaria than in those with uncomplicated malaria andhigher in patients with acute malaria than in non-infected volunteers orconvalescent malaria patients (Trenholme et al, 1976: White et al, 1982:Sabchareon et al, 1983; White et al, 1983c; White, 1985). In cerebral malariapatients given 10mg/kg quinine dihydrochloride every eight hours, oncesteady state levels were reached, serum levels consistently exceeded l(mg/Iand in 60% of patients exceeded 15mg!I (White et al, 1982). The increase inquinine levels with increasing severity is thought to be due to a decrease inthe volume of distribution of the drug and a decrease in hepatic metabolismin patients with severe malaria, resulting in a decrease in clearance and alonger half-elimination time (White et al. 1982: White, 1985). The half-elimination time is approximately 11 hours, but becomes shorter duringconvalescence, and may be shorter in children than in adults. If the parasiterequires a high concentration of quinine for inhibition, the quinine dose ma

178 S. L. HOFFMAN

have to be increased on day 4-5 after initiation of therapy (Chongsuphajai-,- .,., siddhi et al, 1981a). During the third trimester of pregnancy pharmaco-

kinetics are similar to those in children; elimination half-life and volume ofdistribution decrease, but clearance is similar to other adults (Looareesu-wan et al, 1985a; White, 1985). Quinine pharmacokinetics have been inade-quately studied in patients with severe parenchymal liver disease. Quininemetabolites have less antimalarial activity than quinine.

Toxicity. Serious side-effects of quinine are infrequent, but minor side-effects are common (Powell and McNamara. 1972). Quinine has a bittertaste. Side-effects increase with increasing plasma levels of quinine. Head-ache and tinnitus are the most common side-effects. Cinchonism, whichincludes tinnitus, headache, nausea, vomiting, abdominal pain, blurredvision, transient loss of hearing, vertigo, and tremors, often occurs duringthe first two to three days of therapy. sometimes subsides spontaneouslyduring therapy, but always subsides after discontinuation of the drug. It ismore common in women than men and in adults than children, and issometimes so unpleasant as to necessitate a change in therapy. Drug fever issometimes confused with an inadequate response to therapy. Diarrhoea,constipation, pruritus, and nervousness have also been described, Rarelyencountered serious reactions include urticaria, bronchospasm.angioedema of the face, mucous membranes and the lungs, deafness,blindness or amblyopia, haemolytic anaemia, and agranulocytosis. Thedeafness and amblyopia are occasionally irreversible. Overdose of quinine,usually caused by rapid injection of a large dose, may result in convulsions,hypotension, heart block, ventricular fibrillation, and death. Intravenousquinine given by slow infusion and oral quinine for acute malaria areassociated with minor electrocardiographic changes (IYi lengthening ofQT interval and T wave flattening) with no other evidence of cardiotoxicit\(White et at, 1983b). Quinine is a local irritant which occasionally causesnausea, vomiting, and midepigastric pain when given orally. thirombo-phlebitis with sclerosis of veins when given intravenously, and tissuenecrosis and sterile abscesses when given intramuscularly. Many cliniciansconsider it to be an abortifacient inducing uterine contractions. A recentstudy in Thailand indicates that this is not the case (LooareCstuwan Ct al,1985a).

Measurecient of quinitie levels. High-performance liquid chromatography(ltPLC) is the best method for measuring quinine levels (Edstcin et al,1983). The benzene extraction .tiorescence technique (Cramer andlsaksson, 1963) does not distinguish between quinine and quinidine, andmay measure metabolites (Edstcin ct al. 1983). A metaphosphoric acidprecipitation method has been used to assess quinine metabolism (Tren-holme et al, 1976).

Mechanism of antimalarial action. This is unknown, but the drug is thoughtto intluence hacnoglobin digestion by the parasite leading to developmentof a haemolvtic complex that dishupts the parasite-host membranes. It is


apparently bound at a different site within the parasite than is chloroquineand leads to a modification of the ultrastructure of malarial pigment(Warhurst. 1981).

Resistance to quinine. It is believed that minimal inhibitory concentrations(MIC) of quinine must be maintained for four to seven days to effect radicalcure of P. falciparuin infections (Chongsuphajaisiddhi et al, 198 1a). Since ittakes two to three days to achieve steady state plasma levels of quinine when10mg/kg are given every eight hours, quinine must be given for at least sevendays and perhaps 10 days, depending on the parasite's MIC. Resistance of P.falciparum to quinine was described in Brazil in 1908 where as much as 25.5 gof quinine base given during 21 days was unable to cure all P. falcipartiminfections (Neiva, 1910; Nocht and Werner. 1910: Bruce-Chwatt. 1981).Relative resistance was also described in Italy, Panlama. and New Guinea.but, in spite of widespread use of quinine before the introduction of syn-thetic antimalarials. P. falciparurn has remained remarkably sensitive toquinine, especially in Africa (Bruce-Chwatt. 1981). In recent years P.falciparwan infections resistant to quinine have been described in Vietnam(Hal., 1972), Thailand (Pinichpongse et al, 19827). Irian Java (Hoffman.unpublished data), and Tanzania (Mutabingwa et al. 1982). In Vietnam14% of 36 adults treated with 10 days of intravenous quinine (1800 mg/dav)were found to be resistant (Hall, 1972). In Thailand, 25% , of 28 children wh~oreceived quinine 30mg/kg/day. 38.5% of 26 who received quinine plus asingle curative dose of pyriniethamine-sulfadoxine. and 13% of 23 whoreceived 30 mg/kg/day for four days and then 45 mg/kg for three days wverefound to be resistant (95% t RI level, one case RuI) (Chongsuphajaisiddhiet al, 1981Ia). Increasing the dosage at a time when quinine clearance wasincreasing (see above) appeared to be associated with an improved radicalcure rate. The sensitivity of P. falciparum to quinine is now, also beingmonitored by in vitro tests. In Thailand the MIC of quinine increased from amean of 12. 1 to 19.4 ' moI/l (3.9 to 6.3 mg/I) from 1978 to 198 1. Some isolatesrequired 32.0ltmol quininc/l (10.4mg/Il for inhibition. Some isolates fromIria n Jaya have been shown to produce schizonts in the presence of51 .21tmol/l (16.5mg/I) of quinine (Hoffman. unpublished data). The WorldHealth Organization now considers the production of schizonts in thepresence of 51.2iimol/l (256pmo1) quinine to indicate in vitro resistance (D.Payne. personal communication). When seven days of tetracycline weregiven with quinine in Thailand. cure rates of 951% Were obtained (Pinich-pongse et al, 1982).

The way in which 1. falciparutn becomes resistant to quinine is unknown.It has been suggested that resistance to quinine develops more readily inareas where chloroquine resistance is widespread and is related to chloro-quine resistance. However, in vitro resistance to quinine and metloquinehave been observed in P. alciparumn infections showvn to be sensitive in vivoand in vitro to chloroqUine (Hoffman et al. 1986).

P. viv-ax infections respond less rapidly than P. falciparumn infections toquinine. Neither P. vivax. 1P. ovake. nor P. nialariae er'throcv tic stages haveever been documented to be resistant to quinine. 'On the other hand.

I180 S. L. 1i01 FNIAN

clinicians anecdotally report the appearance of P. iax parasitaemia four to-five da\-s after initiating appropriate therapy for 1'. fialciparum infections.

Formulations. Quinine is available as tablets containing quinine sulphate(125-300mg). quinine bisulphate (301 rg), quinine dihydrochloride(300 ig). and quinine hydrochloride (300mig). capsules of quinine sulphate(125-300mg), ampoules of quinine dihydrochloride: (500-I000mg).ampoules of quinine-antipyrine. and ampoules containing 385 rug ofquinie-resorcinol bichlorhvd rate. 10mg of quinidine-resorcinol bichlor-hydrate. 2.7mg of cinchonine-resorcinol bichlorhydrate. and 2.7 rug ofcinchonidine-resorcinol bichlorhydrate (Quinimlax). In the United Statesquinine dihydrochloride for intravenous use can be obtained from theCenter for Disease Control. Atlanta. Georgia.

Uses. Treatment of complicated malaria and miultidruig resistant uncomlpli-cated P. falciparlini infections is shown in Table I.

Quillidilm'

Quinidine, a diastereoisornecr of quinine, Was found1L to be effective aiait Pfalcipariti over 100 years ago,( in India. Although show\n to be ats effectiveand perhaps more effective 1 than quinine for thie treatment of falciparummalaria, it was largely ignored as anl antimialarial until recently (Sanders andDawson, 1932: Sanders. 1935; Taggart et al. 1948). Studies in Thailand havesuggested quinidine is ats effective ats quinine in complicated and uncomnpli-cated falciparum malaria and shown quinidine'to be effective in infect ionsresistant to quinine (White et l., 1981 : Phillips ct all, 1985).

Antimalarial actirit 'I. This has niot been ats extensivel\ tested, but is appar-ently similar to that of quinine. QinIIdineC hall been Nhow\n to have at lowerM IC for 1P. faliparuim In Thailand than quinine and to be effective againstquinine resistant strains (White ct all. 1981)

Absorption and disposition. Few pharniacokinetic data aire availablIe onlhumans infected with inalaria, but it appears that thle pliarmlacokinetics aresimilar to q1uinine (White et al. 1981, Phillips el alI. 1985). Mleanl plasmlalevels are slightly lower than with equivalent (loses of quinine. Neonatalconcentrations were 82"(' and breast milk concentrations 70(;, of maternalserum %,aluies in at woma n with cairdiovaiscuilar diiseon long-term quinidinetherapy: levels much highe r than those obscrx ed for short-terml quinlintetherapy (see above) (I Iifll and l~kiisian, 1 979),

Me~tabolxpp and elimination . Th is is primarik hvlepat ic (WtJ-851~) but renalclearance may be higher than for quinine ( 2t-35'( ). Lllrited experieceICfromt Thailand suggests that total clearance of qutiiiidin lii not reduced inlpatients with renal farilure any\ more t han in ot her patients with Iew remialaria ( Phillips et all. 198 5). The limination half-lite I,, riot prt'0lonucd innon-mnalarious patients with renal failure.

TREATM ENIOF MALARIA 181

Toxicity. This is also similar to the toxicity of quinine. Prolongation of theQT interval (-24'/-) of the electrocardiogram was two to three timesgreater than with quinine (White et al, 1983a). Two of I1 patients withsevere malaria developed hypotension during the loading dose infusion.Hypotension resolved with discontinuation of the infusion. Quinidine hasbeen given throughout pregnancy without adverse effect to mother or infant(Hill and Malkasian, 1979).

Measurement of levels. The benzene extraction mcthod does not distinguishbetween quinine and quinidine. Newer techniques. including HPLC, arelikely to be more specific.

Mechanism of antimalarial action, This is unknown, but is probably the sameas for quinine.

Resistance. Resistance patterns have not been extensively tested. Quinidinehas been effective in treating quinine resistant infections. It may bind to theparasite's 'clumping site' more effectively than quinine. Resistance toquinidine can be expected to develop with increased use.

Children. No data are available on this for malaria patients.

Formulations. Quinidine sulphate. gluconate, and polygalacturonate areavailable as tablets and capsules containing 10}-324 mg of the drug. Ouini-dine gluconate is available in It ml vials containing 80mg/ml and quinidinesulphate is available in I ml ampoules containing 200mg'ml,

Uses. Ouinidinc is used in the treatment of complicated malaria and multi-drug resistant uncomplicated P. filciparun infections when quinine is notavailable (Table.1 ).

4-Aminoquinolines

Chloroquine and amodiaquine are the only two 4-aminoquinolincs in-ommon use. Both are rapidly acting antimalarials.

Chloroquinc

Chloroqui nc was the blood schizonticide of choice for treating all malariainfections from tle late 1940s to the early 197t)s. ChloroquinC is inCxpcnsi\e,safe and widely available and is still tile drug of choice for treating I'. vivax,P. ov7h and P. tialariatc infections. I lo %eer. due to the dcvelopment ofresistance by 1). filartm to this drug. in 1986 chloroquine can onlx berecommended for treating non-i mmunes with 1). /fdcipartum infectionsacquired in West Africa, ('cntral America above Panania, Ilaiti and the)ominican Republic.

Antimalarial activity. Chloroquine is a rapidly acting blood schizonticide

182 s. L. HOFFMAN

Z

E E

u . d R _ z ii

r V) ,- x r- -

,,-

2& .._

12

- U 7z _ 4

>I I>

-. s - ., - z, ,L -

-. ; ri -.

tL u t

"" - - I=m limill I • i - I I

L)

- Ei0


=.E r- E......

-- - - _uE

,.. , -C , . ... ,.. .-. . .- .

I C ,,

<s- - =

E E- E

uu

r - S E E

< c

E E~

U

CLC

Z3~

U >

184 S. L. HOFFMAN

against P. vivax, P. ovale. and P. malariae, and sensitive strains of P.. - falciparum. It is not effective against exoerythrocytic (liver) stages. but has

some gametocyticidal activity against gametocytes of P. vivax, P. ovale, andP. ,nalariae. and immature gametocytes of P. falciparum.

Absorption and disposition. There have been few studies of the pharmaco-kinetics ofchloroquine in malaria patients and no published studies in severemalaria. Most studies were done in non-infected volunteers and untilrecently used non-specific techniques for determination of levels of the drugin body fluids and tissues. In recent years studies in non-infected volunteersin Sweden (Gustafsson et al, 1983a,b) and in children with uncomplicatedmalaria in Nigeria have been carried out (Adelusi ct al. 1982: Walker et al.1983). In one study of 12 children with malaria who were treated with aninitial oral dose of 10 mg'kg base and a total dosage of 25 mg/kg base during48 hours, chloroquine levels were measured by HPLC. Average peakplasma concentrations of 144 [tg/l were reached in one to eight hours and theterminal half-life after the last dose was 75 hours (Walker et al, 1983). Theabsdrption was more variable than in non-infected volunteers. In anotherstudy in which a fluorometric technique was used for measuring drug levels,erythrocyte/plasma levels of chloroquine showed a progressive decreasefrom a peak of 21 shortly after starting therapy to a stable ratio of 5.3. 72hours later (Adelusi et al, 1982). The decline in ratio correlated directly withthe decline in parasitaemia. a finding consistent with the observation thatparasitized erythrocytes concentrate chloroquine. Peak plasma and ervthro-cyte levels occur at the same time. Studies in healthy subjects have shownterminal half-lives to be longer and erythrocyte/plasma ratios to be lowerthan in infected subjects (Gustafsson et al, 19,3ab).

In healthy adults, peak plasma concentrations after intravenous injectionof 300mg of base have been shown to be 1(0 times higher than after oraladministration of the same (lose (0.831tg/ml compared to 0.07ug,inil)(Gustafsson et al, 1983a). The distribution phase is rapid and may beassociated with potentially serious cardiovascular side-effects: it is notapparent with a four hour infusion of 1()mg/kg base. There is no informationon absorption or distribution after intramuscular injection.

Animal studies indicate that chloroquine accumulates in the tissues:concentrations in spleen. kidney. lungs. heart, and liver were 300-500 timeshigher than those found in the plasma (World I lcalth Organization, 1984).Other studies have shown extensive binding to granulocytes and platelets. Inhealthy subjects the volume of distribution has been as high as 1)01) kgindicating extensive tissue distribution (Frisk-Ilolnberg et al. 1984).Binding to plasma proteins in health- subjects is approximatcly 5(0'.

Aetaholism and elimination. The drug is nmetaboli/ed b\ sidc-chain dc-ethylation in the liver leading Succcs,i\e elv to dcsethIchoroquine and thenbisdesethylchloroquine. a priniar. amine. It can be further dcalk\ latcd to7-chloro-4-aininoqui noline. but in man the primaiy metabolite is dcCerh\ I-chloroquine, which is bioloicall\ acti\c. IPlasnia Ic\cls t the metabolite arc


generally 25-40% of chloroquine levels and it has the same profile ofdistribution and tissue binding as the parent drug. Chloroquine is eliminatedfrom the body slowly, after a single dose of 300mg of base, the drug and itsmetabolites can be detected for up to 56 days in plasma. Because of exten-sive tissue binding and continuous redistribution from the tissues to theplasma, determination of true terminal half-life is difficult, and requires longstudies and extremely sensitive methods. In healthy adults, renal clearanceis approximately 50% of total clearance of chloroquine (mean 412ml/min)(Gustafsson et al, 1983a). Approximately 50%c of chloroquine is recoveredunchanged in the urine. In a single study of the kinetics of elimination of asingle oral dose of chloroquine in patients with renal failure, it was estimatedthat the elimination half-life of chloroquine would be longer in patients withrenal failure (Salako et al, 1986). Chloroquine metabolism and eliminationhas not been studied in patients with severe liver disease.

Toxicity. Toxic manifestations are uncommon and mild with oral doses usedfor treatment of malaria (Weniger, 1979a). They include nausea andvomiting when the drug is taken on an empty stomach. dizziness, headache,blurred vision, fatigue. diarrhoea, and confusion. Symptoms disappearwhen the drug is discontinued. Pruritus, particularly of the scalp, palms, andsoles, has been reported, mostly from Africa. and is associated withrepeated treatment with chloroquine and higher than normal skin levels ofchoroquine and lower than normal levels of desethylchloroquine.

Rapid intravenous administration of chloroquine has been associatedwith hypotension, acute circulatory failure and respirator\, and cardiacarrest, particularly in infants and children. This has not been described withslow intravenous infusion, but has been reported after intramuscularadministration.

There is no information on the disposition of chloroquinc in pregnancy.No adverse effects on the fetus or mother have been reported. It is generallyused as for non-pregnant adults.

Measurement of levels. ItPLC is presently the most sensitive and specificmethod for determining chloroquine levels, which should be measured inplasma (Bergquist and Frisk- Holnberg, 1980). Whole blood levels are 3-1Itimes higher than plasma levels and serum levels are considerably higherthan plasma levels (White, 1985). This is thought to be due to the fact thatchloroquinc and its major metabolite are extensively bound to granulocN tesand platelets with up to 80% of total blood cell contents localized in thesecells (Bergquist and Domcij-Nybcrg, 1983). Serum levels are spuriouslyhigh because of release of chloroquinc from platelets during clotting.

Mechan.m (if antintahrial action. Chloroquine is thought to influencehaemoglobin digestion by the parasite. It binds to haematin (ferriprolo-porphyrin IX). a transient breakdown product of haemoglobin. within theparasite to form a hacmolytic complex \which may disrupt parasite aind hostmembranes, killing the plasmodium (Filch. 1983: World I lealth Organi/a-tion, 1984).

186 s. L. HOFFMAN

Resistance. No infections with P. vivax, P. ovale, or P. malariae have beendocumented to be resistant to chloroquine. However, many clinicians inendemic areas believe that they have treated chloroquine resistant vivaxmalaria. Documentation of resistant vivax infections is difficult because ofthe problem of distinguishing between relapse (not resistance) and recrud-escence (resistance).

P. falciparum infections resistant to chloroquine were first suspected inColombia and first documented in Thailand in the late 1950s (Harinasuta etal, 1962; Peters, 1970); they have now been documented from all parts of themalarious world, except Central America (north of the Panama Canal), theCaribbean islands and West Africa. It is likely that chloroquine resistancewill soon spread to these areas. The prevalence and degree of resistancevaries from that in Thailand and other countries of South-East Asia. wherethe drug is essentially useless for treating non-immunes with falciparummalaria, to that in parts of Africa where it is still highly effective for mostinfections. Production of schizonts in the presence of 1.14 !tmol/l of chloro-qiiine in the in vitro test is considered evidence of resistance (Lepes et al,1980).

There has been much work done on the mechanism of development ofresistance, but there is still no clear explanation. Some hypothesize thatresistant parasites may effectively isolate themselves from the drug byincreasing their surface area, that they induce increased production ofproteolytic enzymes which metabolize haemoglobin and decrease thequantity of haematin available for binding with chloroquine, and that theysynthesize a protein that binds with haematin and segregates it in the form ofthe malaria pigment, haemozoin, making it unavailable for binding withchloroquine. Resistance is maintained throughout the life cycle and trans-ferred to progeny (World Health Organization, 1984).

Renalfailure. Elimination half-life may be prolonged in renal failure (Salakoet al, 1986). However, if chloroquine is used to treat severe malaria withrenal failure, the dosage need not be reduced.

Formulations. Chloroquine is available as tablets of chloroquine phosphate.diphosphate, and sulphate containing from 100 to 3t0mg of chloroquinebase, as a suspension, and as ampoules of chloroquine hydrochloride,diphosphate, or sulphate solution containing 40mg of chloroquine base perml.

Uses. Chloroquine is used in the treatment of all P. vivax, P. malariae, andP. ovale erythrocytic stage infections and sensitive P. filciparum infections(Table 1). It is also used in the chernoprophylaxis of malaria (see Chapter 7).

Amodiaquine

Amodiaquine has always been considered to be similar to chloroquine inpharmacokinctics, clinical efficacy and toxicity. The drug has recentlyreceived increased attention because of new observations regarding its


toxicity, pharmacokinetics (Pussard et al, 1985) and because it has been-: - shown to be more effective than chloroquine for treating infections in Kenya

and Thailand (Hall et al, 1975b; Watkins et al, 1984), effective at anincreased dosage with erythromycin for clearing parasitaemia in multidrugresistant P. falcipartrn in Thailand (Looareesuwan et al, 1985b), and usefulparenterally for clearing parasitaemnia in moderately ill falciparum patientsin Thailand (Looareesuwan et al, 1985b).

The pharmacokinetic findings indicate that amodiaquine undergoes rapidfirst-pass biotransformation in the liver and that monodesethylamodiaquineis the principal metabolite with antimalarial activity (Pussard et al. 1985).The metabolite may be the more appropriate compound for in vitro drugsensitivity testing.

Several studies in Kenya have shown that amodiaquine is slightly moreeffective than chloroquine in achieving radical cure of infections; cure ratesof approximately 80-97% as compared to 50-75% have been found(Watkins et al, 1984; Brandling-Bennett et al. 1985). In Thailand 41 mg/kgamodiaquine base given during three days in combination with five days oferythromycin led to initial clearing of parasitaemnia in 94% of cases, butsubsequent recrudcscence in 52% (Looareesuwan et al, 1985b). Also inThailand, 10mg/kg base given over four hours by intravenous infusionfollowed by three doses of 5mg/kg at 24-hour intervals (total dosage25mg/kg) to patients with moderately severe falciparum disease led toclearing of parasitaemnia and a clinical response similar to that expected withquinine infusion; 55% had subsequent recrudescences (Looareesuwan et al.1985b).

The enthusiasm for amodiaquine has been tempered by the results ofstudies from the Philippines where 25mg/kg amodiaquine base was lesseffective than chloroquine (Watt et al. 1985). and from Pakistan where theywere equally ineffective (Khaliq et al, 1986); 20mg/kg amodiaquine basewas used in Pakistan.

Formnulations. Amodiaquine is commercially available as syrup and tablets,but not for parenteral use.

Uses. Amodiaquine can be used as a substitute for chloroquine (Table 1). Itis now also used in some areas with moderate chloroquine resistance. Themagnitude of increased antimalarial efficacy is not great enough to wariantits use in non-immunes wvith suspected chloroquine resistaint infections. Therole of parenteral amodiaquine for treating moderately severe and severefalciparum malaria remains to be clarified, as does thec appropriate totaldosage for treating chloroquine resistant /P. falciparumn infections.

Diaminopyrimidines

Pyrimethamine is the only drug of this class in use for the treatment ofmalaria. Diaminopyrimidines are slowly acting blood schizonticides andbecause of the rapid and nearly complete development oif resistance the%should not be used alone to treat 1P. falcipyaruin infections. Their antimnalarial

188 S. L. HOFFMAN

activity is augmented by the addition of sulphonamides, leading to a svner-gistic. sequential block of folic acid synthesis.

Pyrimethatnine

Antimalarial activity. Pyrimethamine is active against the erythrocytic stagesof all four human malarias (blood schizonticide) and against the exoervthro-cytic stages of P. falciparwn and to a lesser extent P. vivax and perhaps P.ovale and P. malariae. It is not effective against hypnozoites of P. vivax andP. ovale and cannot be used for radical cure of these infections. It has nogametocytocidal activity, but has some sporonticidal activity.

Absorption and disposition. Pvrimethamine is absorbed relatively rapidlyafter oral administration. The peak plasma level is reached in two to sixhours in healthy volunteers and then declines slowly with an eliminationhalf-time of 80)-95 hours (Jones and Ovenell, 1979: Ahmad and Rogers,1980; World Health Organization, 1984). In malaria patients, plasma con-centrations are 300-600 ig/l 24 hours after a standard therapeutic dose ofpyrimethamine-sulfadoxine (Hoffman et al, 1985). Red cell and plasmaconcentrations are similar (Ahmad and Rogers, 1980). The drug is moder-ately bound to body tissues with a volume of distribution of approximately31/kg (Ahmad and Rogers, 1980). Pyrimethamine has been reported to be85-87% protein bound (Ahmad and Rogers, 198(0).

Metabolism and elimination. Urinary excretion has been shown to continuefor over 30 days and account for 16-32,, of a single oral dose of 100mg(Smith and lhrig, 1959). After a single dose of 50mg. a mean of 3.4% of thetotal dose was excreted daily for seven days (Sheehy et al. 1969).

Toxicity. No significant toxic symptoms have been reported for the doses ofpyrimethamine used for treatment of malaria (Weniger, 1979b). It may beused for treatment of malaria in pregnancy. The question of teratogeniceffects of long term chemoprophylaxis during pregnancy and the fatalcomplications associated with use with sulfadoxine are discussed in Chapter7 and in the section on pyrimethamine-sulfadoxine below.

Measurement of levels. Spectrophotometric and chromatographic tech-niques have been used. An HPLC technique has recently been repored(Timm and Weidekamm. 1982), In vitro growth of drug sensitive P. .alci-parum is inhibited by It) giI pyrimethaminc (Nguven-Dinh and Payne,1980). Following a single 1.25 mg'kg dose this level is maintained for morethan a week (I loffman et al, 1985).

M'chanism o'antimalarial atimn. Pyrimethamne is an inhibitor of dihvdro-folate reductase, an enzme that is essential for s\ nthesis. by the parasite, ofthe active form of folatc which is required for nucleic acid svnthesis.

Resistance. Resistance of 1'. hlciparitn to pyrimcthaminc was first noted in

TREATMENI OFMALARI. 189

the 1950s shortly after pvrirnethamine was introduccd. Thus far the onlymechanism of resistance to any antimalarial that has been clearly identitiedis the production of mutant dihvydrofolate reductase in pyrimethainineresistant P. berghei (World Health Organization. 1984). It is assumned thatresistance develops in the same way with P. falciparuni.

Rena/failure. No information is available oil this point.

Formulations. Pyrimethamine is available as 25mg tablets and as a syrupcontaining 6.25 mg pyrimethamine per 5 mi.

Uses. Pyrimcthamine is no longer used by itself for the treatment of malaria(see sulfadoxine-pyrimethamine below).

Suiphonamides and suiphones

Sulfadoxine. sulfamre topyrazi ne. and dapsone are the most commonly usedantimalarials in this class. Only the two former compounds are used fortreatment of acute malaria, while dapsone is used for chemloprophylaxis.Because of the toxicity of long acting sulphonamides. there is now renewedinterest in the use of short acting drugs such as sulphamethoxazole. particu-larly for chemoprophylaxis.

Sulfadoxinte anid sulfamnetopyraziiie

These are both long acting sulphonamides. Both are used in combinationwith pyrimethamine for the treatment or prophylaxis of malaria. Sulfa-doxine hats at longer half-life and is more commonly used.

Antimialarial activitY. They are slow-acting blood schizonticides which areeffective against sensitive strains of P. falciparum., but less so against theerythrocytic stages of the other species which infect man. They have noeffect on exoerythrocvtic st ages, may lead to a brief increased pro;duction ofgametocytes. and may have some sporonticidal activity.

Absorption and disposition. They' are rapidly and well absorbed. They arehighly bound to plasma proteins (Mandell and Sande, 1980).

Metabolism and1( elimination. Only at small proportion is metabolized, about5(4; to the acetyl derivative and 2-31( to the ghucuronide. Acetvlation isgenetically determined, some people being fast and some slow acetvlators.Distinction between fast and slow acety lators is of little practical importancein treatment of mialaria, since little of the drugs is metabolized. They areexcreted slowly in the urine. Tile half-elimnination time of sulfadoxine isestimated to bie between 100and 2001 hours and that of sulphalene is, about 65hours ( Mandell and Sande. 1980).

ToxicitY. Silphionarniides are generally well tolerated, but they can cause

190 S. L. HOFFMAN

hepatitis, urticaria, erythema multiforme, Stevens-Johnson syndrome,toxic epidermal necrolysis, agranulocytosis, serum sickness, haemolysis inindividuals with glucose-6-phosphate dehydrogenase (G-6-PD) deficiency,methaemoglobinaemia in patients with hereditary nicotinamide adeninedinucleotide (NAD) methaemoglobin reductase deficiency, and kernicterusin premature infants (Mandell and Sande, 1980). Recently, severecutaneous skin reactions have been associated with the use ofpyrimethamine-sulfadoxine for chemoprophylaxis of malaria (see below)(Editorial, 1985a; Miller et al, 1986). Sulphonamides are contraindicated inthe first month of life. There is no evidence that they are teratogenic; theyare often used to treat pregnant women with acute malaria infections.

Mechanism of antimalarial action. Sulphonamides and sulphones inhibitplasmodial dihydropteroate synthetase an enzyme necessary for incorpor-ation of p-aminobenzoic acid (PABA) into folic acid.

Resistance. Resistance to sulphonamides is widespread and they cannot beused alone for the treatment of malaria. The mechanism of resistance isunknown. Several reports indicate that rodent malarias can thrive in theabsence of PABA and that sulphonamide resistance can be induced bypassaging parasites in PABA-deficient animals (World Health Organiza-tion, 1984).

Renal failure. No information is available on this in malaria.

Formulation. Oral and parenteral formulations of sulphonamides areavailable in different areas.

Uses. Sulphonamides are used only in combination with pyrimethamine.There is now interest in combining short acting sulphonamides such assulphamethoxazole with trimethoprim or proguanil for daily chem oprophy-laxis.

Pyrimethamine-sulfadoxine (pyrimethaeiine-sulfaetopyrazine)

The combination of pyrimethamine (dihydrofolate reductase inhibitor) witha sulphonamide or sulphone (PABA inhibitor) has been shown to potentiateantimalarial activity and produce radical cure of malaria infections which areresistant to each of the individual components (World Health Organization.1984). The most commonly used combination is pyrimethamine-suifadoxine(SP, Fansidar) because the half-lives of the two components are long andsimilar (90-200 hours) allowing for single dose treatment and weekly chemo-prophylaxis. Sulfametopyrazine (half-life 65 hours) has also been used withpyrimethamine for treatment and prophylaxis, and dapsone (half-life. 17-33hours) with pyrimethamine (Maloprim) for prophylaxis.

Pyrinethamine-sulfadoxine (SP)

When first introduced. SP was considered an ideal drue for the treatment of


uncomplicated falciparum malaria; it was effective in a single dose and-. . .without significant side-effects. Resistance has developed in many parts of

the world; in some parts of Thailand it is totally ineffective. In addition, itsuse has been associated with fatal skin reactions (see section on toxicitybelow).

Antimalarial activity. SP is effective for treating many P. falciparum infec-tions resistant to 4-aminoquinolines and some which are resistant to pyri-methamine and sulfadoxine alone. It is effective for clinical cure of P. vivaxinfections, but the time until clearing of parasitaemia and clinical cure issignificantly longer than with chloroquine. It has not been extensively testedagainst P. malariae or P. ovale. It has no effect on exoerythrocytic infec-tions. It has no gametocyticidal activity and may have limited sporonticidalactivity. Studies in Thailand have indicated that use of SP is associated withan increase in P. falciparum gametocytes during the subsequent month(Andre and Doberstyn, 1977) when compared to other antimalarials, andstudies in Pakistan have shown the opposite (Strickland et al, 1986).

Absorption and disposition. Limited information suggests that the combi-nation does not affect the pharmacokinetics of the constituents.

Metabolism and elimination. These are also the same for the combination asfor the constituents.

Toxicity. Toxicity is as expected for the constituents. SP was first recom-mended for routine chemoprophylaxis of American travellers to chloroquineresistant malarious areas in 1982. From 1982 to July 1985 there were 24 casesof severe cutaneous reactions (erythema multiforme, Stevens-Johnsonsyndrome and toxic epidermal necrolysis) documented in Americans takingSP; seven of the reactions were fatal. Six of the seven fatal reactions were inindividuals who continued to take SP after the onset of the toxic symptoms.Twenty-three of the 24 reactions were associated with multiple (two to five)doses of SP. It is estimated that the incidence of fatal reactions in Americantravellers takingSP hasbeen 1/11 OO0to 1/25 000. It is thought, but not proven,that the reaction is to sulfadoxine and has no relationship to either pyrimeth-amine or chloroquine (see Chapter 7) (Editorial, 1985a; Miller et al, 1986).

SP is not recommended for infants less than one month of age. The safetyof SP in pregnancy has not been established, but it has been used to treatmalaria infections in pregnant women without complication (Main et al,1983). Many think that it can be safely used for malaria chemoprophylaxis inpregnancy.

Measurement of eLels. This is as for the constituents.

Mechanism of antimalarial action. The sequential blockade of folic acidsynthesis potentiates the antimalarial activity of pyrimethainine and sulfa-doxine.

192 S. L. HOFFiMAN

........ -~ Resistance. Resistance to SP has developed rapidly in some areas of theworld. This is a major problem in Thailand and neighbouring countries, animportant problem in Brazil and New Guinea, and an emerging problem inIndonesia, East Africa, and South America (Darlow et al, 1982; Pinich-pongse et al, 1982; De Sousa, 1983; World Health Organization. 1984;Hoffman et al. 1985).

Renal failure. No information is available on this.

Formulations. Tablets and ampoules contain 500rag of sulfadoxine (orsulfametopyrazine, tablets only) and 25mg of pyrimethamine. SP is avail-able as a syrup in some parts of the world.

Uses. The major use of SP is the treatment of uncomplicated. chloroquineresistant P. falciparurm infections (Table 1). The parenteral preparation hasbeen used with quinine for treating cerebral malaria (Naparstek et al, 1981).Oral SP is also used for chemoprophylaxis (see Chapter 7).

Tetracyclines

Tetracycline, doxycycline, and minocycline are weak and slowly actingblood schizonticides that can be used effectively to treat chloroquine and SPresistant P. falciparuin infections in combination with other antimalarials.Because of their slow onset of action and inadequate efficacy when givenalone, they should be used with a faster acting antimalarial such as quinine.The combination of quinine and tetracycline for seven days can be expectedto cure 95% of multi-resistant P. falcipartom infections (Pinichpongse et al,1982).

Tetracycline

Antimalarial activity. Tetracycline is effective against the exoervthrocvticand erythrocytic stages of !. falcipartim. but not gametocytes. Its activityagainst other species of malaria is unknown, but is thought to be inadequate.

Absorption and disposition, metabolism and elimination, east'remtent oflevels and toxicity. See a standard textbook of pharmacology for details ofthis.

Mechanism of action. This is unknown but. by analogy with its mchanisin ofaction in bacteria, it is thought to interfere with protein synthesis.

Resistance. Tetracyclines have not been extensivel, tested as single drugtherapy in the field. When seven days of tetracycline were given with threedays of quinine for treatment of P. falcipartm in Eastern Thailand. an areawith multi-resistant 1. falciparumn. seven of 71 patients had RI resistance,and none had RII or RIll responses (Boudreau et al, 1984). The combi-


nation of tetracycline and chloroquine was inadequate for treating chloro-quine resistant P. fah'iparwn infections in Thailand (Phillips et al, 1984).

Renal failure. See a standard textbook of pharmacology for details on this.

Children. Tetracyclines are not recommended for children less than eightyears of age because of the possibility of causing tooth discoloration, hypo-plasia of tooth enamel, and impaired bone growth.

Pregnancy. Tetracyclines are contraindicated in pregnancy for the samereasons as in young children.

Formulations. Oral and parenteral (see standard text).

Uses. Tetracycline is used in combination with a faster acting antimalarial.usually quinine, to achieve radical cure of multidrug resistant P. fidciparwm(Table 1). In populations where side-effects to quinine are common. thelength of treatment with quinine can be reduced to three days if tetracyclineis given with quinine. Tetracycline has also been used with amodiaquine(40-50mg/kg) to achieve radical cure of P. falciparuin from an area ofThailand known to have a high prevalence of chloroquine resistance(Noeypatimanond et al, 1983a).

Doxycycline

The actions of, and indications for, doxvcycline are similar to those fortetracycline. but it only needs to be given twice daily.

Quinoline methanols

The only drug of this class in use is mefloquinc.

Mefloquine

Mefloquine is the most important antimalarial drug developed by the USArmy antimalarial drug development programme. When lirst developed itwas thought to be the ideal antimalarial: effective against all species ofhuman malaria, effective against in ultidrug resistant P'. fitlciarum, admin-istered in a single oral dose, rapidly acting, and without serious side-effects(Trenholme et al. 1975). Ilowcver. isolated caes of resistance have beendocumented from many parts of the world (Editorial. 1983). and it appearsthat resistance is now developing in Thailand (Boudreau ct al, 1982, 1984)and is present in Irian Java (I loffiman ct al. I1985).

Antimalarial activit'y. Nictloquinlc has been shown to be an cffcctive bloodschizonticidc against P. .fahiparun, P. vivax and P. malriae (Iren holme etal. 1975: l)oberstyn et al. 1979a. Dixon et al. 19S3, 1985: E-ditorial. 1983). It

194 S. L. HOF-FMAN

has not been tested against P. ovale. Its other actions are unclear, but they' are likely to be similar to that of quinine.

Absorption and disposition. Mefloquine is available in tablet form, but it isbetter absorbed as a liquid (Desjardins et al. 1979). Limited studies suggestthat elimination half-life is prolonged in malaria patients compared tovolunteers and in adults with malaria as compared to children (White, 1985).The pharmacokinetics are not the same as for quinine. There has beenconsiderable individual variation in absorption and pharmacokinetics-observations which led early investigators to predict that there would alwaysbe a small percentage of P. falciparumn infections not cured by mefloquine(Desjardins et al, 1979). In adult, non-infected volunteers given17-22mg'kg mefloquine in tablet form, the time required to reach peakwhole blood concentrations was 12-28 hours, the peak whole blood concen-tration was 0.7-1.5[tg/ml, the apparent volume of distribution was4.6-16.81/kg and the whole blood elimination half-life was 8.1-19.5 days(Desjardins et al, 1979). In another study in which plasma levels weremeasured, peak plasma levels of I jig!ml were reached in 2-!2 hours, theapparent volume of distribution was 13.5-29.1 /kg, and the terminal half-life was 15-33 days (Schwartz et al. 1982). In malaria patients given 15 mg kgmefloquine in combination with SP. serum levels were 1. 1-1.9 tg'ml after 24hours (Hoffman et al. 1985).

The large volume of distribution indicates that the drug is extensivelytissue bound. In plasma it is 99% bound to protein. Mefloquine is concen-trated in erythrocytes by high affinity binding to the red cell membrane. Involunteers, the concentration in ervthrocvtes has been estimated to bedouble that in plasma (Schwartz et al. 1982). and in vitro as high as 60 timesthat in the extracellular fluid (San George et al. 1984). Pharmacokinetic dataderived from plasma and whole blood measurements will differ. The volumeof distribution, clearance, and terminal half-life have been shown to bedecreased in children. When given to comatose patients by nasogastric tube.absorption was good, but less complete and rapid than in patients withuncomplicated malaria (Chanthavanich, 1985). It could not be detected inthe cerebrospinal fluid or peritoneal dialysate of these patients.

Merabolism atnd elimination. The drug is primarily eliminated by biotrans-formation, and within four hours of oral intake the mmi metabolite.2.8-trifluoromethyl-quinoline-4-carboxylic acid, can be detected in theplasma. Within a few days. the concentration of the metabolite exceeds theconcentration of nefloquine the metabolite has a much smaller volume ofdistribution. Only about 5'(' of a doe of inefloquine is excreted unchangedin the urine during four weeks. Clearance of metloquine ma\ be more rapidin children than in adults (World I lealth Organizat ion. I9841.

Toxicity. No serious adverse reaction"s hme been associated \\ith the u,,e ofmefloquine. Side-effects were monitored in o\er S1)11 ptlicnls included inclinical trials throughout the world (World I lealth Organiiat ion. 984). Theoverall incidence of reactions was: natusct 17.7'( , \omiting 13.3( . diair-


rhoea 14.9% dizziness 14.7%. abdominal pain 8.3, self-limited sinus

bradvcardia 8.9%, and neuropsychiatric changes 0.9%. No adverse bio-chemical or haematological changes have been noted. No information isavailable on use in pregnancy.

Measurement of levels. A number of techniques have been used foimeasuring mefloquine levels. HPLC (Grindel et al, 1977) and gas-liquidchromatography with electron-capture detection (Heizman and Geschke,1984) are recommended.

Mechanism of antimalarial action. This is unknown, but is thought to besimilar to that of quinine.

Resistance. Most initial clinical trials showed cure rates of >950. Resistantinfections were attributed to inadequate absorption due to either vomitingor host factors. Cases of primary drug resistance were first described fromThailand (Boudreau et al, 1982) and East Africa (Bygbjerg et al, 1981).Among 62 patients treated with mefloquine in Thailand, five showed RI typeresistance and two showed RII type resistance (Boudreau et al. 1984).

In vitro studies have been extensive. In vitro findings predictive of in vivoresistance have not been established by rigorous field testing. However,most investigators have considered growth of schizonts in the presence of3.2umol mefloquine/l blood (I.2.ugml) as indicative of in vitro resistance(Smrkovski et al. 1983). Using this criterion, in vitro resistance has beendocumented in the Philippines (Smrkovski et al. 1983), Indonesia (Hoffmanet al. 1985) and, with increasing frequency, in Thailand (G. Childs, personalcommunication). Recently the World Health Organization has indicatedthat it may be more appropriate to consider the growth of schizonts in thepresence of 6.41tnmol/I rather than 3.2i.mol/l as indicative of resistance (D.Payne. personal communication).

The mechanism of drug resistance to mefloquine is unknown. It has notbeen estat'ished whether there is cross-resistance between mefloquine,quinine, an, I chloroquine. Limited observations in Thailand (K. Webster,personal communication) and Indonesia (lloffman et al, 1986) suggestcross-resistance betwecn1 quinine and metloquine but not with chloroquine.Resistance to mefloquine develops more readily in P. berghei parasites thatare already resistant to chloroquine than in those that are sensitive tochloroquine.

Renalfailure. No information is available on this.

Formulations. Mefloquinc is available as tablets of 250)nmg (Lariam.

ULse.. Mefloquine (Lariam) is now\ conimercialh available only in S\wi,zer-land where its use is reserved for the treatment of multidrug resistant P.falciparum infections (Table 1). As resistance of 1). fidcipartn to chloro-quine and SI' increases, the use of niefloquine, pairticularly in non-endemicareas, is likel\ to increase.

196 S. .. Ho0VViAN

Mefloquine-pyrimethatnine-sulfadoxine (MSP)

Mefloquine (M) has recently been released for clinical use in Thailand incombination with SP (MSP, Fansimef). The combination is being used in thehope that, as in experimental models, the emergence of resistance to thecomponents by drug pressure and selection, especially to mefloquine, can bedelayed. The animal studies suggest additive antimalarial activity (Merkli etal, 1980; Peters and Robinson, 1984). Multiple clinical trials indicate that thecombination is well tolerated and curative in over 95% of P. falciparurninfections (World Health Organization. 1984). There is, however, dis-agreement among malaria experts regarding the appropriateness of wide-spread use of the combination as opposed to the individual components.This disagreement is based on several facts and observations. In animalmodels there is no reduction in the rate of emergence of drug resistant P.falciparum by use of the combination if the isolate is already resistant to M orSP (Merkli et al. 1980: Peters and Robinson, 1984). In many areas whereMSP is being used or will be used, resistance to SP is common. Fatalreactions to SP have been described (Editorial, 1985a; Miller et al. 1986).These reactions are rare and SP is still appropriately and extensively used.However, some people wonder about the wisdom of trying to preserve theefficacy of mefloquine by using a potentially dangerous drug. None of thehuman studies have demonstrated a clinical advantage of using the combi-nation compared to the components. Limited observations from one clinicalstudy (Hoffman et al, 1985) and one in vitro study (Milhous et al, 1983) havesuggested that there may, be antagonism between M and SP in some isolates.

Formulations. MSP (Fansimef) is available in tablets containing 250mg ofmefloquine, 25 mg of pyrimcthamine and 5)0 mg of sulfadoxine.

Uses. MSP is recommended for the treatment of multidrug resistant P.falciparuim (Table 1).

Sesquiterpene lactones

QinghaosU and its derivatives are the only ait imalarials of this class.

Qinghaosu and defrlatires

Reports from China indicate that use of linglhaosu (OIlS) and its deriva-lives, artemet her and sodium artesunate. is associated with high clinical curerates and more rapid defer\escence and pari,,ite clearance than \\ithmetloquinc. chloroquine. quininc, MSP or SP. RIaCs of recrudescence arehigh. indicating that imtproved dosage regimenis or concomit ant administra-tion of another blood schizonticide is required (Oinghaosu AntimalariaCoordinating Research Group. 1979. China Cooperative Rc,,earch Groupof Oinhaosu nd its Dnerivatiimmvials. 1982: Gioqia ct al.1982: liang ei al. 1S 2ia( Guoqlio, 1984; Ii ct al. 1984: Kla\nian. 1985).

TREATMF-NT OF MALARIA 197

Antimalarial activity. Available information indicates activity against theerythrocytic stages of P. falciparum and P. vivax. but not against exoery-throcytic stages of P. vivax or gametocytes of P. falciparum (L. Guoqiao andK. Arnold, personal communication).

Absorption and disposition. Plasm'a protein binding of artemether has beenreported to be 77% (China Cooperative Research Group of Qinghaosu andits Derivatives as Antimalarials. 1982). No other human studies areavailable,

Metabolism and elimination. There are no available reports of humanstudies on this.

Toxicity. QHS and its derivatives are apparently well tolerated and have notbeen shown to produce haematological, renal. hepatic or electrocardio-graphic abnormalities. Little information is available regarding use in preg-nancy. QHS was used in 16 pregnant women with cerebral malaria, 15 ofwhom survived (Guoqiao et al, 1984). QHS has been reported to beembryotoxic in rats and mice (China Cooperative Research Group of Qing-haosu and its Derivatives as Antimalarials, 1982, World Health Organiza-tion, 1984; Klayman, 1985).

Measurement of levels. Thin-layer chromatography (Xinyl et al, 1985) andHPLC (Klayman, 1985) have been used to measure levels in animals.

Mechanism of action. The mechanism of action of QIS is unknown but it isthought to act by interruption of protein synthesis. QHS and derivativesaffect plasmodia in a number of ways, including inducing mitochondrialswelling (Jiang et al, 1985). Studies in China indicate that 1IS works earlyin parasite development by destroying the tiny and small ring forms, ascompared to other antimalarials which work later in the life cycle (Guoqiaoet al, 1984; Li et al. 1984).

Resistance. Recrudescence rates for P. f]iihipariom and 1P. vivax are highafter treatment with OilS (Guoqiao et al, 1984). It is not vet clear whetherthis indicates resistance or inadequate dosages of the drug. Rates of P.falciparumn recrudescence at one month were I I) for intramuscularartemether (oil preparation), 40-51)' for 01IS suppositories and intra-venous artesunate, and 75% for oral 01 IS (Guoqiao et al, 1984, L. Guoqiaoand K. Arnold. IM i>onal comniunication). Resistance of I'. berghei to Of IShas been easily induced in the laboratory.

Renal failure. Studies of the use of 01 IS in renal failure are incomplete. butit has apparently been well tolerated in patients with renal failure (Guoqiaoct al, 1982: (iuoqiao et al, 1984).

Forinulations. 01 IS (tablet. rectal Suppository. water and oil suspension forintramuscular use), artmct her (oil suspcnsion for intramstcular use) and

198 S. L. HOFFMAN

sodium artesunate (for intravenous use) have been studied in China. New-".*.. .. -,formulations are apparently being developed.

Uses. The efficacy of OHS has only been evaluated in China. Availableinformation suggests that the most important potential use for OHS is forrapid clearing of parasitaemia in patients with severe falciparum malaria.QHS reduces parasitaemia by 95%, 25% faster than quinine and clearsparasitaemia twice as fast as quinine. However, historical comparisons donot indicate any difference in mortality between OHS- and quinine-treatedpatients with cerebral malaria. A controlled trial comparing OHS andquinine in severe malaria is required.

Phenanthrene methanols

This is another class of antimalarials developed by the US Army pro-gramme.

Halofantrine

The most promising drug in this class is halofantrine. It has been tested involunteers with induced and naturally occurring malaria and found to beeffective in multidrug resistant falciparum infections in Thailand. Initialtrials in Thailand showed radical cures in only 65% of patients given a single1500mg dose. When the dosage regimen was modified to three 5(X) mg dosesgiven at six-hour intervals, greater than 95% radical cures were achieved(World Health Organization, 1984). Further research is in progress todetermine optimal formulations and dosing schedules.

8-Aminoquinolines

Primaquine is the only drug of this class in widespread clinical use.

Primaquine

Primaquine is the only drug used to prevent relapse (tissue schizonticideagainst late exoerythrocytic stages). It is also an excellent causal prophy-lactic (primary exoerythrocytic stages) and the only effective drug used toreduce transmission (gametocyticide and sporonticide). It is not used totreat acute blood stage infections.

Antimalarial activit'. Primaquine is gametocyticidal and sporonlicidal for allhuman species of malaria. It is highlv effective against the exoervthrocvtic(liver) stages of P. falciparum and I'. vivax and probablv P. ovale (acti\ itvagainst P. malariae unknown). It is an effective blood schizonticide. but onlyat dangerously high doses.

Absorption and disposition. Primaquine is rapidly absorbed after oraladministration. Peak plasma levels are reached in one to three hours (Bruce-


.. "Chwatt, 1981). Tissue distribution of the parent drug is unknown. Studies inanimals with pamaquin, a related 8-aminoquinoline, indicated extensivetissue distribution, but there was no pamaquin in the tissues of a human whodied of an overdose of pamaquin.

Metabolism and elimination. After oral administration, primaquine israpidly converted in the liver to carboxyprimaquine. The elimination half-life of primaquine is three to seven hours. Twenty-four hours after a singledose, plasma concentrations of the metabolite are 50 times that of the parentcompound. None of the metabolite has been detected in the urine, so it islikely that carboxyprimaquine is further metabolized before excretion. Theantimalarial activity and toxicity of the metabolites are unknown, but anti-malarial activity is likely to be significant since daily and even weekly dosageregimens have been successful (Greaves et al, 1980: Mihaly et al. 1984;Ward, 1985; White. 1985).

Toxicity. Gastrointestinal side-effects including nausea, vomiting, anorexia,dizziness, epigastric distress and abdominal pain or cramps can be expectedin 5-10% of adults receiving 15-30mg of primaquine base per day for 14days. The incidence of gastrointestinal side-effects increases with increasingdoses and is reduced by ingestion of the drug with meals (Weniger, 1979c).

Dose-dependent, reversible agranulocytosis and granulocytopenia havebeen described with extremely high doses of primaquine. but not withtherapeutic doses. Dose-dependent, reversible methaemoglobinaemia iscommon with high doses of primaquine and has been described after usualtherapeutic doses. It is less common in glucose-6-phosphate dehydrogenase(G-6-PD) deficient individuals than in normal individuals, since oldererythrocytes are the major source of methaemoglobin and these are also themost susceptible to haemolysis. Methaemoglobinacmia may be severe inindividuals with congenital deficiency of NAD methaemoglobin reductase.

Acute intravascular haemolytic anaemia is the most serious side-effect ofprimaquine. It is caused by oxidant stress in individuals with erythrocyteG-6-PD deficiency, an inherited X-linked trait occurring most frequently inBlacks and persons of Mediterranean and Asian extraction. In most Blackswho have 1(-20% of normal G-6-PD activity, haemolysis is generally self-limited, even when drug administration is not stopped. Mediterraneans andAsians may have only 0-7% of normal activity and hacmolysis is moresevere and may continue even after the drug has been withdrawn. In adultBlacks weekly administration of 45 mg of primaquine base has been associ-ated with less haemolvsis than dailv administration of 15 Ing. If possible,testing for G-6-PD deficiency should be done before primaquine is given.

The safety of primaquine in pregnancy has never been established and itsuse is not recommended.

Measurement of levels. Recently IIPLC and gas chromatography-massspectrophotometry have been used to measure primaquine levels (Greaveset al, 1979: Baker et al, 1982: Ward et al, 1983).

200 S. L. HOFFMAN

Mechanism of antimalarial action. This is unknown, but is thought to involvean effect of a metabolite on the mitochondria of exoerythrocytic stageschizonts.

Resistance. Strains of P. vivax vary in the susceptibility of exoerythrocyticstages to primaquine. The Chesson type strain of P. vivax detected in NewGuinea in 1944 and similar strains subsequently described in the SolomonIslands, Indonesia, and Thailand is relatively resistant to primaquine andrequires doubling the dosage of primaquine (Bruce-Chwatt, 1981).

Renal failure. No information is available on this, but indications arelimited.

Formulations. Primaquine is available in tablets containing 13.2 and 26.3 mgof primaquine phosphate, equivalent to 7.5mg and 15 mg, respectively, ofprimaquine base.

Use. Primaquine is used for radical cure of P. vivax and P. ovale infections(tissue schizonticide) (Table I) and for blocking malaria transmission(gametocyticide and sporonticide). It is sometimes used as a causal prophy-lactic for all four human malaria infections, but to be effective for causalprophylaxis it probably has to be given more frequently than once a week.More research is needed to establish the safety and efficacy of primaquinefor chemoprophylaxis and for reducing transmission of malaria.

Biguanides

Proguanil, cycloguanil, and chlorproguanil are the three antimalarials of thisclass that have been used. Like pyrimethamine they are dihydrofolatereductase inhibitors. Because of their slow onset of action, in recent v'earsthey have only been used for causal prophylaxis of P. falciparum infectionsand suppressive chemoprophylaxis of all four human malarias. For reasonswhich are unclear, proguanil, the biguanide with the shortest half-life, is theonly one of the three in common clinical use. Biguanides are highly inhibi-tory to the primary exoerythrocvtic stages of P. falciparum (not P. viax), toasexual crythrocytic stages of all four human malarias. and to the develop-ment of sporozoites in mosquitoes (probably all malaria). They are thusused as causal prophylactics (P. falciparum). suppressive prophylactics (allfour human malarias), and transmission blocking agents (all four humanmalarias). Unfortunately, resistance of all stages of the parasites tobiguanides may develop rapidly, either by biguanidc drug pressure or bypyrimcthamine drug pressure. Because of the rapid spread of chloroquineresistance and the lack of toxicity of biguanides. recently there has beenrenewed interest in the use of biguanidcs for chenoprophylaxis, either aloneor in combination with other anlinalarials such as short acting sulphon-amides or sulphones. There is presently no indication for their use fortreatment of acute malaria. Use of higuanidcs in chemoprophvlaxis isdiscussed in Chapter 7.


Other antibiotics

Although many antibiotics, including chloramphenicol and rifampicin, havesome antiplasmodial activity, only the tetracyclines and lincomycin deriva-tives and perhaps erythromycin have been shown to have significant anti-plasmodial activity.

Clindamycin

Clindamycin is a slow-acting blood schizonticide which, both alone and withquinine, has been used for the treatment of falciparum malaria with moder-ately good to excellent results, but often with acute gastrointestinal side-effects. Based on the results of a number of studies (El Sadiq et al, 1985;Westerman, 1985), the manufacturer now recommends clindamycin10mg/kg twice a day for five days for treatment of P. falciparum infections(Westerman, 1985). Further studies are required, but clindamycin mayprove to be a useful adjunct to quinine or other rapid acting blood schizonti-cides for therapy of multiresistant P. falciparum in children who cannot begiven tetracycline. Although clindamycin is often used in pregnancy, itssafety during pregnancy has not been established.

Erythromycin

In vitro studies indicated that erythromycin and chloroquine were syner-gistic against chloroquine-resistant strains of P. berghei (Westerman, 1985).Unfortunately, field studies in Thailand (Phillips et al, 1984) and Africa (D.Brandling-Bennett, personal communication) showed that chloroquine anderythromycin were not effective for treating chloroquine resistant P. falci-parum infections. Recently the combination of erythromycin and high doseamodiaquine was shown to be effective for clearing parasitaemia. but not forradical cure (52% recrudescence) in Thais with P. falciparun infections(Looareesuwan et al, 1985b). Clearing of parasitaemia may have beenimproved by addition of erythromycin, or may have been produced by highdose amodiaquine therapy alone.

Other blood schizonticides

Pyridinemethanols, triazines, acridines, pyronardine, piperaquine, dabe-quine, and naphthoquinones have all been evaluated for treatment ofmalaria. None are ready for widespread clinical use (World tlcalth Organi-zation. 1984).

TREATMENT OF SPECIFIC INFECTIONS

P. falciparum: complicated

Any patient with a 1. falciparum infection who has > 3- parasitaemia, anabnormal level of consciousness, renal, cardiac, hepatic or pulmonary dys-

202 S. L. HOFFMAN

...- .. .function, shock, or severe diarrhoea or vomiting should be considered tohave complicated malaria. Resistance to chloroquine has been reportedfrom nearly all malarious areas of the world. The drug of choice for treatingall patients with complicated malaria is quinine dihydrochloride by slowintravenous infusion (Table 1). This recommendation could be modified ifone were practising in an area such as West Africa, the Caribbean, orCentral America above Panama, where the parasites were known to besensitive to chloroquine and patients with complicated malaria consistentlyresponded to chloroquine, or in China where qinghaosu or its derivatives areavailable. If quinine dihydrochloride is not available, intravenous quinidinegluconate is an excellent substitute.

Quinine treatment

The dosage of quinine is dependent on the sensitivity of the organism toquinine. Parasites should be cleared from the circulation as rapidly aspossible. In areas of the world, such as Thailand and Irian Jaya. where theminimal inhibitory concentration of quinine is high, a loading dose of20mg/kg quinine dihydrochloride (16.7mg/kg base) administered in3-6ml/kg of intravenous fluid during two to four hours, followed by 10mg/kgevery eight hours for seven days. has been safely and successfully used torapidly achieve and maintain plasma levels of 10-15mg/I (White et al, 1983b;Hoffman et al, 1984a). Dosage regimens for complicated malaria in areas ofthe world where P. falciparun is more sensitive to quinine have not beenestablished. Regardless of the dosages required, a loading dose should beused to rapidly achieve appropriate plasma levels of quinine, unless thepatient has already received quinine. Patients, specially children and preg-nant women, recovering from their infection may require increased doses ofquinine on days five to seven to achieve radical cure of the infection withquinine alone (Chongsuphajaisiddhi ct al, 1981a: White, 1985). Quininetherapy is best monitored by measuring plasma levels of the drug by HPLCor benzene extraction fluorescence. Levels of 5-15mg/I are required,depending on the sensitivity of the organism, and levels above 2(1mg/I areconsidered dangerous. Toxicity is monitored by measuring blood pressureand by electrocardiogram. If plasma levels are unobtainable and the patientdoes not improve within 48-72 hours, individual doses should be reduced by30%, but still given every eight hours. Since 80% of quinine is metabolizedin the liver, renal failure is not an indication for a marked reduction indosage and the same guidelines pertain. Quininc pharmacokinetics have notbeen studied in patients with severe parenchvmal liver disease. If plasmailevels cannot be followed, prudence would suggest reduction of doses by50% in such patients. Levels of parasitemiia frequently increase in the six to12 hours after initiation of therapy, but should be less than 25 ( of initiallevels within 48 hours of the onset of therapy. Reports from New Guineaindicate that intramuscular quinine dihydrochloridc is safe, \well absorbedand effective in severe malaria (Stace et al, 1983). Others suggest thatabsorption of intramuscular quinine may be erratic in severe malaria(White, 1985) and abscesses and ner\e damage at injection sites are

• " I II I I I [[ [ [


common (Guyer and Candy, 1979; Thuriax, 1982ab). If it is possible toestablish an intravenous infusion, delivery by this route is highly preferable.If an intravenous route cannot be established, quinine can be given by deepintramuscular injection (10-15mg/kg) every 8-12 hours until the patient isable to tolerate oral medication. Slow intravenous injection over 15 minuteshas been used, but is not recommended. Quinine therapy should be con-tinued for at least seven days, but patients may be switched to oral quinine assoon as they are able to tolerate it. In South-East Asia, Irian Jaya and someother areas of the world, addition of tetracycline when the patient is able totolerate oral medication is required for radical cure.

Quinidine treatment

If quinine is not available, quinidine gluconate can be used as an adequatereplacement (Table 1). The same principles pertain to quinidine as toquinine therapy. In Thailand. a loading dose of 24mg/kg salt (15mg/kgbase), followed by 12 mg/kg every eight hours has been safely and success-fully used to achieve therapeutic levels of 5-10mg/l. Renal excretion maycomprise 20-35% of total excretion. In renal failure. plasma levels should beclosely monitored. The adequacy of therapy and toxicity are otherwisemonitored in the same way as for quinine.

Chloroquine treatment

In areas of the world where P. falciparumn is still sensitive to chloroquine. it isused as the drug of choice for severe malaria (Table 1). Rapid intravenousadministration of chloroquine has always been considered dangerous andintramuscular administration of the drug has been practised. There havebeen no published pharmacokinetic studies of the use of chloroquine insevere malaria and thus recommendations are widely variable. As withquinine, the elimination half-life is likely to be considerably longer incomplicated malaria. Children may be more susceptible to toxicity thanadults. If used in severe malaria, it is preferable to give chloroquine by slowintravenous infusion rather than by intramuscular injection. For adults.6-10mg/kg base should be infused intravenously over four hours. This doseis repeated every 12 hours for a total of three to four doses. Children shouldreceive an initial dose of 5-8mg/kg base, followed by two to three doses of3.7-5mg/kg every 12 hours. Further studies are required to determineoptimal doses and whether administration of a loading dose would give moreappropriate plasma levels without significant toxicity'. Chloroquine shouldnever be given by rapid intravenous injcCtio1 because of considerabletoxicity. If an intravenous infusion cannot be established. chloroquine maybe given intramuscularly (5-1)ig kg base, follovwed by two to three doses of2.5mg/kg base at 12-hour intervals).

Ainodiaquine trcattnent

A parenteral formulation of amodiaquine is not commerciall\ available.Ilowcver, a recent study in Thailand dho\\ed that an intra\enous infusion of

,V.

204 S. L. HOFFMAN

amodiaquine was well tolerated and effective in rapidly clearing parasit-_- ,. ..... : ....- ; aemia in moderately ill patients with P. falciparum infections (Looareesu-

( wan et al, 1985b). This regimen has not been studied in severe malaria andwas associated with a high rate of recrudescence. Use of intravenous amo-diaquine for severe malaria must still be considered experimental. It mayprove to be useful as a substitute for parenteral chloroquine.

Qinghaosu treatment

Optimal dosage schedules for qinghaosu and its derivatives are still beingdetermined. A number of formulations have been shown to be effective, butin China only three peparations, qinghaosu suppositories, artemether (oilpreparation), and artesunate, are currently being evaluated (L. Guoqiaoand K. Arnold, personal communication). All three are considered to be aseffective as quinine for the initial treatment of cerebral malaria in adults.(Guoqiao, 1982; Guoqiao, 1984). They have a rapid onset of action andrapidly clear parasitaemia. However, they have to be used with anotherblood schizonticide because of a high rate of recrudescence. Artemether isgiven to adults as single intramuscular doses of 300mg on day 1 and150-200 mg on days 2 and 3. Sodium artesunate is given intravenously, 60mgtwice on day 1 and once on days 2 and 3. Qinghaosu suppositories are giventwice a day; 600mg doses on day 1 and 400mg doses on days 2 and 3.

Other antimalarials, including pyrimethamine-sulfadoxine (Naparstek etal, 1981), tetracyclines, and clindamycin, are sometimes used with quinine.but should never be substituted for quinine. Mefloquine is not available as aparenteral formulation, but a mefloquine suspension has been successfullyadministered to severe malaria patients by nasogastric tube (Chanthavanichet al, 1985). Preliminary findings indicate adequate bioavailability andclinical response.

P. falciparum: uncomplicated

The physician practising in a non-malarious area who sees only an occasionalpatient with P. falciparum infection should consider all P. faiciparum infec-tions acquired in Oceania. Asia, South America and East and Central Africato be resistant to chloroquine. Infections acquired in West Africa, Carib-bean, and Central America above Panama in 1986 are likely to be sensitiveto chloroquine. Chloroquine may still he effective in treating falciparummalaria contracted in chloroquine-resistant areas, but in treating an indi-vidual patient only practitioners whose personal experience has shown thisshould continue to use chloroquine. In many cases, the combination ofchloroquine and the immune response of an individual who has hadnumerous P. falciparum infections may be adequate to achieve clearanceand radical cure of chloroquine-resistant organisms. Amodiaquine has beenshown to be more effective than chloroquine in some areas of East Africa(Watkins et al, 1984: Brandling-Bcnnctt et al. 1985) and Thailand (I lall etal, 1975b) with chloroquinc resistance, but no more effective than chloro-

TREATMENt OF MALARIA 205

quine in the Philippines (Watt et al. 1985) and Pakistan (Khaliq et al. 1986).' - ') ,, The same principles regarding use of chloroquine apply to the use of

amodiaquine.

Chloroquine and amodiaquine treatment

Chloroquine is available as phosphate, and diphosphate salt (500mg salt =300mg base) It is generally given as a total dosage of 25mg/kg base during48 hours (this may be given as 10mg/kg, 10mg/kg, and 5mg/kg at 0, 24 and 48hours or 10mg/kg, 5mg/kg, 5mg/kg and 5mg/kg at 0, 6. 24 and 48 hours). Intreating chloroquine resistant organisms, increasing the total dosage to 40 or50mg/kg will increase the parasite clearance rates, delay the onset ofrecrudescences and may improve cure rates (Powell et al, 1964ab: Hoffmanet al, 1984b, Coosemans et al, 1985). Chloroquine. even at higher dosagelevels, is not recommended for treating non-immunes infected with, pre-sumably, chloroquine-resistant organisms. Amodiaquine is available as thedihvdrochloride salt (500mg salt = 300mg base). The same dosage scheduleas for chloroquine is commonly used. However, in two recent studies inThailand 40-50mg/kg amodiaquine base in combination with tetracycline(Noeypatimanondh et al, 1983b) or erythromycin (Looareesuwan et al.1985b) was effective in clearing chloroquine resistant P. falciparuni parasit-aemia.

If the P. falciparumn is presumed to be resistant to chloroquine.pyrimethamine-sulfadoxine. quinine, quinine plus tetracycline. meflo-quine, and MSP (Fansimef) are the mainstays of therapy. In some areas,amodiaquine or amodiaquine plus tetracycline or erythrom cin can be used.and in selected patients there may be a role for clindamycin alone or incombination with quinine or other antimalarials.

Pyrimetlhmine-silfadoxiiue (SP) treatnn

Ten years ago SP appeared to be an even more ideal antifalciparum agentthan chloroquine, primarily because it could be given in a single dose. Inrecent years the prevalence of resistance of 1'. falciparum to SP hasincreased in most malarious areas of the world. In some areas of Thailand itis of little value. Prevalence of resistance is high in Brazil and Colombia. andPapua New Guinea. but much lower in Irian Java and Africa (Darlow et al,1982: Pinichpongse et al, 1982: De Sousa, 1983: World Health Organiza-tion, 1984: 1 loffman et al. 1985). SP can be used as a first line drug for thetreatment of acute uncomplicated infcction acquired in areas with low levelsof resistance, but patients should be monitored closely. SP is given as a singledose of three tablets to an adult. Lach tablet contains 0(ti me of sultadoxineand 25mg of pyrimcthamine. Children should receive 25 tug kg sulpha-doxine and 1.25 mg kg pyriniet hamine.

Quittitte sul)hate treatlnent

Quinine sulphate is given as Ittmg kg every eight hours for 7-1II dam,,.

206 S. L. HOFFMAN

Cinchonism will occur frequently within this regimen. In areas of the world...... .where parasites are less sensitive to quinine, it should be combined with

tetracycline 15-25mg/kg/day in four equally divided doses, or doxycycline3-5mg/kg/day for seven days. Use of this quinine-tetracycline regimen isassociated with 95% radical cure rates (Pinichpongse et al, 1982). It is likelythat substitution of clindamycin (10mg/kg twice a day for five days) fortetracycline would result in similar cure rates. Studies in Thailand haveshown that the combination of three days of quinine with tetracycline is alsoassociated with high radical cure rates (Boudreau et al, 1984). Quinine isused to reduce parasitaemia while waiting for the slow onset of tetracycline'sschizonticidal activity.

Mefloquine and MSP treatment

Mefloquine has recently been introduced for clinical use in Switzerland andThailand. In Switzerland, mefloquine (Lariam) is only available fortreatment of multiresistant organisms and in Thailand it has been introducedcombined with SP in a single tablet (Fansimef). Mefloquine can be given as asingle dose, is effective against all species of Plasmodium that infect humans,has a rapid onset of action, is not associated with any serious side-effects and iseffective against most strains of multiresistant P. falciparutn. However, invivo and in vitro resistance to mefloquine and MSP have now been docu-mented (Bygbjerg et al, 1981, Boudreau et al, 1982, 1984; Smrkovski et al,1983; Hoffman, 1985). While mefloquine and MSP are unquestionably thebest commercially available single dose antimalarials, they will possibly beless effective in coming years as resistance develops. Mefloquine is given as asingle dose of 15-25 mg/kg or as MSP in combination with SP (Fansimef) asthree tablets for an adult, each containing 250mg of mefloquine, 500rag ofsulfadoxine, and5 mg of pyrimethamine. Children may require higher dosesthan adults.

P. vivax, P. malariae, and P. ovale: complicated

Any patient thought to have a pure infection with P. vivax. 1. ,ilahriae. orP. ovale and the clinical manifestations of severe malaria, should beassumed to have a mixed infection and treated as a patient with complicatedP. falciparun infection.

P. vivax and P. ovale: uncomplicated

Erythrocytic stage

Chloroquine is the drug of choice. 1. vit'ax is much more sensitive tochloroquine than is P. fidciparm. There have been no well docuenntedcases of resistance of 1'. virax or P. ovalh to chloroqiinc. Chloroquine oramodiaquine is given in the same losagc as outlined aboVc for uncompli-cated P. fa/cipartm infections. Quinine. muctloquine, and SP are alsoeffective. Use of S11 is often associated with a longer time until clinical cure


and clearing of parasitaemia (Doberstyn et al, 1979b). The tetracyclines and-. "chloroguanides do not appear to have any effect on P. vivax.

Exoerythrocytic stage

To achieve radical cure, that is elimination of exoerythrocytic stages of theparasite, primaquine must be given. It is administered as 0.25 mg/kg baseonce daily for 14 days. If the patient has G-6-PD deficiency it is given as0.75 mg/kg once a week for eight weeks. However, if the patient has severeG-6-PD deficiency (Mediterranean and Asian type), it may be preferable totreat relapses with chloroquine. In New Guinea and other areas of Asia, theChesson and other strains of P. vivax have been shown to be less sensitive toprimaquine and may require increased doses: 0.5mg/kg/day for 7-14 daysand 0.25mg/kg for 28 days have been used.

P. malariae: uncomplicated

Chloroquine is the drug of choice. Mefloquine is also effective.

RECOGNITION OF HIGH RISK PATIENTS

The major challenge to the clinician managing malaria patients is to recog-nize those patients at risk of developing complicated, severe malaria and toprevent death in those who have complicated disease (Chapter 3). Mostmalaria patients recover quickly and uneventfully after initiation of appro-priate antimalarial therapy. However, some patients deteriorate rapidly.Recent studies in Thailand indicate that, even when modern intensive carefacilities are available, mortality for patients with severe falciparum malariais 15-25% (White et al, 1982; Warrell et al, 1983; Phillips et al. 1985).

High risk patients

Any malaria patient with - 3%c parasitaemia (hyperparasitaemia). historyor findings of abnormal level of consciousness (cerebral malaria), prolongedhyperthermia. pulmonary, cardiac, hepatic. or renal dysfunction, or highoutput diarrhoea or vomiting should be considered to have severe malariaand to be a high risk patient requiring immediate intravenous antimalarialtherapy and intensive care. Input and output, right heart or pulmonaryartery wedge pressures and arterial blood gases should be monitored andfacilities should be available for mechanical ventilatory support. haemo- orperitoneal dialysis. exchange transfusion and continuous infusion of vaso-pressors. Although most such patients will be infected with P. facipartun.all malaria patients with parasitological or clinical findings indicating severedisease should he treated the same. Severe disease is sometimes associatedwith P. vit-ax, P. ova/e. and 1'. malariac infections, but more commonliv amixed infection with a low level of P. fah'ipartim parasitacmia is mistakenlvcalled a pure infection with one of the other species.

208 s. t.. HOFFMAN

Hyperparasitaemia

Any patient with 3% or more of erythrocytes parasitized. regardless of otherclinical findings, should be considered to have hyperparasitaemia and to beat high risk of developing other complications. Patients with hyperparasit-aemia, who otherwise appear to have uncomplicated disease. frequentlyhave a seizure within 24 hours of initiation of therapy and then go into adeep, prolonged coma. The laboratory should provide the clinician with thespecies of Plasmodium and the level of parasitaemia.

The cut-off concentration for hyperparasitaemia of 3% is arbitrary. Notall patients with hyperparasitaemia develop severe disease but, as the para-site count increases, the risk of developing severe disease also increases. Areview of 2316 cases of P. falciparmn infections treated in Kuala Lumpur inthe 1930s and 1940s indicated that only 5% of 2266 patients who survivedhad asexual parasite counts greater than 100000/1.l blood (approximately3% parasitaemia), while 78%4 of patients who died had counts exceeding thisconcentration. Only 0.3% of survivors had a count greater than 500000 ilblood, while 45% of fatalities did (Field, 1949). Among 28 US servicemen inViet Nam who developed acute renal failure secondary to malaria. 20 (71% )had > 10% parasitaemia (Stone et al, 1972). Seven of 12 patients in Bangkokwith acute pulmonary insufficiency secondary to malaria had > 30% parasit-aemia; six of the seven died (Punyagupta et al, 1974). Among 89 patientswith cerebral malaria in lrian Jaya, mortality was 45% in those with >5%iparasitaemia and 12% in those patients with <5% parasitaemia (Hoffmanet al, 1984a).

Cerebral malaria

This is a condition in which patients with P. falciparuin infections aredelirious, obtunded, stuporous, or comatose, and the abnormal state ofconsciousness cannot be attributed to a post-ictal state, a CNS depressant.hypoglycaemia or another infection. A lumbar puncture should be per-formed to exclude meningitis and encephalitis. Nlortalit\ may be as high as20-60% for comatose patients and 10(% for those with stupor. and problablyless than 5% for those with delirium or obtundation. I lowever. deliriouspatients have a higher mortality than patients with uncomplicated malariaand may on occasion deteriorate rapidly. All malaria patients with a historyor finding of abnormal level of consciousness, regardless of other clinicalfindings, should be treated as having severe malaria. T"here is presently noproven adjunct to antimalarial therapy and basic. icinse supportive care forpatients with cerebral malaria. The testing of other forms of therapy. such asexchange transfusion and the comparison of outconcs from different partsof the world require attention to defining the patient's level of conscious-ness, level of parasitaemia. history of ma laria exposure. and ethnic andgenetic background. Otherwisc it will be diffictult to extrapolate findingsfrom one setting to another.

The clinical findings of the ot her conditions aissociated \\ ith se'\ere malariaare described in ('hapters 3 and 5. and the treatment of these complicationsis described below.

| -

TREATMENT OF MALARI A 209

GENERAL ANCILLARY THERAPIES

Antipyretics

Oral temperature should be kept below 38.5°C. Temperatures above thisare associated with an increased incidence of seizures. Prolonged hyper-thermia (temperature > 40'C) is associated with a poor outcome. Quinine isan antipyretic, but is usually inadequate by itself for reducing temperature.Acetaminophen and aspirin may be given orally or by rectal suppository topatients with uncomplicated disease. In the severely ill patient, coolingblankets, fanning, and sponging are frequently necessary and, in the tropics.clinicians often accept the risk of agranulocytosis and use parenteral anti-pyretics such as dipyrone.

Fluid and electrolyte therapy

Parenteral therapy is only required in patients with severe disease. Fluidtherapy must be monitored so as to maintain adequate renal perfusion andto prevent fluid overload leading to pulmonary oederna. This can be accom-plished with intravenous fluids, bladder catheterization, and frequentcareful clinical examinations and monitoring of input and output. It isoptimally carried out in an intensive care unit with right heart or pulmonaryartery catheterization and frequent monitoring of blood electrolytes, bloodurea nitrogen. creatinine, glucose and arterial blood gases. Mild hypo-natraemia (Na', 120-134mEq/I) is common, but generally of little clinicalimportance. It has been suggested, but not proven, that it is due to inappro-priate antidiuretic hormone production. In some cases it is undoubtedly dueto overhydration. When the serum Na + falls below l20mEqiL, fluid restric-tion is advisable if there is no dehydration.

Nursing care

Careful attention must be paid to maintenance of the airway and to pre-vention of pulmonary aspiration and other complications found in criticallyill patients. Patients with severe disease should be nursed on their sides andturned frequently.

Corticosteroids

From 1967 to 1982, corticosteroids were the most commonly recommendedand used adjunct to ant imalarials in the treatment of cerebral malarial(Daroff et al, 1967: Oriscello, 1968: Woodruffa iid )ickin. n, 196S: Mlount.1969: Smitskamp and Wolthuis. 1971). In 1982. Warrell and collcaguesreported the results of a double blind study of moderate do,,es of dexa-methasone given for 48 hours to comatose paticnts with cerebral malaria inThailand (Warrell ct al, 1983). The stud\ sho\ed that the use of dexa-methasone was not associated with a reduction in nortalitv. was rnot associ-ated with a signilicant increase in all complicat ions or any single compli-

210 S. L. HOFFMAN

cation, but was associated with a 33% prolongation time from initiation of..- . .-, .- . - . ., "therapy until full recovery of consciousness. A similar study in Irian Jaya,

Indonesia, has just been completed. In this study, a dosage of dexa-methasone eight times higher than that used by Warrell and colleagues(initial dose 3mg/kg, total dosage during 48 hours 11.4mg/kg) was evaluatedand found to be of no value in reducing mortality in cerebral malaria(Hoffman, unpublished). Cerebral malaria is not an indication for the use ofdexamethasone in any dose. Corticosteroids are sometimes recommendedfor treating the pulmonary aspiration and pulmonary oedema of severemalaria, but their value has never been confirmed.

Exchange blood transfusion

Regardless of the patient's clinical status, if >20% of erythrocytes areparasitized with P. falciparum, the chance of complete recovery is less than50% when standard antimalarial therapy and supportive measures are used.There have been a number of case reports of patients with hyperparasit-aemia who were successfully treated with 5-101 whole blood exchangetransfusion and antimalarials (Nielson et al. 1977; Kurathong et al. 1979;Yarrish et al, 1982; Kramer et al, 1983; Files et al. 1984) and one report ofplasma exchange (Bambauer and Jutzler, 1984). It has been proposed thatthe beneficial effect of exchange transfusion is related to removal of para-sitized erythrocytes, erythrocyte and parasite debris and mediators and theprovision of unparasitized erythrocytes, platelets, and clotting factors.There have been no controlled studies which have evaluated the efficacy ofexchange transfusion. However, because of the poor prognosis associatedwith hyperparasitaemia, most experts would recommend exchange trans-fusion for all patients with greater than 15% parasitaemia and any patientwith >5% parasitaemia who has evidence of cerebral involvement or otherorgan dysfunction. The value of large (5-101) and small (2-41) exchangetransfusions compared to standard therapy needs to be critically evaluated.

Other measures

Heparin (Munir et al, 1980), adrenaline (epinephrine) (Patrick. 19S2) andlow molecular weight dextran (Smitskamp, 1971 ) have all been advocatcdfor treatment of severe malaria. None have been critically evaluated incontrolled trials. Many clinicians with experience in treating severe malariadoubt their efficacy and none of thcsc are recommended.

TREATMENT OF TIlE COMPLICATION'S OF MALARIA

Anaemia

Most malaria paticnts develop ,acnmia primnril caucd y halemnoLI , sis, andhone marrow dysfunction (see Chapter 31). Specific treatment of anamiia is


not necessary in most patients, who only require antimalarial therapy.However, if the haematocrit is less than 21% or is falling rapidly in a patientwho is critically ill, blood transfusion is required. The anaemia of malariacan be worsened by oxidant-induced haemolysis in individuals with G-6-PDdeficiency. If possible, individuals from population groups with a highprevalence of G-6-PD deficiency should be screened before being treatedwith primaquine.

Seizures

Seizures are common in malaria patients. It is often impossible to distinguishbetween febrile seizures and seizures caused by hypoglycaemia or associatedwith cerebral malaria. Seizures are frequently recurrent and prolonged inpatients with cerebral malaria and a seizure in a patient with hyperparasit-aemia is often the first sign of rapid clinical deterioration. Diazepam is usedfor status epilepticus (0.1-0.4mg/kg intravenously during two to fiveminutes and repeated every 20 minutes if no response to a maximum of1-2mg/kg per 24 hours, children may require higher doses at slower ratesthan adults) and Dilantin, carbamazepine, phenobarbitone (phenobarbital)or other anticonvulsants for prevention of recurrence. Reduction of tem-perature is important in preventing seizures. Hypoglycaemia and electrolyteimbalance should be corrected, but they are uncommon causes of seizures inmalaria patients. There have been no studies of the value of short termprophylactic anticonvulsants in malaria patients with cerebral involvement,hyperparasitaemia, hyperthermia, or a single seizure. Some cliniciansrecommend their use.

Hypoglycaemia

Plasma glucose of less than 40mg% has been shown to occur in 8% and 15%of cerebral malaria patients in Thailand and Indonesia, respectively (Whiteet al, 1983d; Hoffman et al, 1984a). It is more common in pregnant patientsand those who are critically ill or have hyperparasitaemia. It most commonlyoccurs after institution of quinine therapy. but can occur before and can berecurrent. Clinical diagnosis is difficult in critically ill patients. Glucoselevels should be monitored every six hours and whenever there is clinicaldeterioration. This can be done at the bedside using commercially availabledipsticks (Dextrostix, Ames) which are analysed by using a colour chart orhand-held reflectance colorimeter (Dextrometer, Ames). Treatment is with50% dextrose (1-2mg/kg) followed by a four-hour infusion of 1(1dextrose, glucagon has also been used. If the glucose level is > 60mgc% aftera four-hour infusion. 10% dextrose is discontinued. 5%i dextrose infusionbegun, and glucose levels are monitored every six hours.

Renal failure

Renal failure in falciparum malaria may be associated with hyperparasit-

212 S. L. HOFFMAN

... . aemia, hypovolaemia, or intravascular haemolysis which lead to decreasedrenal capillary blood flow, decreased renal blood flow, and haemoglobinuria(blackwater fever), respectively. All may end in a clinical syndrome suggest-ing acute tubular necrosis. When faced with a patient with presumed renalfailure, the clinician must exclude hypovolaemia as the cause of azotaemiaand oliguria. If possible, pulmonary artery catheterization should be under-taken, a bladder catheter passed, haematocrit, glucose, electrolytes, bloodurea nitrogen and creatinine and arterial blood gases measured, and aurinalysis and electrocardiogram performed. If there is no evidence of fluidoverload, the central venous or pulmonary arterial wedge pressure is lowand the urine specific gravity is high, a fluid challenge with normal salineshould be undertaken. This can be accomplished by estimating percentagedehydration and administering maintenance and replacement fluids accord-ingly. If there is <20ml/hour urine output after right heart pressures haveincreased to adequate levels and after what is considered adequate volumereplacement, increasing intravenous doses of a diuretic such as frusemide(furosemide) should be tried (initial dose 0.5 mg/kg with doubling the doseevery 30 minutes if there is no response). If this is unsuccessful, a vaso-pressor which increases renal blood flow, such as dopamine, may be tried. Ifall these manoeuvres are unsuccessful, the patient is in the oliguric stage ofacute tubular necrosis and management is that of any such patient with strictattention to fluid and electrolyte balance, and institution of dialysis whenindicated. Haemodialysis is preferable to peritoneal dialysis, but is generallyunavailable in areas of the world where most cases of severe malaria arefound. Peritoneal dialysis is generally adequate, but less preferable becauseof the risk of bleeding and infection and, theoretically, because splanchnicblood flow may be reduced in severe malaria and solute clearance across theperitoneum may also be relatively reduced (Canfield et al. 1968, Donadio ctal, 1969).

Clearance of quinine is not substantially altered by renal failure, sinceonly 20% of total clearance is through tle kidneys (White et al. 1982).Recommendations for use of quinine in patients with severe malaria andoliguric renal failure are as for any patient with severe malaria (see above).If possible, dosage should be adjusted according to plasma levels. If theseare not available and the patient is not improving after 2-3 days of therapy,individual doses should be reduced by 30'r' and the electrocardiogram andblood pressure carefully monitored for evidence of toxicity. liaemodialhsisis thought to remove quinine and a standard dosage is used (Donadio et al.1969). The same principles apply to the use of quinidinc. I lowever, it shouldbe recognized that there is a greater chance of developing toxicity becauseup to 35%, of quinidine may be cleared through the kidneys.

There is little information available on the use of chloroquine in renalfailure, either with or without dialysis. If chloroquine must be Ised it shouldbe used at a standard dosage.

Fresh whole blood should be used for transfusion, careful attention paidto general care and nutrition, the dosages of all other (drigs ad justedappropriate to the level of renal failure and the polyvuric phase of rcco\eryexpected and treated appropriately.

TREATMENT OF MALARfA 213

Pulmonary oedema

Pulmonary oedema is an uncommon, but frequently fatal, complication ofsevere P. falciparum infection that is most often associated with hyper-parasitaemia (Punyagupta et al, 1974). It resembles adult respiratory dis-tress syndrome (ARDS) and it is likely, but unproven, that the primaryabnormality is increased permeability of pulmonary capillaries (Chapter 3).Although pulmonary artery wedge pressures may be normal in thesepatients, the use of excessive fluids is dangerous. Prevention requires carefulfluid management with maintenance of adequate cardiac output and peri-pheral perfusion, but low right heart pressures. Treatment is that of pulmon-ary oedema and ARDS in a critically ill patient. Intermittent positivepressure ventilation (IPPV) with positive end expiratory pressure (PEEP) isthe mainstay of treatment. It is unlikely that high frequency jet ventilation orintermittent mandatory ventilation will prove to reduce mortality whencompared to IPPV with PEEP. Corticosteroids are frequently used inARDS, but have never been shown to reduce mortality.

Pneumonia

Aspiration pneumonia is common in cerebral malaria patients who areunconscious and have frequent seizures and vomiting. Nursing on the side,anticonvulsants, and antiemetics may be helpful for prevention. Treatmentis that of aspiration pneumonia.

Gram-negative sepsis

Gram-negative organisms are often cultured from the blood of patients withsevere falciparum malaria. These unconscious patients have multipleintravenous lines and urinary catheters and sometimes have diarrhoea. Thesources of infection may be similar to those of nosocomial infections in otherseverely ill patients. However, passage of organisms from the gut, throughan intestinal wall subjected to the stress of microcirculatory obstruction byparasitized erythrocytes, is also possible. Any patient who is not respondingto antimalarial therapy as expected should he investigated for bacteraemiaand empirical institution of antibiotic therapy considered.

Hlypotension, shock and myocarditis

Most malaria patients have low but normal arterial blood pressures andpostural hypotension is common. Postmortems on humans and studies innon-human primates indicate that myocardial microcirculatory obstructionwith parasitized ervthrocytes is frequent (Miller, 1969: Jcrvis et al, 1972:Uys et al. 1984). lIowevcr, cven in patients with cerebral malaria, clinical orelectrocardiographic evidence of myocarditis or myocardial ischaemia israre, as is marked hypotension with evidence of decreased organ perfusion.If severe hypotension is present, gram-negative sepsis. pulmonary oedema.metabolic acidosis, gastrointestinal haemorrhage. hypovolaemia and

214 S. L. HOFFMAN

splenic rupture should be suspected. Treatment with fluids, blood, or vaso-pressors may be required.

Splenic rupture

This is an infrequent complication which is essentially the only fatal compli-cation of P. vivax infection, but can occur with all malarias. Diagnosis isdependent on suspicion and demonstration of blood in the peritoneum.Treatment is surgical.

Disseminated intravascular coagulation (DIC)

While chemical DIC is common, clinically important DIC with bleeding israre in malaria patients (Chapter 5). If encountered, it is usually found inpatients with multi-organ failure and hyperparasitaemia. Clinically signifi-cant DIC should be treated with fresh whole blood. The use of heparin iscontroversial, but it is generally no longer recommended.

TREATMENT OF MALARIA IN SPECIAL GROUPS

Malaria in semi-immunes

Individuals with a history of repeated malaria infections may require lowerdoses of antimalarials and often can be treated with an antimalarial whichwould not be effective in treating P. falciparum infections in non-immunes.They rarely develop severe malaria. In the past, semi-immunes were oftentreated with lower doses of chloroquine than nor.-immunes (10mg/kgcompared to 25mg/kg base). This is no longer iccommended by somemalariologists because of the potential for selecting resistant organisms.There have been case reports and immunological studies indicating that asemi-immune becomes fully susceptible to malaria infection and the develop-ment of severe malaria within 12 months of leaving a highly malarious area,whatever immunity is acquired over many years is rapidly lost (Editorial.1985b).

Malaria in pregnancy

Pregnant women are apparently at higher risk of developing severe and fatalmalaria than non-pregnant women. They should be treated promptly withappropriate doses of antimalarials and closely monitored for complications.Hypoglycaemia which may be quinine related is more common in pregnantwomen than in other groups with severe malaria. Quinine has long beenthought to induce uterine contractions and abortion. Ten women between30 and 40 weeks of gestation with severe falciparum malaria, all of whomreceived standard doses of 10mg/kg quinine, were evaluated in Thailand.No deleterious effects of quinine infusion on uterine or fetal function weredetected (Looareesuwan et al, 1985a). Severe falciparum malaria requirestreatment with doses of quinine adequate for parasite inhibition and! malaria


is associated with spontaneous abortion. Uterine and fetal activity must be

monitored in pregnant women with severe malaria receiving quinine, butquinine should be administered in doses expected to be effective against theparasite so as to prevent death of the patient. In complicated malaria,concern about quinine inducing labour is of secondary importance to pro-viding adequate doses of quinine so as to save the patient's life. Uncompli-cated acute infections can be safely treated with chloroquine, quinine, andSP. Mefloquine has not been adequately evaluated in pregnancy, andtetracyclines and primaquine are not recommended in pregnancy because ofpotential toxicity to the fetus. Pregnant women who develop P. vivaxinfections should be treated with chloroquine and then placed on weeklychloroquine chemoprophylaxis (Chapter 7). Radical cure with primaquinecan begin after delivery.

Malaria in children

Treatment of malaria in children is essentially the same as treatment inadults. Children with severe malaria are apparently more susceptible to lifethreatening side-effects associated with parenteral use of chloroquine andare usually treated with lower parenteral doses (see above). They may alsorequire up to a 50% increase in doses of quinine during the last days oftherapy to achieve radical cure of falciparum infections (see above) (Chong-suphajaisiddhi et al, 1981a).

TREATMENT OF MALARIA IN AREAS WITH LIMITED FACILITIES

A health care worker supplied with chloroquine, SP, quinine, tetracycline,and an antipyretic can adequately treat all acute, uncomplicated malariainfections. Treatment of patients with severe malaria is best accomplished in afacility equipped to provide modern intensive care, including exchange bloodtransfusion. Unfortunately, most patients with severe malaria are not treatedin such facilities. Most patients with severe malaria can be adequatelyevaluated and treated in outlying hospitals where the following are available:quinine dihydrochloride; intravenous fluids; a parenteral antipyretic;dipsticks to check glucose; 50% dextrose; blood for transfusion; diazepam; anantibiotic such as chloramphenicol; an antiemetic; urinary catheters: anursing staff trained to measure vital signs and input and output and tosuction, turn, and cool severely ill patients; anda laboratory that can stain andread malaria films, measure the haemoglobin concentrations or haematocrit,and count cells in the cerebrospinal fluid. An algorithm for fluid therapy,initially based on maintenance requirements, temperature (insensible losses)and estimated state of hydration, and subsequently on input and output, ishelpful. The most important component of therapy is the provision ofadequate doses of antimalarial as soon as possible. Any patient with sus-pected severe malaria should be started on parenteral antimalarial therapywithin 10 minutes of first being seen. There is no reason to await the results of amalaria blood film before initiating therapy. Patients who do not respond as

216 S. L. HOFFEMAN

expected or deteriorate should have repeated blood films examined quanti-

":: . .tatively and be frequently checked for hypoglycaemia and suspected of

having, and treated for, gram-negative sepsis.

TREATMENT OF SYNDROMES ASSOCIATED WITH CHRONICMALARIA

Tropical splenomegaly syndrome

Patients with the tropical splenomegaly syndrome may be debilitated,severely anaemic and unable to function normally because of splenic pain ormass (Chapter 4). Long term malaria chemoprophylaxis with chloroquine orproguanil has been effective in dramatically improving clinical condition,anaemia, and activity and in reducing spleen size (Sagoe. 1970; Lowenthal etal, 1971; Crane et al, 1973). This is presumably secondary to the reduction inmalaria antigen load that leads to the immunological abnormalities thoughtto be responsible for pathogenesis of the condition. There is usuallyimprovement in the general condition within six months, but significantreduction in spleen size may take several years or may not occur in about20% of patients (Crane et al, 1973; Hoffman unpublished). In sonic areas,moderate residual splenomegaly is common even after long term chemo-therapy. A minority of patients (< 10% ) do not respond to malaria chemo-prophylaxis, deteriorate while on therapy, or are unable to take suchtherapy. Although there is concern about the long term infectious risks topatients in the tropics who have had splenectomy, there is evidence thatsplenectomy is appropriate and beneficial to highly selected patients whohave failed on chemoprophylaxis (Hamilton et al. 1971; Crane et al, 1972).If possible, patients should receive pneumococcal vaccine before splen-ectomy and be maintained on malaria chemoprophylaxis after splenectomy.There has never been a trial comparing medical versus surgical treatment ofpatients with tropical splenomegaly syndrome.

Nephrotic syndrome

The nephrotic syndrome is thought to be associated with P. luilariae infec-tion and caused by glomerular immune complex deposition (Chapter 4)(Hendrickse et al, 1972; Houba et al, 1975" Greenwood and Whittle, 1981).It should be treated with antimalarials and standard measures used fortreatment of nephrotic syndrome.

REDUCTION OF TRANSMISSION

The only effective gametocyticidal and sporonticidal drug in general use isprimacluine. A single 45 mg dose of prinmaquinc base is usuallh effective inpreventing infection of mosquitoes. The effectiveness of properly admini-stered primaquine in reducing transmission has never been rigorouslystudied (Tigertt, 1985).

TREATMIENT OF MALARIA 217

~ . ~ .:i~.$~:$ REFERENCESAdelusi SA. Dawodu Ali & Salako LA (1982) Kinetics of the uptake and elimination of

chioroquine in children with malaria. British Journal of Clinical Phtarmnacology 14:483 -487.

Ahmad RA & Rogers Hi (1980) Pharmacokinetics and protein binding interactions of dapsoneand pyrimethamine. Britislh Journal of Clinical Pharmtacology 10. 519-524.

Ahmad RA & Rogers Hi (1981) Salivary elimination of pyrimethamine. British Journtal ofC'linical Pharmacology HI: 101-102,

Andre RG & Doberstyn EB (1977) A preliminary report on the evaluation of the sporonticidaleffect of pyrimethamine-sulfadoxine. quinine, and quinine-pyrimethamine against Plas-modiamfalciparatn. In Tan DSK (ed.) Current Concepts in the Diagnosis and Treatment ofParasitic and Other Tropical Diseases in South East Asia. Proceedings of the 18thSEAMEO-Tropical Medicine Seminar. Kuala Lumpur. Malaysia, 2-5 August. 1977.

Avraham H. Golenser 1, Gazitt Y, Spira DT & Sulitzeanu D (1982) A hiighly- sensitivesolid-phase radioimmunoassay for the assay of Plasinodiumn falciparuon anttgens andantibodies. Journal of Immunological Methods 53: 61-68.

Baker JK. McChesney JD, Hufford CD & Clark AM (1982) High performance liquidchromatographic analysis of the metabolism of primaquine and the identification of a newmammalian metabolite. Journtal of ChroinatographY 230: 69-77.

Bambauer R & .iutzlcr GA (1984) Malignant falciparum malaria successfully treated withplasma exchange. Plasma Therapeutic Transfusion Techniology 5: 343-347.'Barker RH Jr. Suebseng L, Rooney W et Al (1986) Specific DNA probe for the diagnosis ofPlasrnodiumnfalciparon malaria. Science 231: 1434-1430.

Bass CC & Johns FM (1915) A method of concentrating malaria plasmodia for diagnostic andother purposes. Amecrican Journal of Tropical Disease 111: 298--303.

Beale GH el, al (1978) Genetics. In Killick-Kendrich R & Peters W (eds) Rodentt Malaria,p 2 13-245. London: Academic Press.

Bergquist Y & Domeij-Nvberg B (1983) Distribution of chloroquine and its metabolitedesethyl-chloroquine in human blood cells and its implication for the quantitative determi-nation of these compounds in serum and plasma. Journtal of' C/troitatograpi 272:137-148.

Bergquist Y & Frisk-llolmberg M (19801) Sensitive method for the determination of chloro-quine and its metabolite desethyl-chloroquine in human plasma and urine by high-performance liquid chromatography. Journal of Cltroniatograpltv 221: 119-127.

Blount RE Jr ( 1969) Acute falciparum malaria: field experience with quinine~pvrimiethaminecombined therapy. Ann~als o 'f .lInternal Medicine 70: 142-147.

Boudreau EF. Webster 141K. Pavanand K & Thosingha L (1982) Type 1 IICeloquine resistancein Thailand. Lancet if: 1335.

Boud reau EF. Pang LW. Dixon KE et al (1984) Comparable efficacy of mc floquinec and thecombination of qunn n etaylnhrapy for falcipari malaria in) easte rn Thai -land. Presented at the Joint Meeting of the Royal and American Societies of TropicalMedicine and Illvgiene. 33rd A niual Mcitiotg of ie Ap,,trican Society ol lropical ldiineand 1lhgiene. Baltimore. D~ecember 2-0, 1984. Abstract 107.

Brandli ng- Bennett Al). Watkins WW, Oloo AJ. Koech DK & Spencer IK 1198Sf Sensitivityof Pastdonfcirutto 4-amntiioquino li nes in coatstal and w~estern Kenywa. Presen tedat tlte Joint Meeting of the Amettrica n Society of Iropical Medicinre an ml I iene anid theAmerican Society of Tropical Veterinary NIedici ne. 34tht Annotod,%lcetit o Iic 4 ,,eloSociety of Tropical Aledicinte aou lhtgiene. Novetuber 3-7. 1985. Abstract '57.

Brooks NM11 & Barry K(G (I969)I Fatal transfusion of toalaria. 116 od 3-I: 80 6-8 M(.Bruce .Chwatt Li (ed. ) (1981) C hemnotherapy of Mlaria . 2nd edn . C encva : World H eaflth

Organization.Bygbje rL IC, Schapira A. Flachs If & ( om me ( (181) Mefloqine resist ane of falcipa rumi

malaria fronm Tanzania enhanced by treat me nt. Launuc i: 21I-26.Canfield 0,1 Miller 1,11. llarlelloni PH. Eichler P & Barr% K6 (19)(8) Acutle renal failure in

f'lasnodiuon fldcipartn malaria. A rcitie% oifhInernal .ifidic,,te 122: 1')')- 203.Chanthavanich P. Looareesiiman S. White NJle t al ( 1985) lintraueastric tuetloquine is absorbed

rapidly in patients withI cerebral malaria. Amncmian Jtournaul ol Io lit tl ,Meditm -ot' ndllsgien' .34: 11128-10136.

218 S. L. HOFFMAN

China Cooperative Research Group of Qinghaosu and its Derivatives as Antimalarials (1982)Metabolism and pharmacoki nc tics of Qinghaosu and its derivatives. Journal of TraditionalChinese Medicine 2: 25-30.

Chongsuphajaisiddhi T, Sabcharoen A & Attanath P (1981 a) In vivo and in vitro sensitivity offalciparum malaria to quinine in Thai children. Annals of Tropical Paediatrics 1: 21-26.

Chongsuphajaisiddhi T, Sabehareon A, Chanthavanich P & Attanath P (1981h) Treatment offalciparum malaria in Thai children in 1981. Abstracts, the Faculty of Tropical Medicine,Mahidlol University. Bangkok, p 2.

Clyde DF (1983) Theoretical constraint to cross-resistance between chloroquine and meflo-quine. World Health Organization meeting of principal investigators of the regionalcollaborative studies on drug resistant malaria-Jakarta. Indonesia, 2-6 May. 1983.SE/MALIDRUG/83'24.

Coosemans MH. Hendrix L, Barutwanayo M, Butovi G & Onori E (1985) Pharmacordsistanede Plasmodium falciparurn au Burundi. Bulletin of the World Health Organization 63:331-338.

Cramer G & Isaksson B (1963) Quantitative determination of quinidine in plasma. Scandi-navian Journal of Clinical and LaboratorY Investigation 15: 553-556.

Crane GG, Pryor DS & Wells JV (1972) Tropical splenomnegaly syndrome in New Guinea. 1I.Long term results of splenectomy. Transactions of the Royal Society of Tropical Medicineand Hygiene 66: 733-742.

Crane GG, Hudson P & Hudson BET (1973) The effect of suppressive antimalarial therapy intropical splenc'rnegaly syndrome in New Guineans. Papua New Guinea Medical Journal16: 46-50.

Darlow B, Vrbova H. Gibney S et al (1982) Sul fadoxine-pyrimethamine for the treatment ofacute malaria in children in Papua New Guinea 1. Plasmiodium falciparurn. AmericanJournal of Tropical Medicine and Hilgiene 31: 1-9.

Daroff RB, Deller JJ Jr. Kastl AJ Jr & Blocker WW Jr (1967) Cerebral malaria. Journal of theAmerican Medical Association 202: 679-682.

Desjardins RE. Pamplin Ill CL. von Bredow J, Barry' KG & Canfield CJ (1979) ClinicalPharmacology a,:d Therapeutics 26: 372-379.

De Sousa J (1983) A phase If clinical trial of mefloquine in Brazilian male subjects: Bulletin ofthe World Health Organization 61: 81.5-820.

Dixon KE. Pitaktong U. Bamnetpandh 5, Teopipithaporn S & Na-Nakorn A (1983) Treatmentof acute case of Plattsodium mialariae malaria with mefloquine. Arnerican Journal ofTropical Medicine and HI'ygiene 32: 631-632.

Dixon KE. Pitaktong U & Phintuyothin P (1985) Aeclinical trial ofmcfloquinc in the treatmentof Plasmodiurn vitcax malaria. American Journal of Tropical Medicinie andl Ilgiene 34:435-437.

Doberstyn Eli. Phintuyothin P, Nocypatimanondh S & Teerakiartkamjorn C (1979a) Single-dose therapy of falciparum malaria with melloquine or pyriinethamine-sulfadoxine.Btlletin of the World Hlealth Organizauiont 57: 275-279.

Doberstyn EB. Tecrakiartkamjorn C. Andre RG, Phintuyotbin P & Noevpatimationdh S(1979b) Treatment of vivax malaria with sulfadoxine-p rinithamine and with pyriiaeth-amine alone. Transactions ol tlu Royval Society- of Tropical Medicine and II vgiene 73:15- 17.

Donadio JV, Whelton A & Kazy'ak L (1969) Quinine therapy and peritoneal dialysis in acuterenal failure complicating malarial bac iaoglobin uria . Lancet i: 375-379.

Editorial (1983) D~evelopment of inefloq uine its an anti malarial drug. Bulletin of the WIorldHealth fOrganization 61: 169-178.

Editorial (1 985a) Rex iscd recommendations for preveinting malaria in travellers ito areas withchloroquine. resistant l'aWoin acpru obdiyad.lo~hi leck/Report 3:185-195.

Editorial (1985b)) Plasinoditun fitlcparumn: a major health hazard to Africans and Asian,returning home. Lancet ii: 871- S72.

Edstein NI. Stace J & Shann F ( 1983) Quaintification of quinine in human serum by high-performance liquid chroimatography'. Journal of Chromnatographiy 278: 445-451.

El Sadiq El Wakeed. I loiida NINA. Alt I INI . Gjeary FG & Jensen ill I1985) Clindamyicin forthe treatment of falciparo m mailaria in Sudan. Anetruanz Journal ol Tropical .tedicine andHygiene 34: 1065-10)68.

I K '


Field JW (1949) Blood examination and prognosis in acute falciparun malaria. Transactions of. .. .. ,:..:. ,the Royal Society of Tropical Medicine and Hygiene 43: 33-46.

Files JC, Case CJ & Morrison FS (1984) Automated erythrocyte exchange in fulminantfalciparum malaria. Annals of Internal Medicine 100: 396-397.

Fitch CD (1983) Mode of action of antimalarial drugs. Ciba Foundation Symposium 94:222-232.

Franzen L, Shabo R, Perlmann H et al (1984) Analysis of clinical specimens by hybridisationwith probe containing repetitive DNA from Plasmodiumfalciparum. A novel approach tomalaria diagnosis. Lancet i: 525-527.

Frisk-Holmberg M, Bergquist Y. Termond E & Nyberg-Demeij B (1984) The single dosekinetics of chloroquine and its major metabolite desethvlchloroquine in health subjects.European Journal of Clinical Pharmacology 26: 521-530.

Garnham JC, Raymond K, Shotton E & Turner P (1971) The bioavailability of quinine. Journalof Tropical Medicine and Hygiene 70: 264-269.

Greaves J, Evans DAP, Gilles HM & Baty ID (1979) A selected ion monitoring assay forprimaquine in plasma and urine. Biomedical Mass Spectrometr-V 6: 109-112.

Greaves J, Evans DAP. Billes HM et al (1980) Plasma kinetics and urinary excretion ofprimaquine in man. British Journal of Clinical Pharmacology 10: 399-405.

Greenwood BM & Whittle HC (1981) Immunology of Medicine in the Tropics. London:Edward Arnold.

Grindel JM, Tilton PF & Shaffer RD (1977) Quantitation of the antimalarial agent meflo-quine, in blood, plasma and urine using HPLC. Journal of Pharmaceutical Sciences 66:834-837.

GuoX, Jian H, Fan T& Huang W (1984) Comparative evaluation of parasite counts in capillaryblood, bone marrow and intradermal smears in patients with cerebral malaria. XI Inter-national Congress for Tropical Medicine and Malaria. September 16-22, 1984, Calgary.Canada.

Guoqiao L. Xingbo G, Rui J et al (1982) Clinical studies on treatmcnt of cerebral malaria withqinghaosu and its derivatives. Journal of Traditional Chinese Medicine 2: 125-130.

Guoqiao L, Guo X, Hwa-Xiang J & Rui J (1984) Clinical studies on qinghaosu and itsderivatives in the treatment of falciparum malaria and cerebral malaria: a review. Journalof Traditional Chinese Medicine 5: 26-28.

Gustafsson LL, Walker 0, Alvan Get al (1983a) Disposition of chloroquine in man after singleintravenous and oral doses. British Journal of Clinical Pharmacology 15: 471-479.

Gustafsson LL. Rombo L, Alvan Get al (1983b) On the question of dose-dependent chloro-quine elimination of a single oral dose. Clinical Pharmacology and Therapeutics 34:383-385.

Guyer B & Candy D (1979) Injectable antimalarial therapy in tropical Africa; iatrogenicdisease and wasted medical resources. Transactions of the Royal Society of TropicalMedicine and t"ygiene 73: 23G-232.

Haggis AW (1941) Fundamental errors in the early history of cinchona. Bulletin of the Historyof Medicine 10: 568-592.

Hall AP (1972) Quinine infusion for recrudescences of falciparum malaria in Vietnam: acontrolled study. American Journal of Tropical Medicine and Ihgiene 21: 851-856.

Hall AP, Czcrwinski AW. Madonia EC & Evensen KtL (1973) Human plasma and urinequinine levels following tablets and intravenous infusion. Clinical Pharmacology andTherapeutics 14: 580-585.

Hall AP. HIanchalay S, Doberstyn E & Bumnetphune S (1975a) Quinine dosage and serumlevels in falciparum malaria. Annual Report o" SEA TO Medical Research Laboratories241-2511.

Hall AP, Segal HE, Pearlman EJ. Phintuyothin P & Kosakal S (1975b) Amodiaquine resistantfalciparum malaria in Thailand. American Journal of Tropical Medicine and Ilygiene 24:575-580.

Hamilton PIS, Stuiver PC & Zeigler JL (1971) Splenectomy in tropical splcnomegalysyndrome-a five year follow-up. Journal of Tropical Medicine and lhtpiene 74: 23--232.

Harinasuta T et al (1962) (?hloroquine resistance in Plasmnodium fidciparumn in Thailand. FirstRegional Symposium on Scientific Knowledge of Tropical Parasites. University of Singa-pore. .5-9 November 1962. pp 14K-153. University of Singapore.

Heizmann P & Ceschke R (1984) Determination of the antimalarial mefloquine in human

220 S. L. HOFFMAN

plasma by gas chromatography with electron -capture detection. Journal of Chromato-graphy, 311: 41 1-417.

Hendrickse RG. Adeniyi A & Edington GNI (1972) Ouartan malarial nephrotic syndrome.Collaborative clinicopathological study in Nigerian children. Lancer I: 114-l148.

Hill LM & Malkasian GD (1979) The use ofquinidine sulfate throughout pregnancN. Obstetricsand Gynecology 54: 366-368.

Hoffman SL. Harun S, Dimpudus AJ & Mlarwoto HA ( 1986) In vitro studies of the sensitivity ofPlasmodium falciparin to mefloquine in Indonesia. Proceedings of the Third NationalParasitology Semninar, Bandung. August 1983 (in press).

Hoffman SL, Dimpudus AJ. Campbell JR et al (1985) RIh and Rill type resistance ofPlastnodium falciparumn to combination of mefloquinc and sulfadoxine~lpyrimethamine inIndonesia. Lancet ii: 1039-1(040.

Hoffman SL, Rustama D. Punjabi NH et al (1984a) Cerebral malaria in Jayapura, Irian Jaya:clinical observations in 45 patients. Presented at the XI Internauional Congressfor TropicalMedicine and Malaria. Calgary, Alberta. 16-22 September. 1984.

Hoffman SL, Masbar S. Hussein PR et al ( 1984h) Absence of malaria nmortality in villagers withchloroquine-resistant Plasmodium falciparwun treated with cltloroquinc. Tranrsactions offie Royal Society of Tropical Medicine antd Hygiene 78: 175-178.

Houba V (1975) Immunopathology of nephropathies associated with malaria. Bulletin of fiheWorld Health Organ izationz 54: 416.

Jervis HR. Sprinz H, Johnson AJ & Weilde BT (1972) Experimental infection with Plasmno-diumnfalciparuin in Aotus monkeys. 11. Observations on host pathology. Ainerican.Journalof Tropical Medicine and Hy' giene 21: 272-281.

Jiang J. Guo X. Li G. Kong YC & Arnold K (198-'a) Antimalarial activ ity of meloquine andqinghaosu. Lancet ii: 285-288.

Jiang JB. Huang JC. Liang DS et al (1982b) Long incubation of Plasmnodjin iiax inulti-nucleatum as demonstrated in three experimental human cases. Transatctions ofdie RoyalSociety. of Tropical Medicine and lHgiene 76: 845-847.

Jiang J, Jacobs G. Liang D & Aikawa M (1985) Oinehaosu-induced chiinges in the morphologyof Plasiodiwn inui. Amzerican Journal of Tropical Mrdic i and Hygiene 32: 424-428.

Jones CR & Ovenell SNI (1979) Determination of plasma concentrations of dapsone. mono-acetyl dapsone and pvrimethamine in human subjects dosed with Nialoprim. Journal of"Chromatographyv 163: 179-185.

Khaliq AA. Fox E. Sarwar M S: Strickland GT (1986) Amodiaqtiine fails to cure chloroqUineresistant Plasmioditan falciparium in the Punjab. Tranisactions of' file RoYal Society, ofTropical Medicine and ly-giene (in press).

Kitchen SF (19419) Svm-rptornatology: general considerations. In Boyd NIF (ed.) M talriologv%.vol. 2. Philadelphia: WBI Saunders. 966 pp.

Klayman DL (1985) Qirighaosu (artcmnisinin): an antimialarial drug from Chinta. Science 228:10144-1055.

Kramer S.Campbell C C & Nioncrie ff P.E (1983) FI'I nitia nt Platoiumti .ilciparum Vciontreated with e xchange blood transfusion. Journaid olie A ircnAci lAsca n249:244-245.

Kurathong S, SrichaikUl "F, Isarangkura P & Phanichphant S (1979) Exchange transfusion incerebral malaria conmpl icated by diisse mi nated in tras asco lar coag~ulat ion . Soutluast Am anJournal of Tropical Medicine andI public Health 10: 384-391,

Le Bras J & Pay et NM ( 1978) Concentration of parasiti/ed erythrocytes in mnalaria diagnosis,Transactionis olft'e IRoal Seiiity of Tropical .edricine an' tmid giene 72: 552.

Lepes T, Molincaux L & Wernsdorler Wit1 (19811 Onirn of drug sensitivits, in) Plasio-tliuntladciparion. Geneva: WIHO( MAP. I19801:801.2.

Li G. GUI X. Arnold K. Jian If & Fit L ( 1984) Ranidom ised conpa ratise slthd of inc tloqine,qinghaosu. and] pvriiiethainci-sutltadoxinie in paiticrits ss nh lalciparurnitlaria . Lant ii:136Wl 30 1.

Looareccsuwan S. Wh ite NJ, Kairbwan g J eit a 1 9185:!) OUi 111Il it and %c \ c re fat ci pit ruIi ma I at ri at inlate pregnancy. Lancet ii: 4-8.

Looaresuwan S, White NJ. Iteniasurat Y et Al 1 1)85b) 1 ntravcnotis amnOdiar(Itinc and oritlaimldiaiqiiince'erythrloinyciI Ii the treatment of chloroquine-resistant falcipiirum mnalaria.Lancet ii: 80(5-8018,

Lov~cnthal %IN. O'Riordan EC & thaut %ISR (19)71) Tropical ,plenoinega1% syndrome in

TREAtIMEN-r OFSMALARIA 221

Zambia: further observations and effects of cycloguanil and proguanil. British Medical'*--~.Journal i: 429-432.

Mackey L. McGregor IA & Lambet PH (1 9S0) Diagnosis of Plasmrodiumnfalciparurn infectionusing a solid-phase radioimmunoassay for the detection of malaria antigens. Bulletin of theWorld Health Organization 58: 439-444.

Mackey LU. McGregor IA, Paounova N & Lambert PH (1982) Diagnosis of Plasinodiumfalciparum infection in man: detection of parasite antigens by ELISA. Bulletin of theWorld Health Organization 60: 69-75.

Main EK. Main DM & Krogstad DJ (1983) Treatment of chloroquine-resistant malaria duringpregnancy. Journal ofrte American Medical Association 249: 3207-3209,

Mandell GL & Sande MA (1980) Antimicrobial agents. Sulfonamides. trimethoprim-sulIfame thoxazole. and urinary tract antiseptics. In Goodman LS & Gilman A (eds)Pharmacological Basis of Thterapeutics. 6th edn. pp 1106-1125. New York: Macmillan.

Merkli B. Richle R & Peters WV (1981) The inhibitory effect of a drug combination on thedevelopment of mefloquine resistance in illasmodiumn bergltei. Annals of TropicalMedicine and Parasitology 74: 1-9.

Mihaly GW. Ward SA, Edwards G. Le Orme M & Breckenridge AM (1984) Pharmacokineticsof primaquine in man: identification of the carboxylic acid derivative as a major plasmametabolite. British Journal of Clinical Pharinacologv 17: 441-446.

Milbous WK. Weatherly NF. Bowdre JH and Desjardins RE (1983) Interaction of mefloquineand a fixed combination of sulfadoxine and pyrimethamine (Fansidar) against Plasmodiuntfalciparum in vitro. Presented at Joint Meetintg of Amierican Society"% of Tropical Medicineand Hyvgiene and American Societv of Parasitologists. San Antonio. Texas. December 4-8.1983.

Miller LH ( 1969) Distribution of mature trophozoites and schizonts of Plasmnodiumnfalciparnin the organs of Aotits trivirgatus. the night monkey. American Journal of TropicalMedicinie and Hvgiente 18: 860-865.

Miller L (1975) Transfusion malaria. In Greenwalt Ti and Jamieson GA (eds) TransmissibleDisease and Blood Trantsfusion. pp 24 1-266. Orlando: Grune and Stratton.

Miller KD. Lobel HO. Satriale RF et al (1986) Severe cutaneous reactions amnong Americantravellers using pyrimethamine-sulfadoxine (Fansidar,) for malaria prophylaxis. Submit-ted for publication.

Mucenski CM. Guerry P. Buesing M ct al (1986) Evaluation of a synthetic oligonucleotideprobe for diagnosis of Plasinoodiunt falciparuin infections. Submitted for publication.

Munir MI. Tjandra H1. Rampcngan Ill. Mustadjab I & Wulur FIll (1980) Heparin in thetreatment of cerebral malaria. Paedliatrica lIndotesiuata 20: 47-501.

Mutahingsva 1K. Hills E & Kilama WL (1982) Response of !'lasinodiumn 14ciparuin tochloroquine and to quinine, in hospital patients in Muheza. Tanzania. World HelalthOrg~aniz.ation 1982. WIHO MAL. 84.1(012.

Naparstek Y. WVeiler-Ravell 1). Shecmer I eta~l 191 .oewnJunlo rpclMdcnand lgienu' 30: 1342-1343.

Neiva A j19101) Uber die Ilildting ciner chininresistenten Rassc des N fitlariaparasi ten.,Meniorias dto lInstititto Os, it aldo C ruz 2: 131-141.

Nguyen -Dinh P1 & Payne 1) 1(18) Pyri me thaiine se nsitivit Pi Pii I'oiii,, Jalciparutndetermination in vitro by a modified 48-hour test. B~ulletini vitle World Health O)rganiza-tion 58: 9(09-912.

Nielson R. Kohler RB, Chin W, McCarthy IJ & Loft EU (1977) Case report. The use ofexchange t rantsfusionN: at potential ly useful adjunct in the treatment of tulmi nant falci-paruim malaria. Amenrican Jmurnal ol ,ledical Ssicnce 277: 325- 329.

Nocht B & Werner H1 (1910)1 llcobachtuni!eti 1iber relatie ('hininresi~teni bei Malaria ausllrasilien. Derh .ld~nice(oc/tenscri0 136: 155;7-I SODf.

Nocypaotimanond S. NI iik of S. lent apssng W .lu rtya nonda I) & nck a%%it hongkul .1I I 19s3)Freatmnent of P'lasmiodiumi iaciparuppt malaria with at combinatiotn of ainoifiaquine and

te tracycli nein cc ntral I lba iIa nd. Irais sactiom tei Rot (il Si cctt 0fioii ~ciis n11s s.icne 77: 331-340.

Ochs I IR . (, rectiatt DJ1 & Woo E I ((10 (fital ph arniacoki neties of qui n dine. ClinicalP/iarpniok.inucs 5: 1Sf)- (i.

Orisce lb R.( i ( 196S)M Ce re bral mnalari. lriti sit .lsdical is urnal iii: 617-6kPat rtck I( 1 9S2) Ma naging cere bral malaria. B/ritishi .Mcdial iourntal 284: 1954.

222 S. L. HOFFMAN

Peters W (1970) Chemotherapy and Drug Resistance in Malaria. London: Academic Press.'..., . . .... -Peters W & Robinson BL (1984) The chemotherapy of rodent malaria. XXXV: Further studies

on the retardation of drug resistance by the use of a triple combination of mefloquine.pyrimethamine and sulfadoxine in mice infected with P. berghei and 'P. berghei NS.'Annals of Tropical Medicine and Parasitology 78: 459-466.

Phillips RE, Karbwang J, White NJ et al (1984) Failure of chloroquine-erythromycin andehloroquine-tetracycline combinations in treatment of chloroquine-resistant falciparummalaria in eastern Thailand. Lancet i: 300-302.

Phillips RE, Warrell DA, White NJ, Looareesuwan S & Karbwant J (1985) Intravenousquinidine for the treatment of severe falciparum malaria. Clinical and pharmacokineticstudies. New England Journal of Medicine 312: 1273-1278.

Pinichpongse S, Doberstyn EB, Cullen JR et al (1982) An evaluation of five regimens for theoutpatient therapy of falciparum malaria in Thailand 1980-81. Bulletin of the World IHealthOrganization 60: 907-912.

Pollack Y, Metzger S, Shemer R et al (1985) Detection of Plasmodium falciparun in bloodusing DNA hybridization. Anerican Journal of Tropical Medicine and Hvgie,' 34:663-667.

Powell RD & McNamara JV (1972) Ouinine: side effects and plasma levels. HelninthologicalSociety of Washington. Proceedings 39: 331-338.

Powell RD, Brewer GJ, Alving AS & Millar JW (1964a) Studies on a strain of chloroquine-resistant Plasmodium falciparumn from Thailand. Bulletin of the World Health Organi:a-tion 30: 29-44.

Powell RD, Brewer GJ, Degowin RL & Alving AS (1964b) Studies on a strain of chloroquine-resistant Plasmodiumn falciparum from Vietnam. Bulletin of the World Iealth Organiza-tion 31: 379-392.

Punyagupta S, Srichaikul T, Nitivanant P & Petchclai B (1974) Acute pulmonary insufficiencyin falciparum malaria: summary of 12 cases with evidence of disseminated intravascularcoagulation. American Journal of Tropical Medicine and If tygiene 23: 551-559.

Pussard E, Verdier F, Clavier F et al (1985) A new approach to pharmacokinctics ofamodiaquine and its contribution of prophylaxis and treatment of Pla'nodit .(dct-parum malaria. Joint Meeting of the American Society of Tropical Medicine and I tygicncand the American Society of Tropical Veterinary Medicine. 34th Annual ,lectng of theAmerican Society of Tropical Mcdicinu and Iiygie'. November 3-7. 1)85, Miami.Florida.

Qinghaosu Antimalaria Coordinating Research Group (1979) Antimalaria studies on Qing-haosu. Chinese Medical Journal 92: 811-816.

Sabchareon A, Chongsuphajaisiddhi T & Attanath P (1983) Serum quinine concentrationsfollowing the initial dose in children with falcipa rum malaria. Sotthca,t 4.ian Journal ofTropical Aedicine and Public health 13: 55(6562.

Sagoe A-S (1970) Tropical splenomegaly syndrome: long-term proguanil therapy correlatedwith spleen size. serum IgM. and lymphocyte transformation. British Medical Jornal iii:378-382.

Salako LA, Walker 0 & lyun AO (1984) Pharmacokinemics of chloroquine in renal in,,uf-ficiency. African Journal of Medicine and Medicia Science 13: 177-182.

Sanders JP & Dawson WT ( 1932) Efficacy of quinine in malaria. Journal of the 4?neri(atiMedical Association 99: 1773-1777.

Sanders JP (1935) Treatment of malaria with a short course of quinidine. ,,tmerian Journal ofTropical Medicine 15: 651-660.

San George RC, Nagel RL& Fabrv ME (1984) On the mechanism for the red-cell accumulationof mefloquine, an antimalarial drug. Ritomhtowa ift Biphu .,ica A eta 803: 174- 181.

Schwartz DE, Eckert G, I lartmann 1) ct al ( 1982) Single lose kineticS of mnCeloquiIle in mM.Plasma levels of the unchanged d rug and of one of its metabolites. Chemotherap 28:70-84.

Sheehv TW, Reba RC & Parks GR (1969) Combined primehammne-quinine thciap\ forchloroquine-resistant I'. falciparo in lections. Southern .Medical Jourial 62: 152- 1 5

Shmitskamp 11 & Wolthuis Fl I (1971) British Medical Journal i: 714-716.Silanut K, White NJ. Looarecsu%an S & Warrell I)A ( 19S5 Binding of quinine to pliina

proteins in falciparum malaria. American Journal of "roipi'al ,leduinc and I/Ii incn .34:681-686.

41


Smith CC & Ihrig J (1959) Persistent excretion of pyrimethamine following oral administration.American Journial (if Tropical Medicine and Ifyvgiene 8: 60-62.

Smitskamp H & Wolthuis FH (1971) New concepts in treatment of malignant tertian malariawith cerebral involvement. British Medical Journal i: 714-716.

Smrkovski LL, Buck RL, Alcantara AK, Rodriguez CS & Uylangcoi CV (1983) In vitromefloquine-resistant Plasmodiumn falciparunt from the Philippines. Lancet ii: 322.

Stace i. Shann FA. Walters S et al (1983) Serum levels of quinine following intramuscularadministration to children. Papua New Guinea Medical Journal 26: 21-24.

Stone WJ. Hanchett JE & Knepshield iH (1972) Acute renal insufficiency due to falciparummalaria. Archives of Internal Medicine 129: 620-628.

Strickland GI, Fox E, Sarwar M. Khaliq AA & MacDonald M (1986) Effects of chloroquine.amodiaquine and Fansidlar on Plasmnodium falciparum gametocvtemnias. American Journalof Tropical Medicine and HYgiene (in press).

Taggart iV. Gate DP, Berliner RW et al (1948) Studies on the chemotherapy of the humanmalarias. Ill. The physiological disposition and antimalarial activity of the cinchonaalkaloids. Journal of Clinical In vestigation 27: 8("-6.

Thuriaux MC (1982a) Quinine by intravenous infusion for falciparum malaria. British MedicalJournal 285: 1429.

Thuriaux MC (1982b) A prevalence survey of lower limb motor disorders in schoolage childrenin Niger and an estimation of poliomyelitis incidence. Tropical and Geographical Medicine34:163-168.

Tigertt WD (1985) A role for 8-aminoquinolines in falciparum malaria? Editor's page.American Journal of Tropical Medicine and HYgiene 34: 65 1-652.

Timm U & Weidekamm E (1982) Determination of pyrimethamine in human plasma afteradministration of Fansidar or Fansidar-mefioquine by means of high-performance liquidchromatography with fluorescence detection. Journal of Chromatograpliy 230: 1(17-114.

Trenholme GM, William,; RL. Desjardins RE et a) (1975) Scienice 190: 792-794.Trenholme GM. Williams RL. Rieckmann KIu. Frischer H & Carson PE (1976) Quinine

disposition during malaria and during induced fever. Clinical Pharmacologyv andTherapeutics 19: 459-467.

Uys C1, Burns DG, Tiltman AJ & Philcox DV 11984) Clinicopathological conference. Fever.diarrhoea and confusion. South African Medical Journal 65: 519-523.

Verdrager J (1964) Observations on the long'evity of Plasooun falciparumn: with specialreference to findings in Mauritius. Bulletin of the World Health Organization 31: 747-751.

Walker 0. Birkett Di. Alvan G, Gustalsson LL & Sjoquist F (1983) Characterization ofchloroquine plasma protein binding in man. British Journal of Cinical Phiarmiacology 15:375-377.

Walliker D (1982) Genetic variation in malaria parasites. British Medical Bulletin 38: 123-128.Ward SA. Edwards G,. L'e Orme NIl & lrs..kenridee AM (1983) Determination of primaquine

in biological fluids by reversed phase high-pcerform ance liquid ch romatographv J 'urnal of(hromotorap/o, 3605: 2.39-243.

Ward SA, Mihaly GW., Edwards G et Al (1985) Pharniacokinetics of primaquine in man. 11.Comparison of acute vs chronic dosage in Thai subi-cts. Brihi~h Journal of clinicalPharmacology 19: 751-755.

Warhurst [DC (1981) The quinine-haemnin interaction and its relationship to antimalarialactivitv. Biochetmical Pharoiacologs- 30: 3323-3327.

Warhurst DC, Robinson 13L & Peters W (1976)' The chemnotherapy of rodent malaria. XXIV.The blood sehizontocidal action of ervthromvcin upon Plastnodiuoi heri.1ui. .4nnabh ofTropical At edictne and l'artisitoloi 701: 253-258.

Warrell DA. LooareeSuiwan S. Warrell Mi et Al (1983) IDexamcthasonc proves deleterious ince rebral malaria. New Engl/andi Journal of M~edijcine 306: 31.3-319,

Watkins WM, Spencer I IW. Kariuki DMl et all( 1984) Effectiveness of amodiaquine as, treatmentfor cliloroquine- resistanit Puas nodiuoi (4dciparunt in fect ions itt Ke I a . Lapicet i: 357-359.

Watt G. Long (,W. Padre Ne cal (19851 1 ligh-prade amodiaquine resistance in the Philippines.['resented at the Joint .M eeting of the American Society oif Tropical Medicine and I I gieneand the American Society olf 1ropical Vcte ri n ir MIedici ne 34th A1tnntuil kIeeting (of thelAmerican Sotciety of Tropial .tediine and /1%yi'u'i. Novemiber 3 -7. 19t85. Abstract 2"9.

Weni~'er II ( 1979a) Review of the side effects ard toxicity oft cbliroquine. World IHealthOJrganization, 1979. WIHO( MA. 1r79. (X 16

224 S. L. HOFFMAN

Weniger H (1979b) Review of the side effects and toxicity of pyrimethamine. World HealthQ>.~-i-~ :.<~ -Organization, 1979. WII0/MIAL/79.907.

Weniger H (1979c) Toxicity and side effects of primaquine and other 8-aminoquinolines. WorldHealth Organization. 1979. WHO/MAL/79.905.

Wesselhoeft C (1914) The discovery of' the cinchona bark. New Orleans Medical and SurgicalJournal 68: 702-727.

Westerman RL (1985) Clindamycin as an antimalarial. Presented at the Joint Meeting of theAmerican Society of Tropical Medicine and Hygiene and the American Society of TropicalVeterinary Medicine. 34th Annual Mfeeuing of the American Society of Tropical Medicineand IHygiene. November 3-7, 1985. Abstract 289.

White NJ (1985) Clinical pharmacoki ne tics of the antimalarial drugs. Clinical Phiartnaco-kinetics 10: 187-215.

White NJ, Warrell DA, Bunnag D et al (1981) Quinine in falciparum malaria. Lantcet ii:1069-1071.

White NJ, Looareesuwan S, Warrell DA et al (1982) Quinine pharmacokinetics and toxicity incerebral and uncomplicated falciparum malaria. Amiericant Journal of Medicine 73:564-572.

White NJ, Looareesuwan S & Warrell DA (1983a) Quinine and quinidine: a comparison ofEKG effects during the treatment of malaria. Journal of Cardiovascular pharmnacology 5:173- 175.

White NJ, Looareesuwan S, Warrell DA et al (191sTh) Ouinine loading dose in cerebralmalaria. American Journal of Tropical Medicinte and HYgiene 32: 1-5.

White NJ, Looarcesuwan S & Silamut K (1983c) Red cell quinine concentrations in falciparummalaria. American Journal of Tropical Medicine and lrgiene 32: 456-460.

White NJ, Warrell DA, Chanthavanich P et al (1983d) Severe hypoglycemnia and h yperinsulin-emia in falciparum malaria. New England Journal of'Medicine 309: 61-66.

Woodruff AW & Dickinson CF (1968) Use of dexamethasone in~ccrcbral malaria. BritishMedical Journal iii: 31-32.

World Health Organization (1973) Chemotherapy of malaria and resisance to anti-malarials:Report of a WHO Scientific Group. World Ifealh Organization Technical Report St ries529: 30-35.

World Health Organization Scientific Group on the Cherttotherapv of, Malaria (1984) Aldvance,%in Malaria Chemnotherapy. Geneva: World Health Organization.

Xinyl N. Liyi 11, Zhihong R & Zhenvu S (1985)I Metabolic fate of Oitghaosu in ratls: a new% LCdensitometric method for its determination in biological material. European Journal of'Drug Metabolism and I'.tarmnacokine'ics 10: 55-59.

Yarrish RL. Janas JS. Nosanchuk JS, Steighigcl RT & Nusbacheri (1982) Transfusion mnalaria.Treatment with exchange transfusion after delaYedI dia.gnOSis. .Archives of InuernalMedicine 142: 187-188.

treatment of malariatreatment o malaria 12. pe.sonal ,uf1or(s) hotman s,. 13a. type of report 13b....

Documents