American Journal of M edicine and M edical Scien ces 2013, 3(4): 81-90

DOI: 10.5923/j.ajmms.20130304.05



Artemisinin-Based Therapy for Malaria


Jagtis h Raje ndran


Faculty of M edicine, Universitas Uday ana, Denp asar, Bali, 80232, Indonesia



Abstract Malaria is a s erious and common proble m a mong travellers all over the world es pecially travellers travelling to
Indones ia. This des criptive s tudy focus on artemis inin-bas ed therapy for ma laria es pecially in Indones ia. According to
Centers for Dis eas e Control (CDC), ma laria is s till pres ent in mos t part of Indones ia. In April 2001, W HO reco mmended the
us e of artemis inin-bas ed combination therapies (ACTs ) to minimize the burden caus ed by Plasmodium falciparum
res is tance to conventional anti-ma larial medicat ions . Artemis inin is a s es quiterpene lactone produced from a p lant called
Artemisia annua. It is active agains t all Plas modiu m s pecies and its able to destroy all the blood s tages of the paras ite.
Artemis inins caus es les s toxic e ffect if co mpared with other antimala ria l agents . The year 2004 marks the beginning of
adoption of artemis nin-bas ed combination therapies (ACTs ) into national ma laria control progra m in Indones ia. 3 types of
ACT which a re d ihydroartemis inin-p iperaquine, arte mether-lu me fantrine and artes unate-amodiaquine. have been us ed
recently to treat uncomplicated ma laria in Indones ia. Res is tance to artemis inin and its derivatives has been recently reported
fro m Tha iland-Ca mbodia border.

Keywords Ma laria, Arte mis inin, ACT in Indones ia, Res is tance



1. Introduction

Malaria is trans mitted by fe ma le Anopheles mos quito that
us ually b ites fro m dus k to da wn wh ich a re in fected by
protozoan paras ites s pecies of Plasmodium genus . There are
4 types of Plasmodium which are Plasmodium falciparum, P.
vivax, P. ovale and P. malariae. In addition, P. k nowlesi, a
paras ite of Old World (Eas tern He mis phere) monkeys , has
been identified in South Eas t As ia[1,2]. Es timation by The
World Hea lth Organization (WHO) of reported cas es from
Indones ia were 2.5 million in 2006. Papua (300,000) and
Eas t Nus a Tenggara (70,000) prov inces we re the h ighes t
provinces of clinica l mala ria cas es , annually[3]. Bas ed on the
2011 World Ma laria Report, in 2010, 4.3 million mala ria
cas es were repo rt ed, o f wh ich 2.4 million we re paras ito lo
gically con firmed . Th ree countries accounted for 94% of
confirmed cas es : India(66% ), Myan mar(18%) and Indones ia
(10%). A total of 2426 mala ria deaths were reported from
eight countries , the great majo rity (93% ) in India, Indones ia
and My an ma r. Indon es ia rep orted litt le cha nge in t he
incidence of ma laria between the year 2010 and 2011[4].
According to Centers for Dis eas e Control (CDC), Mala ria is
s till pres ent in mos t part of Indones ia. Chloroquine-res is tant
P. falciparum mala ria is pres ent in Indones ia. Malaria is s till
endemic in a ll rura l areas in Kalimantan, Su mat ra, Su lawes i,
and Nus a Tenggara Barat; a reas of Bali outs ide the ma in

* Corresponding author: jaish8904@yahoo.com
(Jagtish Rajendran) Published online at
http://journal.sapub.org/ ajmms
Copyright 2013 Scientific & Academic Publishing. All Rights Reserved
res ort areas ; all areas of eastern Indones ia including Papua,
Nus a Tenggara Timur, Ma luku and Ma luku Utara; and
Lo mbok is land. There is no ma la ria trans mis s ion in Ja karta;
ma in res ort areas of Bali or the is land of Java (with the
e xception of Menorah Hills , central Java, ris k s till preva ils
there); and urban areas in Su matra , Kalimantan, Sula wes i
and Nus a Tenggara Barat. There is a lo w trans mis s ion in
rural a reas of Java[2]. In April 2001, W HO reco mmended
the us e of artemis inin-bas ed combination therapies (A CTs )
to min imize the burden caus ed by Plasmodium falciparum
res is tance to conventional anti-ma larial med ications s uch as
chloroquine, s ulfadoxine-pyrimetha mine and a mod iaquine.
However, production and ma rket ing of a rte mis inin
monotherapies in the private s ector of the endemic countries
increas es the chances of res is tance to artemis nin. Due to this
reas on, WHO is s ued press releas e in January 2006 to s top the
production of artemis inin monotherapies and was
imple mented in April 2006 at the WHO b rie fing on Malaria
Treatment Guidelines and artemis inin monotherapies in
Geneva. This s tep was taken to avoid development of
res is tance and compro mis e the effectivenes s of ACTs [5].


2. Literature Review

2.1. Ar te mis inin

Artemis inin is a s es quiterpene lactone produced fro m a
plant called Artemisia annua which als o known as s weet
wormwood, s weet Annie or "Qinghao". It is a ch ines e
med icina l herb which has been us ed as treatment for fevers
in China for mo re than 1500 years in the form of antipyret ic
82 Jagtish Rajendr an: Artemisinin-B ased Therap y for M alaria American Journal of M edicine and M edical Scien ces 2013, 3(4): 81-90 82




tea. Artemisia annua is s ix-foot in height and has fernlike
leaves . This plant grows in China and Vietnam and its origin
believed to be fro m the Luofus han area of Guangdong
which is a province in s outhern China. The active
anti-mala rial cons tituent qinghaosu was is olated from
qinghao in 1971 by Ch ines e s cientists and is named
artemis inin. This plant is als o now grown in Tanzania, South
Africa, India and Madagas car[6-8].
In Indones ia, at Tawangmangu, Centra l Java Province, the
plant has been breeded s ince 2006 at a field taken care by the
Health Min is trys Agency for Res earch in Medicinal Plants
and Traditional Medic ines , after Indones ia got the s eed from
China[9].

2.2. Ar te mis nin Deri vati ves

Artemis inin is e xtracted and purified fro m the plant us ing
s olvent s uch as hexane and chro matography, res pectively.
The e xtract cons is ts of arte mis in in and its precurs or,
artemis inic ac id which will be t rans formed into a rte mis inin.
Artemis inin is a highly crys talline compound which does not
dis solve in oil and water and can only be given by enteral
route[6,7]. Organic reagents such as is oplugelol can be
utilis ed for the total s ynthes is of artemis inin[8].
Se mi-s ynthetic derivatives of arte mis inin was ma inly
formulated to overcome the poor bioavailability of
artemis inin which reduce its effectiveness . Artemis inin
undergo s emi-s ynthetic process to produce dihydroartemis i
nin then the proces s continue to produce a water s oluble es ter
called artes unate and two oil s oluble preparations called
artemether and arteether (Figure 1)[6,7]. Artes unate is
available in oral, rectal, intra mus cular inject ion, or
intravenous injection form. Arte mether is available in o ral,
rectal or intra mus cular form. Arteether is available in
intra mus cular injection form. Other derivatives of
artemis inin a re arte lin ic ac id, artenimo l and arte motil.

Fi gure 1. Derivat es of Art emisinin

Che mical s tability of thes e derivatives varies a mong one
another. The leas t s table among thes e derivatives is
dihydroartemis inin whereas artes unate is the mos t s ens itive
to humidity and to combination with amodiaquine. Due to
acceleration of degradation by the pres ence of e xcip ients ,
active s ubs tance powder mixtu res are more s table than
combination of powders in tablets . If a rtes unate and
amodiaquine phys ically s eparated, they can only be us ed in a
fixed dos e combination. On the hand, a fixed co mbination of
artemether-a mod iaquine tablet does not demand this
phys ical s eparation and is les s vulnerable to high hu midity
s ituation[10].

2.3. Anti-Mal arial Pr operties

The arte mis inin derivatives are active agains t all
Plas modiu m s pecies es pecially P. falciparum and P. vivax..
Thes e derivatives are able to rapidly destroy all the blood
s tages of the paras ite. Thes e res ults in the shortes t fever
clearances times of all antima larials . Arte mis inin has blood
s chizonticides characteris tics against P. falciparum and P.
vivax. These drugs act on the blood forms of the paras ite and
thereby terminate c lin ical attacks of mala ria[6].
Artemis inin's main anti mala ria l properties comes fro m its
endoperoxide bridge wh ich can generate free radicals .
Malaria paras ites are very s ens itive to uns table free rad icals
which are liberated through heme-catalyzed c leavage of
peroxide. The plas modiu m paras ite inges ts hemoglobin and
releas es free heme , an co mple x-mo iety of iron-porphyrin
during the infection of the red blood cells . Reactive o xygen
radicals are produced from the reaction the comple x and
artemis inin. This caus es the paras ite to get damaged and
eventually die . Plas modiu m paras ite requires convers ion of
toxic he me into non-toxic he mozo in, a ls o known as ma larial
pigment, for its s urvival. Arte mis in in inhib its the hemozo in
formation activ ity of ma laria paras ite wh ich ultimately leads
to its des truction[6-8].
Artemis inin and its derivatives als o interfe re with
s arcoplas mic/endoplas mic calc iu m AT Pas e (SERCA), as
well as da maging of norma l mitochondrial functions of
plas modiu m paras ites . Arte mis in in works on the electron
trans port chain, yields local reactive o xygen s pecies , and
leads to the paras ites mitochondria l me mbrane depolarizati
on[6,8].
Artemis inin is the fas test acting anti mala ria l available. It
res tricts the growth of the trophozoites and thus inhibits
development of the dis eas e. Circulat ing paras ites are
destroyed at early s tage of life to avoid the m fro m
s equestering in the deep microvas culature. Thes e drugs starts
its action within 12 hours of consumption. Thes e properties
of the drug are very c rucia l in treating co mplicated P.
falc iparu m mala ria . Thes e drugs are als o active agains t the
chloroquine res is tant P. falc iparu m. s trains .
Artemis inin co mpounds have been reported to reduce
gametocytogenes is , thus reducing trans mis s ion of mala ria,
this fact being s pecially s ignificant in preventing the s pread
of res is tant s trains Thes e drugs prevent the gametocyte
development by their action on the ring s tages and on the
early (s tage I-III) ga metocytes which differ fro m other
anti-mala rial drugs available (Figure 2). It has broad s tage
s pecificity, des troying all as e xual s tages but not effective in
e xo-erythrocytic s tages [7]. Due to this reas on artemis inin is
not recommended as prophylaxis for ma laria infection.
83 Jagtish Rajendr an: Artemisinin-B ased Therap y for M alaria American Journal of M edicine and M edical Scien ces 2013, 3(4): 81-90 83






Fi gure 2. Ant i-malarial act ivity of art emisinin. Art emisinins kill parasit es more effect ively and at an earlier stage in t he erythrocyt ic part of it s life cycle
than most of the other ant i-malarial current ly in use. They also kill the gametocyt e st age and may cont ribut e to int errupt ing transmission. They do not work
on t he exo-erythrocyt ic forms, hence do not prevent relapses in P . vivax or P. ovale (Hommel, 2008)

2.4. Phar mac okinetics

Intra mus cular or o ral application of arte mis in in derivativ
es are well-abs orbed. Oral formulat ions are generally
quickly abs orbed whereas intramus cular artemether has s low
and erratic abs orption. In treating s evere ma laria, intra mus uc
ular artes unate is pharmacokinetica lly s uperior to arte mether
for the treatment of, s howing rapid and re liab le abs orption.
Intrarectal artes unate s hows rapid abs orption and is a
promis ing treat ment for patients with moderate ma laria when
oral ad min is tration is not poss ible, and until hos pital care is
available [6].
Mos t ess ential a rte mis in ins are metabolis ed to dihydroar
temis inin in wh ich form they have comparable antima larial
activity. Dihydroarte mis in in has elimination half-life of
about 45 min, It is rapidly cleared, predo minantly through
the bile[6]. Monotherapy treatment of thes e drugs is related
with h igh incidences of recrudes cent infection. Due to this
reas on it has been recommended to co mbine thes e drugs with
other antima larials to increas e its efficacy.

2.5. Li mitati ons of Arte mis inins

Artemis inins caus es less toxic effect if co mpared with

other antima laria l agents . Artemis inin derivatives are we ll
tolerated by patients [11]. The mos t common advers e s ide
effects that have been identified are naus ea, vomit ing,
anorexia, and dizzines s ; thes e are probably due, in many
patients , to acute mala ria rather than to the drugs [6,8].
Neuroto xicity is the greates t concern regarding artemis ini
ns . Intramus cular dos ing was dicovered to be mo re to xic than
oral dos ing in many e xtens ive s tudies conducted in many
s pecies and that, by any route, artemis in ins which are
fat-s oluble we re mo re to xic than artes unate. In addition,
pharmacokinetic s tudies of oil bas ed formulat ions of
parenteral arte mether and arteether have revealed the s low
releas e and cons equently long e xpos ure times s een in both
animals and humans . However, time o f e xpos ure to
artemis inins influences neurotoxicity if co mpared to the
ma ximu m concentrations reached.
Artemis inin is reported to affect areas in the brain s tem
s uch as the reticular s ys tem with regard to autonomic control,
the ves tibular s ys tem, the auditory s ys tem (trapezo id
nucleus ), and the red nucleus , which is important for
coordination. Ataxia, s lu rred s peech, and hearing los s have
been reported in fe w patients treated with arte mis inin.[11].
However arte mis inins is s till cons idered s afe if co mpared to
84 Jagtish Rajendr an: Artemisinin-B ased Therap y for M alaria American Journal of M edicine and M edical Scien ces 2013, 3(4): 81-90 84




other anti -ma larial drugs .

2.6. Alter nati ve Production of Arte mis inin

Alternative to full che mical s ynthes is of artemis inin was
developed becaus e the initial proces s is too comple x and
e xpens ive. The alternative product is fully s ynthetic
peroxides (trio xanes or trio xo lanes ) wh ich is s imilar to
artemis inin including the key endoperoxide bridge but their
mode of action is different. One trio xa lane (Artero lane)
appear to be highly potent agains t P. falciparum in vitro but
the drug prove to be too uns table in vivo. Res earch has been
done to develop more s table molecu les and a hybrid
trio xane-a minoquinoline (t rio xaquine) was dis covered
recently to be a fully s ynthetic anti-ma larial pero xide[7].
An alternative to chemical s ynthes is is mic robial genetic
engineering. Arte mis inic ac id can be gro wn in Escherichia
coli and, even more s uccess fully, in Saccharomyces
cerevisiae (mevalonate pathway). Keas ling and colleagues
s uccess fully trans ferred 10 A. annua genes into E. coli to
create an almos t p lant-like environ ment in the bacteria
[7,8].

2.7. Us es Outs ide Mal aria

Bes ide its anti -ma laria l properties , arte mis inin and its
derivatives is believed to be effective agains t paras itic
diseas es, such asschis tosomias is, and it was discovered
recently that artemis inin could be us eful in curing cancer[7].
There is s ome ongoing res earch about artemis inin's
effectivenes s to inhibit certain v irus es , s uch as human
cytomegalovirus and other me mbers of the Herpesviridae
fa mily (HSV-1, EBV), hepatitis B virus , hepatitis C virus ,
and bovine vira l d iarrhea virus [11]. The co mplete
antimicrobia l potential of this product is yet to be d is covered.

2.8. Ar te mis inin-Bas ed Combi nation Therapy (ACTs )

The evolve ment of d rug res is tance es pecially to conventi
onal ma laria l drugs s uch as chloroquine, sulfadoxine -
pyrimethamin and a modiaquine, throughout the world is a
s erious challenge in co mbating ma laria. In o rder to
overcome this increas ing burden, in April 2001, WHO
recommended the us e of artemis inin-bas ed combination
therapies (ACTs )[5].
Global Fund to fight AIDS, Tuberculos is , and Malaria
(GFATM ) provides financial s upport for the major trans ition
of adopting ACTs by mala ria -endemic countries . US
Pres idents Malaria Initiat ive (PM I) and the World Bank
Boos ter Progra m, which were es tablis hed in 2005 we re
additional res ources to s upport this trans ition[12].
However, production and market ing of arte mis inin
monotherapies in the private s ector of the endemic countries
increas es the chances of res is tance to arte mis inin. Artemis in
in monotherapy is pres cribed for s even days to kill a ll
paras ites , but after a few days of cons umption, patients
us ually s top the treatment when they begin to feel better.
This caus es the balance paras ites to come in contact with low
levels of the drug which ma ximize chances for res is tance.
Due to this reas on, WHO is s ued pres s releas e in January
2006 to s top the production of arte mis in in monotherapies
and was imple mented in April 2006 at the WHO b rie fing on
Malaria Treatment Guidelines and arte mis inin monotherapi
es in Geneva. This s tep was taken to avoid development of
res is tance and compromis e the effectivenes s of ACTs . 15 out
of 41 pa rt ic ipated manu factu re rs ag re ed to wo rk hand-in-
hand with WHO by stopping production and marketing of
artemis inin as monotherapies [5,7].
ACTs are reco mmended becaus e artemis in in and its
derivatives are fas t acting but other drugs are often required
to clear the body of all paras ites and prevent recrudes cence
es pecially in treat ment of uncomp licated ma laria [8]. When
artemis inins effective ly kills mos t of the paras ites in the firs t
few hours of treatment, the partner drug comes in to action to
kill the re ma ining paras ites . This is attributed to different
kinetic act ions of the ACTs . Moreover, one drug protects the
other drug from provoking res is tance[7].
The mos t common co mbinations of ACTs availab le are
artemether-lu me fantrine, a rtes unate-amodiaquine, artes unate
-s ulfadoxine-pyrimetha mine, artes unate-mefloquine, and
dihydroartemis inin-piperaquine. ACTs are more than 90%
efficient in treat ing mala ria [8]. Of the newer co mb inations ,
artemether-lu me fantrine and dihydroartemis inin-piperaquine
reported to be we ll tole rated with e xcellent efficacy in a lmos t
all the s tudies conducted worlwide[13].
65 of 67 countries including 41 in Africa, imp le mented
ACTs as their firs t-line treat ment to treat uncomp licated
falc iparu m ma la ria (Table 1). On ly two countries adopted
ACTs exc lus ively as second-line treat ment. Among the
ACTs , 28 countries adopted artemether/lu me fantrin as
firs t-line treat ment, 19 countries opted for artes unate plus
amodiaquine, a rtes unate plus s ulfadoxine/pyrimethamine
was chos en by 11 countries ; artes unate plus mefloquine by 7
countries ; and dihydroartemis inin/piperaquine by 1 country
[12].
By the year 2010, 84 countries already deployed ACT
treatment in their public health s ector. WHO a lways willing
to provide continuous technical cooperation to minis tries of
health of all ma laria-ende mic countries on all as pects of
national treatment policy change, monitoring therapeutic
efficacy of med icines and imple menting ACT-bas ed
treatment polic ies .

2.9. ACTs in Indones ia

The year 2004 marks the beginning of adoption of ACTs
into national ma laria control progra m in Indones ia. This
adoption is due to the overwhelming burden of res is tant
ma laria paras ites to old conventional ma laria drugs which
affects mo re than 25% provinces in Indones ia. The
Depart ment of Hea lth of Indones ia through dis cus s ion with
ma laria l e xperts , Komisi Ahli Malaria (KOM LI) ca me to
conclus ion to adapt artemis inin-bas ed combination therapies
to treat ma laria. This s tep was als o in conjunction with
WHO's reco mmendation of us ing ACTs to combat
ma laria[14,15].
85 Jagtish Rajendr an: Artemisinin-B ased Therap y for M alaria American Journal of M edicine and M edical Scien ces 2013, 3(4): 81-90 85





Table 1. Count ries that have adopted ACTs and t he ACT choices made by them (Bosman & Mendis, 2007)

Cont inent Count ries ACT choice Indicat ion




Africa
Burundi, Cameroon, Congo, Ct e dIvoire, Democratic Republic of Congo,
Eq. Guinea, Gabon, Ghana, Guinea, Liberia, Madagascar, Malawi, Mauritania,
Senegal, Sao Tom & P rincipe, Sierra Leone, Sudan (S), Tanzania (Zanzibar)

AS + AQ

First-line
Angola, Benin, Burkina Faso, Cent ral African Republic, Chad, Comoros, Ethiopia,
Gambia, Guinea Bissau, Kenya, Mali, Namibia, Niger, Nigeria, Rwanda, Uganda,
Sout h Africa (Kwa Zulu Nat al), Tanzania (Mainland), Togo, Zambia, Zimbabwe

AL

First-line
Ct e dIvoire, Djibout i, Gabon, Malawi, Mozambique, Sudan (N), Sao Tom &
Principe, Tanzania (Zanzibar)
AL

Second-line
Mozambique, Djibout i, Somalia, Sout h Africa (Mpumalanga), Sudan (N) AS + SP First-line



Asia
Cambodia, Malaysia, Myanmar, Thailand AS + MQ First-line
Bangladesh, Bhut an, Laos, Saudi Arabia AL First-line
Indonesia AS + AQ First-line
Afghanist an, India (5 Provinces), Iran, Tajikistan, Yemen AS + SP First-line
Viet Nam DP First-line
P apua New Guinea AS + SP Second-line
Iran, Philippines, Solomon Islands AL Second-line

Sout h America
Ecuador, P eru AS + SP First-line
Bolivia, Peru, Venezuela AS + MQ First-line
Brazil, Guyana, Suriname AL First-line
Count ries that have st art ed deployment of t hese medicines in the general healt h services are shown in italics (sit uat ion as of 31 July 2006).
AQ, amodiaquine; AL, art emether/lumefantrine; AS, art esunat e; DP , dihydroart emisinin/piperaquine; MQ, mefloquine; SP ,
sulfadoxine/pyrimethamine.

2.9.1. Artes unate-amodiaquine

The firs t ACT adopted as firs t line treat ment agains t
ma laria in Indones ia is a rtes unate-amodiaquine (Table 1).
According to s tudy conducted in 2009 by As ih et al. in West
Sumba Dis trict, Eas t Nus a Tenggara Province, it was
concluded that artes unate-amodiaquine co mbination is an
effective treat ment for pers ons with uncomplicated P.
falciparum mala ria in this dis trict wh ich is one of the a rea
with s table ma laria infection[14].
This non fixed dos ed regimen is active agains t P.
falciparum as well as P.vivax. The advantages of this ACT
are s afe for all ages , cheap and affordable whereas the
dis advantage is poor compliance due to a lot nu mber of pills
need to be cons umed. Moreover, in places s uch as Papua,
La mpung, and North Su lawes i or in the areas with high
chloroquine treatment fa ilure, it was reported high treatment
failure with artes unate-amodiaquine[15]. Cons equently, the
efficacy of a rtes unate-amodiaquine was varied (7896%)
[16].

2.9.2. Arte mether-lu me fantrine

Recently, arte mether-lu mefantrine is imp le mented in
Indones ia. In the pres ent study conducted by Sutanto et al.,
artemether-lu me fantrine proved s afe and highly efficac ious
in 59 res idents of eas tern Sumba Is land pres enting with
uncomplicated fa lciparu m mala ria . Another s tudy in
s outhern Papua of Indones ia, an a rea with mult idrug res is tant
P. falciparum als o s howed high cure rate (95.3% ) of
artemether-lu me fantrine[17].
In addition, a s tudy in Papua demons trated that there is
les s respons e to P.vivax compared to other combination
(43%). When it is applied for ma laria v iva x, the regimen may
be comb ined with do xycycline o r tetracyc line o r clinda myci
n to increas e s ens itivity[15,16]. The dis advantage of this
ACT is it s hould be adminis tered twice daily for three days
and given with fatty foods . Bes ides , it is expens ive. All thes e
data limits artemether-lu mefantrine utilization as s econd line
therapy to P. falciparum.

2.9.3. Dihydroartemis inin/Piperaquine

Dihydroarte mis inin/piperaquine is ne xt in line in treating
ma laria in Indones ia. The combination is chos en to
overcome fa ilure of the previous exixting comb ination s uch
as artesunate-amodiaquine[15]. Bas ed on the data of
previous ACT trials in Indones ia, dihydroartemis inin /
piperaquine is found to be the bes t ACT to treat
uncomplicated mala ria in areas with mult i-drug res is tance.
In comparis on with all the e xis ting form of a rte mis inin, a 3
day dihydroartemis in in-piperaquine is the bes t subs titute for
the Indones ian ACT progra mme[16].
Bes ides , dihydroartemis inin/piperaquine is s afe and
effective for both P. falciparum and P. vivax malaria. The
cure rates of DHP for the treatment of P. falciparum and P.
vivax were reported 95.2% and 92.7%, res pectively. It has
been us ed for more than 2 years in Papua as the firs t line of
therapy[16]. In addit ion, d ihydroartemis inin/piperaquine had
post treatment prophylactic effect agains t additional
infection and relaps e but s tudy done by Arinaitwe et al. did
not support the hypothes is that longer pos t-expos ure
prophylaxis s hould be ass ociated with a reduction in the ris k
of additional infect ion in highly endemic areas . The cos t of
this ACT is s imilar to artes unate-amodiaquine[13].

2.9.4. Arte mis in in-naphthoquine

This is the lates t ACT wh ich is being inves tigated in
Indones ia becaus e of its high efficacy in treating ma la ria.
86 Jagtish Rajendr an: Artemisinin-B ased Therap y for M alaria American Journal of M edicine and M edical Scien ces 2013, 3(4): 81-90 86




Naphthoquine which has longer ha lf life (276 hours ) in itiate
its antimala ria l action by 72 hours and clear up any leftover
Plas modiu m paras ites . Naphthoquine has good tolerance and
it is s afe. It is an anti-ma larial s ubstance dis covered in the
late 1980s by Chines e Academy of Military Medical Sc ience.
Although it has s imila rit ies in s tructure with choloroquin, it
does not have any his tory of cros s res is tance[16]. In s hort,
Artemis inin s tart the action, while Naphthoquine proceeds
and ma intain the cours e of the treatment.
Bas ed on limited Chines e clin ical s tudies , a s ingle dos e
adminis tration of naphthoquine and artemis inin co mbination,
was reported to be s afe and effictive with cure percentage of
97.5% for t reat ment of P. falciparum ma laria by day 28, and
90.0% for the treatment of P . vivax mala ria by day 56. T jit ra
et al. conducted a s tudy in Jayapura and Maumere to
compare the efficacy and s afety of a s ingle dos e of
artemis inin-naphthoquine with a three-day regimen of
dihydroartemis inin-piperaquine, the e xis ting programme
drug, in adults with uncomp licated s ympto matic ma la ria.
Artemis in in-naphthoquine and dihydroartemis in in/ piperaqu
ine had day-42 poly meras e chain reaction (PCR) corrected
adequate clinica l and paras itological res ponse (ACPR) of
90% in intent-to-treat and modified population, and >95%
in per-protocol population[16].
Data fro m this s tudy is cons is tent with previous s tudies
conducted to find the efficacy of AN for treat ment of
uncomplicated P. falciparum mala ria in China Myanmar and
Papua Ne w Guinea. Bas ed on this s tudy, we can conclude
that artemis in in-naphthoquine and dihydroartemis inin - pipe
raquine are confirmed very s afe, e ffective, and tole rate for
treatment of any ma laria. Both of these drugs have the
potential to be us ed for mult iple firs t-line (MFT ) therapy
policies in Indones ia[16].

2.10. Treatme nt of Unc omplicate d or Mil d Malari a

The treatment of choice for uncomplicated ma laria is a
combination o f t wo or more anti-ma larial med icines with
diffe rent mechanis ms of action. In Indones ia, 3 types of ACT
have been us ed recently which are Dihydroarte mis in in -
Piperaquine, Arte mether -Lu me fantrine and Artes unate -
Amodiaquine.
The currently us ed firs t line drugs are dihydroartemis inin
-piperaquine[15]. This is currently availab le as a fixed-dos e
co mbinat ion with tab lets conta in ing 40 mg of dihydroarte
mis inin and 320 mg of piperaquine. A target dos e of 4
mg/ kg/day dihydroarte mis inin and 18 mg/ kg/day piperaquin
e once a day for 3 days , with a therapeutic dos e range
between 210 mg/ kg/day dihydroartemis inin and 16 26
mg/kg/dos e piperaquine (Table 2)[18].
As a firs t line or drug for fail treat ment is co mbination of
artemether-lu me fantrine[15]. This is currently available as a
fixed-dos e formu lation with dis pers ible or s tandard tablets
containing 20 mg of arte mether and 120 mg of lu mefantrine.
A 6-dos e regimen over a 3-day cours e is the recommended
treatment. The dos ing is formu lated bas ed on the number of
tablets per dos e according to pre-defined weight bands of the
patients (Table 3)[18].
Lu me fantrine abs orption is enhanced by co-adminis tration
with fat. It is crucia l to info rm the patients or caregivers to
cons ume this ACT immediate ly after a having meal or drink
containing at leas t 1.2 g fat part icularly on the s econd and
third days of treatment[18]. Co mbination with do xycycline
or tetracycline or c linda mycin is necess ary to increase
s ens itivity when treating mala ria viva x.
ACT us ed as the third alternative is a rtes unate
amodiaquine[15]. Th is third - a lternative is pres ently
obtainable as a fixed-dos e formulat ion with tablets
containing 25/ 67.5 mg, 50/135 mg or 100/270 mg of
artes unate and amodiaquine. Separate s cored tablets
containing 50 mg of artes unate and 153 mg bas e of
amodiaquine, res pectively, are a ls o available in the blis ter
packs form.[18].

Table 2. Dose of dihydroartemisinin-piperaquine treatment in malaria falciparum (Harijanto, 2010)


Day
Type of drug Amount of t ablet for age groups
Single dose 0-1 month >1-11 mont h 1-4 year 5-9 year 10-14 year 15 year
H1-3 DHP 1/4 1/2 1 1 1/2 2 3-4
Falc: H1 Primaquine - - 3/4 1 1/2 2 2-3
Vivax: H1-14 Primaquine - - 1/4 1/2 3/4 1
Dihydroartemisinin : 2-4 mg/kg BW; BW > 60 Kg; BW < 60 Kg
Piperaquine : 16-32 mg/kg BW
Primaquine : 0.75 mg/kgBW

Table 3. Dose of art emether-lumefantrine (A-L) administrat ion (Harijanto, 2010)


Day
Type of drug Age <3 yr 3-8 yr 9-14 yr >14 yr
Body weight Time 5-14 kg 15-24 kg 25-34 kg >34kg

1
A-L 0 hr 1 2 3 4
A-L 8 hr 1 2 3 4
Falc: Primaquine 12 hr 3/4 1 1/2 2 2-3

2
A-L 24 hr 1 2 3 4
A-L 36 hr 1 2 3 4

3
A-L 48 hr 1 2 3 4
A-L 60 hr 1 2 3 4
H 1-14 Vivax: Primaquine

1/4 1/2 3/4 1
87 Jagtish Rajendr an: Artemisinin-B ased Therap y for M alaria American Journal of M edicine and M edical Scien ces 2013, 3(4): 81-90 87





Table 4. Dose of art esunate-amodiaquine (AS-AQ) administrat ion (Harijanto, 2010)


Day
Type of drug Amount of t ablet for age groups
Single dose 0-1 month 2-11 mont h 1-4 month 5-9 month 10-14 years 15 years

1
AS 1/4 1/2 1 2 3 4
AQ 1/4 1/2 1 2 3 4
Fal: P rimaquine - - 3/4 1 1/2 2 2-3

2
AS 1/4 1/2 1 2 3 4
AQ 1/4 1/2 1 2 3 4

3
AS 1/4 1/2 1 2 3 4
AQ 1/4 1/2 1 2 3 4
1-14 Vivax: Primaquine - - 1/4 1/2 3/4 1

Table 5. Combinat ion of Quinine + Doxycycline/Tet racycline/ Clindamycin (when the ACT fails) (Harijanto, 2010)


Day
Type of drug Amount of t ablet according t o t he age groups
Single dose 0-11 mont h 1-4 year 5-9 year 10-14 year 15 Year

1
Quinine - 3 x 1/2 3 x 1 3 x 1 1/2 3 x (2-3)
Doxycycline - - - 2 x 50 mg 2 x 100mg
Fal: P rimaquine - 3/4 1 1/2 2 2-3

2-7
Quinine - 3 x 1/2 3 x 1 3 x 1 1/2 3 x 2
Doxycycline - - - 2 x 50 mg 2 x 100 mg
Tet racycline dose - - - 4 x 4 mg/kg BW 4 x 250 mg
Clindamycin dose - - - 2 x 10 mg/kg BW 2 x 10 mg/kg BW
1-14 Vivax: Primaquine - 1/4 1/2 3/4 1

A target dos e of 4 mg/kg/day artes unate and 10 mg/ kg/day
amodiaquine once a day for 3 days , with a therapeutic dose
range between 210 mg/ kg/day artes unate and 7.515
mg/kg/dos e amodiaquine (Tab le 4)[18].
When there is occurrence of ACTs treatment failure
within 14 days of initia l treat ment, treat ment can be
continued with s econd-line anti-ma larial drugs . WHO's
recommended s econd-line treatments are, in order of
preference:
a) an alternative A CT known to be effect ive in the region,
b) artes unate plus tetracycline or do xycycline or
clinda mycin (given for a total of 7 days ),
c) quinine plus tetracycline or doxycycline or clindamycin
(given for a total of 7 days ).
One tablet of do xycycline 100 mg, dos e 3-5 mg/kg BW
once daily fo r 7 days , and tetracycline 250 mg or 500 mg,
dose 4 mg/ kg BW by 4 times a day are reco mmended.
Pregnant wo men and children belo w 11 years of age are not
allo wed to us e doxycycline/tetracycline, and it s hould be
s ubstituted with c linda mycin 10 mg/kg BW, t wice daily for 7
days . Table 5 des cribes the recommendation of the policy
of the Indones ian Department of Health wh ich indicates
that when there is failu re of ACT t reatment, then the
combination of quinine and tetracycline or clinda mycin can
be us ed. Primaquine s hould not be given to babies , pregnant
wo men, and patients with G6PD deficiency[15].

2.11. Treatment of Se vere or Complic ate d Malari a

Severe ma laria is a medical e mergency. Each patient
s uffering s evere ma laria s hould receive the following
therapy s uch as general treat ment, s ymptomat ic treat ment,
adminis tration of anti ma laria drug and treatment for
complication. Full dos es of parenteral anti-ma larial
treatment s hould be s tarted without delay with any effective
anti-mala rial firs t availab le.
Parenteral drugs (intravenous or intra mus cular) are
preferred fo r anti-mala ria drug treat ment for s evere ma laria
becaus e in s evere ma laria, the drug s hould have capacity to
eliminate paras ite rapid ly and re ma ins long s tay in blood
s ys tem in order to rapidly reduce paras itemia s tage[15].
The larges t ever rea l-life tria l for s evere ma laria is
SEAQUAMAT (Southeast As ia Quin ine Artes unate
Malarial T rial) of June 2003 to May 2005. 2,000 part icipants
in Banglades h, Myanmar and Indones ia took part in this trial.
They were divided into two groups where one group was
given quinine and the other group artemis inin. Due to high
diffe rence in morta lity between the two groups , the s tudy had
to be s topped early. According to Arjen Dondorp of Mahidol
Univers ity in Thailand, a leader of the s tudy, Artemis in in is
better than quinine in all s ubgroups of patients with s evere
ma laria. Arte mis inin is the treatment of choice for s evere
ma laria[19].
Artes unate injection is the firs t choice of t reat ment for
s evere ma laria. Intravenous dos e of 2.4 mg/ kg BW/ is us ed at
time of ad minis tration. It is given at 0, 12, 24 hour and
continuous ly in every 24 hour until the patient is cons cious
(Figure 3). The dos e of every s ingle us e is 2.4 mg/ kg BW.
When the patient is cons cious , then it s hall be s ubs tituted
with oral a rtes unate, i.e. tablet of 2 mg/kg BW until the day 7
and after that, it is continued by parenteral us e. To prevent
recrudes cence, it s hould be comb ined with do xycycline
2x100 mg/day for 7 days or clinda mycin 2 x 10 mg/kg BW
for pregnant wo men/children[15].
Artemether, or quinine, is an acceptable alternative if
88 Jagtish Rajendr an: Artemisinin-B ased Therap y for M alaria American Journal of M edicine and M edical Scien ces 2013, 3(4): 81-90 88




parenteral artes unate is not available. Dos e of arte mether is
3.2 mg/ kg BW IM g iven on admis s ion then 1.6 mg/kg body
weight per day Dos e of quin ine is 20 mg s alt/kg body
weight on admis s ion (IV infus ion or div ided IM injection),
then 10 mg/kg body weight every 8 hours . Infus ion rate
s hould not exceed 5 mg s alt/kg BW per hour[18].

Fi gure 3. Administ rat ion of artesunat e (Harijanto, 2010)

Table 6. Ant i-malaria drugs for severe malaria (Harijant o, 2010)


Artesunate (1flacon = 60 mg art esunic acid), dissolved in 1 ml of
5% sodium bicarbonat e(t he solvent) to make sodium
art esunatesolut ion, then it is dissolved into 5 ml 5% dextrose t o be
provided by int ra-venous/intra-muscular rout e

Dose 2.4 mg/kg BW is given in every 12 hr on the first day
andcont inued at dose 2.4 mg/kg BW on the day 2 7/ 24 hr. No
adjust ed dose is necessary for pat ient s with renal/liver dysfunct ion;
it does not cause hypoglycemia, arythmia/hypotension

Artemether (1 flacon=80 mg)
Dose : 3.2 mg/kgBW i.m as a loading dose divided into 2 dose (in
every 12 hr) on the first day, followed by 1.6 mg/kgBW/ 24 hr for 4
days since intramuscular route frequent ly has uncert ain absorpt ion.
It does not cause hypoglycemic effect.
Suppositoria drugs for severe malaria
Artesunate (50mg/100 mg/400 mg)
Dose 10 mg/kg BW administ ered in single dose of 400 mg for
adult s

Artemisinin
Dose 10-40mg/kgBW administered at 0, 4, 12, 24, 48, and 72 hour.

Dihydroartemisinin 40 mg, 80 mg
Adult dose is 80 mg and it is cont inued as 40mg at 24 and 48 hour.


2.12. Res is tance to Arte mis inins

The poss ibility of a rte mis in in's res is tance to occur is very
s mall due to the s hort half-lives of the drugs . However,
increas e us age of arte mis in in, including monotherapy, has
caus ed artemis inin res is tance in ce rtain part of the wo rld[20].
Artes unate res istance have been reported lately fro m
Ca mbodia. A s tudy conducted in Pailin, wes tern Ca mbodia
found that P. falciparum paras ites has decreas ed in vivo
s us ceptibility to artes unate if co mpared with northwes tern
Thailand paras ites . The res is tance was dis tinguis hed by
ma rked ly increas e time to clear the paras ites . These
decreas ed res pons es could not be expla ined by neither
pharmacokinetic nor other factors [21].
Some paras ites dis covered from French Guiana and
Senegal s howed decreas e in vitro s ens itivity to artemether. It
has a ls o been found tha t th e e ffect iv enes s of artemis inin-
bas ed c o mb inat ion age nts has reduce d a long Thailand
Ca mbodia border. A ten year s tudy (2001 to 2010) by
'Lancet' by res earchers at the Shoklo Mala ria Res earch Un it
on the border of Thailand and Myanmar, meas ured the
paras ite clearance time fro m bloods tream. Th is res earch was
participated by 3202 patients with falc iparu m ma laria
cons uming ora l artes unate-containing med ications [22].
The s tudy found that over the ten years the paras ite
clearance time has increas ed fro m 2.6 hours in 2001 to 3.7
hours in 2010 wh ich is a clear indicat ion that the drugs were
becoming les s effective. The ratio of s low-clearing
infections with half-lives of more than 6.2 hours has
increas ed from 6 in 1000 to 200 in 1000. Later in the s tudy, it
was dis covered that the decline paras ite clearance rates was
due to the changes in genetic of the paras ites by exa mining
the genetic ma ke-up of the paras ites . This caus ed the
paras ites to be res is tant towards the drugs [22].
In January 2009, WHO wo rk hand-in-hand with
Ca mbodia's and Tha iland's health min is tries to in itiate a
project to contain and eliminate artemis inin res is tance from
the border area. If this s tep is not taken, there is a pos s ibility
for the world to los e its bes t malaria trea ment. The WHO
res is tance containment activities cons is t of five s teps which
are[23].
a) Stop the s pread of res is tant paras ites .
b) Increas e monitoring and s urveillance to evaluate the
threat of arte mis inin res is tance.
c) Improve acces s to diagnos tics and rational treat ment
with A CTs .
d) Inves t in artemis inin res is tance-related res earch.
e) Motivate action and mobilize res ources .
Although it is tough to overcome arte mis in in res is tance
is s ue, it is important in preventing arte mis inin res is tance
fro m s preading to other regions in the world. All parties
including s cientific and clinica l co mmunit ies and health
policy ma kers s hould work together to overcome this
burdening is s ue. However, for the time being, the cas es of
true arte mis inin res is tance in mala ria paras ites is s till low
and this worry s hould not s top the us age of intravenous
artes unate to treat s evere ma laria[20].

2.13. Challenges

According to data gathered by the Indones ian government,
out of 1,322,451 s us pected ma la ria cas es re corded, ninety-
two percent were e xa mined by either micros cope or rapid
diagnos tic tes t (RPD). Sixty-s ix percent out of 256,592
confirmed cas es received ACT treat ment.[24]
Although there are evidences from prev ious s tudies
claiming that ACT treat ment are efficac ious in combating
ma laria, the e xact cure rates of ma laria after imple mentation
of ACT treat ment in Indones ia is still not available. This is
ma inly due to the incoordination between health fac ilities
s uch as public hos pitals and private practices , and the
Minis try of Hea lth.
According to 2012 World Ma laria Report, the exact cure
rates and trends of malaria in Indones ia is hard to be
complied due to incons istency of cas es being reported to
WHO.[25]
89 Jagtish Rajendr an: Artemisinin-B ased Therap y for M alaria American Journal of M edicine and M edical Scien ces 2013, 3(4): 81-90 89




Indones ian government which has strong treatment policy
in fighting ma laria, s hould take init iative to ens ure the
effectivity of ACT treat ment re main intact and to ban
dis tribution of counterfeit and s ubstandard antima larial
drugs . Thes e s teps will ma ke Indones ia to reach its goal to
eliminate ma laria by the year 2030.


3. Conclusions

Malaria is trans mitted by fe male Anopheles mos quito
which a re infected by protozoan paras ites s pecies of
Plasmodium genus . Es timat ion by The World Health
Organization (WHO) o f reported cas es fro m Indones ia we re
2.5 million in 2006. Indones ia reported little change in the
incidence of mala ria between the year 2010 and 2011.
According to CDC, mala ria is s till pres ent in mos t part of
Indones ia. In April 2001, WHO reco mmended the us e of
ACTs to minimize the burden caus ed by P. falciparum
res is tance to conventional anti-mala ria l medications .
Artemis inin is a s es quiterpene lactone produced fro m a
plant called Artemisia annua which grows in China and
Vietna m. De rivatives of arte mis inin a re artes unate,
artemether, arteether, a rtelinic acid, artenimo l and arte motil.
Che mical s tability of thes e derivatives varies among one
another. artemis inin derivatives are active agains t all s pecies
of Plas modiu m ab le to rapid ly kill a ll the blood s tages of the
paras ite. Arte mis in in's anti ma laria l p roperties are generate
free rad icals , inhibits the hemo zoin fo rmation, interfe re with
s arcoplas mic/endoplas mic calc iu m AT Pas e (SERCA), as
well as da maging of norma l mitochondrial functions of
plas modiu m paras ites . Mos t clinica lly important
artemis inins are metabolis ed to dihydroartemis in in.
Artemis inins caus es less toxic effect if co mpared with
other antima laria l agents . Artemis inin is believed to be
effective agains t paras itic dis eas es and us eful agains t
cancer. ACTs are reco mmended becaus e artemis inin and its
derivatives are fas t acting but other drugs are often required
to clear the body of all paras ites and prevent recrudes cence.
The year 2004 marks the beginning of adoption of ACTs
into national ma laria control progra m in Indones ia. In
Indones ia, 3 types of ACT have been us ed recently to treat
uncomplicated ma laria wh ich are dihydroartemis inin-pipera
quine, arte mether-lu me fantrine and artes unate-amodiaquine.
Artes unate injection is the firs t choice of treat ment fo r s evere
ma laria. Arte mether, or quin ine, is an acceptable s ubs titute if
parenteral artes unate is not available.
Res is tance to artemis in in and its derivatives has been
recently reported fro m Tha iland-Ca mbodia border. In
January 2009, WHO work hand-in-hand with Ca mbodia's
and Thailand's health min is tries to in itiate a pro ject to
contain and eliminate arte mis inin res is tance from the border
area.


ACKNOWLEDGEMENTS

Firs t of all, I would like to s how my grat itude to the Lord
becaus e with his bles s ings I have managed to complete my
paper entitled "Artemis inin-Bas ed Therapy for Malaria".
With pleas ure, I, Jagtis h Rajendr an, would like to
convey my hearties t thank you to dr. Ida Ayu Ika
Wahyuniari, M. Kes , the s upervis or for my paper work
whos e encouragement, guidance, and s upport fro m the init ial
to the final level enabled me to develop an unders tanding of
the topic and s uccess fully co mplete my paper work.
I would like to apologize if there a re any weaknes s es that
could be found in my report and I would be glad to get
feedbacks fro m the readers as it would help me in
improvis ing mys elf in time to come . Las t but not leas t I hope
that my writ ing would be beneficia l to the readers as how it
was for me .




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