Artemisinin-Naphthoquine Combination (ARCO®): An Overview of the Progress
ABSTRACT With the rapidly spreading resistance of Plasmodium falciparum to available non-artemisinin antimalarial drugs, new and novel pharmaceuticals are needed. ARCO® is a new generation ACT, one of several artemisinin-based combinations developed in China to counter antimalarial drug resistance. ARCO® is a derivative of two independently developed antimalarials, artemisinin and naphthoquine phosphate, which were combined to form the artemisinin-naphthoquine combination. Both artemisinin and naphthoquine drugs have proven to be efficacious, safe and well tolerated as monotherapies. The artemisinin-naphthoquine combination offers a novel advantage over existing ACTs: it can be administered as a single oral dose (or a 1-day treatment). Several therapeutic studies conducted recently indicate that a single oral dose administration of artemisinin-naphthoquine combination is equally effective and safe as the 3-day treatment with artemether-lumefantrine combination and other existing ACTs. This would make ARCO® the next generation ACT for the treatment of uncomplicated falciparum malaria.
[show abstract] [hide abstract]
ABSTRACT: This paper seeks to define and quantify the influence of drug elimination half-life on the evolution of antimalarial drug resistance. There are assumed to be three general classes of susceptibility of the malaria parasite Plasmodium falciparum to a drug: Res0, the original, susceptible wildtype; Res1, a group of intermediate levels of susceptibility that are more tolerant of the drug but still cleared by treatment; and Res2, which is completely resistant to the drug. Res1 and Res2 resistance both evolve much faster if the antimalarial drug has a long half-life. We show that previous models have significantly underestimated the rate of evolution of Res2 resistance by omitting the effects of drug half-life. The methodology has been extended to investigate (i) the effects of using drugs in combination, particularly when the components have differing half-lives, and (ii) the specific example of the development of resistance to the antimalarial pyrimethamine-sulphadoxine. An important detail of the model is the development of drug resistance in two separate phases. In phase A, Res1 is spreading and replacing the original sensitive forms while Res2 remains at a low level. Phase B starts once parasites are selected that can escape drug action (Res1 genotypes with borderline chemosensitivity, and Res2): these parasites are rapidly selected, a process that leads to widespread clinical failure. Drug treatment is clinically successful during phase A, and health workers may be unaware of the substantial changes in parasite population genetic structure that predicate the onset of phase B. Surveillance programs are essential, following the introduction of a new drug, to monitor effectively changes in treatment efficacy and thus provide advance warning of drug failure. The model is also applicable to the evolution of antibiotic resistance in bacteria: in particular, the need for these models to incorporate drug pharmacokinetics to avoid potentially large errors in their predictions.Philosophical Transactions of The Royal Society B Biological Sciences 05/2002; 357(1420):505-19. · 6.40 Impact Factor
[show abstract] [hide abstract]
ABSTRACT: The enormous public health problem posed by malaria has been substantially worsened in recent years by the emergence and worldwide spread of drug-resistant parasites. The utility of two major therapies, chloroquine and the synergistic combination of pyrimethamine/sulfadoxine, is now seriously compromised. Although several genetic mechanisms have been described, the major source of drug resistance appears to be point mutations in protein target genes. Clinically significant resistance to these agents requires the accumulation of multiple mutations, which genetic studies of parasite populations suggest arise focally and sweep through the population. Efforts to circumvent resistance range from the use of combination therapy with existing agents to laboratory studies directed toward discovering novel targets and therapies.Annual Review of Pharmacology 02/2005; 45:565-85. · 21.64 Impact Factor
[show abstract] [hide abstract]
ABSTRACT: Malaria, one of the major reemerging parasitic diseases, is caused by protozoal parasites belonging to the genus plasmodia. Antimalarial drugs have played a mainstream role in controlling the spread of malaria through the treatment of patients infected with the plasmodial parasites and controlling its transmissibility. The current line of therapy against malaria is faced with the hurdles of a low or total lack of efficacy due to the evolution of drug-resistant strains of the malarial parasites. Preventive vaccination against malaria is an ideal solution to this problem but is not expected to arrive for at least a decade. Development of antimalarial drugs involving novel mechanisms of action is therefore of imminent importance. Several novel drug candidates of synthetic and natural products origin as well as their combination therapies are currently being evaluated for their efficacy against the drug-resistant strains of the parasites. Various plasmodial targets/pathways, such as the Purine salvage pathway, Pyrimidine biosynthesis pathway as well as the processes in the apicoplast, have been identified and are being utilized for the discovery and development of novel antimalarial therapies. This review provides an overview of the latest developments in terms of drugs, combination therapies and novel plasmodial targets being carried out to counter the menace of drug-resistant malaria.Current Medicinal Chemistry 02/2008; 15(2):161-71. · 4.86 Impact Factor
Pharmaceuticals 2010, 3, 3581-3593; doi:10.3390/ph3123581
Artemisinin-Naphthoquine Combination (ARCO®): An
Overview of the Progress
Francis W. Hombhanje 1,* and Qingyun Huang 2
1 Centre for Health Research, Divine Word University, P O Box 483, Madang 555, Madang Province,
Papua New Guinea
2 Medical Research Institute, Kunming Pharma, West suburb, Xishan Region, Kunming, China;
* Author to whom correspondence should be addressed: E-Mail: firstname.lastname@example.org;
Tel.: +657-4222937 or +675-4241627; Fax: +675-4222812.
Received: 15 November 2010; in revised form: 8 December 2010 / Accepted: 9 December 2010 /
Published: 14 December 2010
Abstract: With the rapidly spreading resistance of Plasmodium falciparum to available
non-artemisinin antimalarial drugs, new and novel pharmaceuticals are needed. ARCO® is
a new generation ACT, one of several artemisinin-based combinations developed in China
to counter antimalarial drug resistance. ARCO® is a derivative of two independently
developed antimalarials, artemisinin and naphthoquine phosphate, which were combined to
form the artemisinin-naphthoquine combination. Both artemisinin and naphthoquine drugs
have proven to be efficacious, safe and well tolerated as monotherapies. The artemisinin-
naphthoquine combination offers a novel advantage over existing ACTs: it can be
administered as a single oral dose (or a 1-day treatment). Several therapeutic studies
conducted recently indicate that a single oral dose administration of artemisinin-
naphthoquine combination is equally effective and safe as the 3-day treatment with
artemether-lumefantrine combination and other existing ACTs. This would make ARCO®
the next generation ACT for the treatment of uncomplicated falciparum malaria.
Keywords: artemisinin-naphthoquine combination; ARCO; artemisinin; naphthoquine;
Pharmaceuticals 2010, 3
Malaria infections, particularly due to Plasmodium falciparum, have been on the rise in the past
decade, mainly because this species of malaria parasite have developed multiple strategies to deal with
the parasiticidal actions of available non-artemisinin antimalarial drugs [1-3]. Declining efficacy of
artemisinins and/or artemisinin-based combinations (ACTs) is being increasingly observed,
particularly along Thai-Cambodia border . These observations pose a serious threat to combination
therapies that include artemisinins. Therefore, not only are new pharmaceuticals needed, but new
generation pharmaceuticals with novel parasiticidal activities are necessary to deal with the life-
threatening situations posed by resistant falciparum parasite pathogen. Several novel drug candidates
of synthetic and natural product origin, as well as their combination therapies, have been evaluated that
seems to exhibit novel anti-parasite activities, particularly against the multi-drug resistant strains of the
Plasmodium falciparum species . The primary objective of malaria therapy is to save life by
reducing the risks of serious complication and/or severe disease, which ultimately leads to death. This
can be achieved by rapidly reducing the total circulating young parasite biomass, thus preventing them
from further development to mature stages which are often implicated in severe disease processes
and/or complications [6-8]. Artemisinin and its derivatives are of special value in this regard, as they
achieve a faster reduction in parasitaemia biomass by acting principally on the circulating young
parasites [9-13]. Artemisinin-based combination therapies (ACTs) represent a promising approach to
dealing with drug-resistant malaria rather than monotherapies. Several ACTs are currently available,
including artemether-lumefantrine (AL), dihydroartemisinin-piperaquine (DHA-PPQ), artesunate-
amodiaquine (AS + AQ), artesunate-mefloquine (AS + MQ), and now artemisinin-naphthoquine
(ARCO®). The later combination is of particular interest because, unlike other artemisinin-based
combinations which require a 3-day regimen, ARCO® requires either a single dose treatment or a two-
dose treatment over 24-hrs (1-day treatment). The effectiveness of this very short therapeutic regimen
of ARCO® against uncomplicated falciparum malaria has now been validated by several clinical
studies within and outside China [14-19]. We provide an overview of ARCO® as the next generation
ACT for the treatment of uncomplicated falciparum malaria.
2. A Literature Overview
2.1. General Aspects
ARCO® is a new generation ACT developed by the Chinese Academy of Military Medical Sciences
(AMMS) in the early 1990s. It is a product of the combination of two independently developed
antimalarials, artemisinin and naphthoquine (Figure 1). Both drugs have shown to be safe, efficacious,
and well tolerated as monotherapies [20-23]. Artemisinin (a sesquiterpene lactone) is the principal
antimalarial compound isolated from the Chinese medicinal herb Qing hao (Artemisia annua) in the
1970s. Because of its poor water solubility, and hence its poor oral bioavailability, until now it has
been paid less attention than its derivatives (artemether, artesunate, dihydroartemisinin, etc.) as a
potent antimalarial, and therefore artemisinin has not been widely deployed for malaria monotherapy.
Naphthoquine is another antimalarial compound developed in China in the late 1980s. It belongs to the
4-aminoquinoline family . The drug (naphthoquine) has never been deployed widely for malaria
Pharmaceuticals 2010, 3
therapy outside China. Nevertheless, both drugs have demonstrated fairly good pharmacological and
anti-parasitological properties as individual antimalarial drugs [24-27]. The main disadvantages of
artemisinin and naphthoquine as monotherapies for malaria infections have been, for artemisinin, a
very short circulating half life as a result of rapid elimination, such that effective concentration levels
might not be sustained to ensure complete elimination of blood parasites over several asexual cycles.
For naphthoquine, the main disadvantage has been the slowness in the onset of the parasiticidal action
following therapy administration. The slowness in the onset of action would create a time-window of
opportunity for young circulating parasites to escape into the central intra-vascular compartment. The
escaped parasites are more likely to avoid the parasiticidal action(s) of the drug. It becomes apparent
therefore, that co-formulation should hypothetically overcome the inherent disadvantages of the
Figure 1. Chemical structure of artemisinin and naphthoquine.
The concept of combination therapy is based on the synergistic or additive potential of two or more
drugs. Apart from improving therapeutic efficacy, combinations may also delay the development of
drug resistance to the individual components of the combination. The rational for artemisinin-
naphthoquine combination is for artemisinin component to provide the rapid killing of parasites and
accelerate therapeutic response. Its rapid action may also prevent early treatment failure and/or
complications by greatly reducing the circulating parasite biomass in a shorter time. The benefits of
adding naphthoquine is to prevent recrudescence by killing residual parasites through its extended half-
life in the body. This action may also reduce the chance of resistant mutants surviving and
propagating. Overall, artemisinin and naphthoquine will complement each other such that the delay
time for parasiticidal action of naphthoquine is covered by artemisinin’s immediate onset of
parasiticidal action, and the short circulating half life of artemisinin would be extended over several
days (covering several asexual cycles) by the long circulating half life of naphthoquine to eliminate
any circulating residual parasites. This is the most novel of the drug combinations because the drugs in
this combination therapy have not been previously used as monotherapies so as to condition parasites.
However, when two drugs are combined into one single tablet, it becomes a new drug entity with its
own challenges in regards to safety issues [28,29].
Pharmaceuticals 2010, 3
The optimal proportion of naphthoquine phosphate and artemisinin in the combined tablet was
determined after a series of painstaking studies [14,15]. The appropriate proportions of naphthoquine and
artemisinin that provided optimal efficacy and safety in a single dose were 400 mg and 1,000 mg,
respectively. This means, one combined tablet would contain 50 mg naphthoquine base (78.3 mg of
naphthoquine phosphate) and 125 mg of artemisinin in a ratio of 1:2.5, and the appropriate dosage regimen
would only be one dose. The fixed-dose combination tablets are manufactured, registered, and marketed as
ARCO (ARCO®) by Kunming Pharmaceutical Corporation (KPC) of the People’s Republic of China.
2.3. Therapeutic Dosage Regimen of ARCO®
The recommended dosage for adult population (age > 16 years) for uncomplicated malaria is a
single dose of eight tablets (total dose 1,000 mg artemisinin /400 mg naphthoquine). For children, it is
recommended that it be adjusted on a body-weight basis (25 mg artemisinin/10 mg naphthoquine). For
younger children, including infants, tablets should be crushed before administration. The
manufacturer’s current recommendation is that all medications are to be taken before meals or after
meals (~2 h post-prandial) but not with a meal.
3. Clinical and Therapeutic Assessment of ARCO®
3.1. General Overview
The progress of ARCO® from its development to clinical assessment in general human populations
has moved forward quickly. In this section, we present some of the progress that have taken place and
provide an overview of recent findings from several clinical trials in the context of the potential
applicability of ARCO® in malaria therapy.
Figure 2. World map indicating countries where ARCO® studies were conducted.
The preliminary clinical assessment undertaken with the single dose administration of ARCO®
tablets in China demonstrated high level of efficacy (cure rates of greater than 95%), safety, and
tolerability in the adult populations with falciparum and vivax malaria [14-16]. Encouraged by these
preliminary findings, further efficacy and safety evaluation of ARCO® was undertaken outside China
in eight (n = 8) different malaria-endemic countries involving almost 2,000 participants (1,127 adults,
Pharmaceuticals 2010, 3
385 children, and 293 adults and children combined), in the Asia-Pacific and African regions (Figure 2).
Most of these clinical studies were industry-sponsored, but were conducted independently at different
sites. Almost all data for this review was obtained from the industry’s archived files and the review
was undertaken objectively and independently. The abstracted profiles of different studies are
(i) ARCO® vs. chloroquine and sulphadoxine-pyrimethamine (SP) combination. This trial was
conducted in an adult population with uncomplicated falciparum malaria infections in Papua New
Guinea (Melanesian-Western Pacific). In this setting the ARCO® tablets were administered as a single
dose versus chloroquine once a day for three days with a single dose of SP at the start of therapy. The
therapeutic responses were monitored for 28 days. Although the two treatments provided relatively
comparable cure rates, ARCO® treatment was superior in rate of clearing parasitaemia .
(ii) ARCO® vs. dihydroartemisinin-piperaquine (DHA-PPQ). This study was conducted in
Indonesia in an adult population with uncomplicated falciparum malaria, vivax malaria, and in co-
infection of falciparum-vivax malaria. In this study, a single dose (8 tablets) of ARCO® versus 3-days
(once/day for 3 days) of DHA-PPQ combination tablets was investigated. The therapeutic responses
were monitored for 28 and 42 days. Both treatments provided comparable PCR corrected cure rates for
Plasmodium falciparum (ARCO® 99% vs. DHA-PPQ 97%), Plasmodium vivax (ARCO® 99% vs.
DHA-PPQ 97%), and mixed infection of Plasmodium falciparum and Plasmodium vivax (ARCO®
79% vs. DHA-PPQ 97%) malarias at day 42. There was no statistically significant difference in
parasite clearance times (ARCO® 28 ± 11.7 vs. 26 ± 12.2 DHA-PPQ) for both treatments; however,
response to ARCO® treatment was low in mixed infection [source: KPC archived data].
(iii) ARCO® vs. artemether-lumefantrine (AL). Two of these studies were conducted in children
populations of Nigeria and Uganda, and one in an adult population with uncomplicated falciparum
malaria in Uganda. For the children, the number of ARCO® tablets administered was based on the
bodyweight (25/10 mg/kg artemisinin-naphthoquine combination) and for the adult population
ARCO® tablets were administered as a single dose of eight tablets. The therapeutic responses were
monitored for 28 days in the Nigerian study and 42 days in the Ugandan study. There was no
significant difference in the efficacy and safety profiles in children in the two studies between the
single dose ARCO® treatment and 6-dose regimen of AL at day 28 and day 42, respectively. Similar
observations were made between the two treatments in the adult population in the Ugandan study at
day 28 [Source: KPC archived data].
(iv) ARCO® vs artemether-lumefantrine vs artesunate-amodiaquine (three-arm study). This study
was conducted in Nigeria in mixed population (children + adults) with uncomplicated falciparum
malaria. ARCO® tablets were administered according to the dosing schedule described above. For AL,
tablets were administered twice a day for three days based on bodyweight for children and
predetermined number of tablets for adults while for AA, once a day treatment for 3 days based on
bodyweight for children and predetermined number of combination tablets for adults. The therapeutic
responses were monitored for 28 days. The study concluded that ARCO® and AA treatments were
marginally better than artemether-lumefantrine in these settings [Source: KPC archived data].
(v) ARCO® (2x/day in divided dosage) vs. artemether-lumefantrine (AL). This study was undertaken
in Ivory Cost, West Africa, in a mixed population (children and adults) with uncomplicated falciparum
Pharmaceuticals 2010, 3
malaria. Drugs were administered as described above. The therapeutic responses were monitored for
28 days. There was no significant difference in the efficacy and safety of 1-day (2x/day in divided
dosage) treatment with ARCO® and 3-day with AL (cure rate: ARCO® 100% vs. 98% AL) .
(vi) ARCO® (single dose) vs ARCO® (2x/day divided doses). This study was conducted in Benin
(Central Africa) in a child population with uncomplicated falciparum malaria. Children received
number of tablets based on bodyweight as a single dose versus same dose divided into two doses give
12 h apart. The therapeutic responses were monitored for 28 days. Therapeutic efficacy and safety
were similar for both therapeutic dose regimens (i.e. both regimens were equally effective).
(vii) ARCO® alone. Two studies were conducted in the adult populations with uncomplicated
falciparum malaria: one in Nigeria and one in Myanmar , with no comparators. The therapeutic
responses were monitored for 28 days. Both studies demonstrated high efficacy and safety profile for
ARCO® in the respective country settings. The above information is summarized in Table 1.
Table 1. Summary data of different studies in different countries (CR = cure rates;
ACPR = adequate clinical and parasitological response; PCT = parasite clearance time;
FCT = fever clearance time).
(ARCO® vs. others)
CQ + SP
DHA + PPQ
Because the methodology of clinical and/or therapeutic assessment had not been prospectively
standardized prior to the conduct of the studies, there existed substantial inter-study differences in
Pharmaceuticals 2010, 3
defining, assessing, reporting, and classifying efficacy and adverse events. However, all studies were
conducted in accordance with the World Health Organization (WHO) guidelines for antimalarial drug
efficacy assessment .
3.2. General Review Findings
3.2.1. Therapeutic efficacy
Analysis of the pooled data did not show any significant differences between ARCO® treatment and
other artemisinin-based combinations (artemether-lumefantrine, dihydroartemisinin-piperaquine, and
artemether-SP) in the rate of reduction of parasite biomass in the blood, except for the non-artemisinin-
based combination . All artemisinin-based combinations reduced the parasite biomass by greater
than 95% at 24/48 h across a wide range of baseline parasitaemias (range: 1,000-200,000 parasites/µL)
from different study sites (data not shown). However, for ARCO®, it would seem remarkable for a
drug combination with shorter duration of treatment within the family of ACTs. With the exception of
few cases, in all the studies fever was cleared within 24 h following treatment (Table 1). In studies where
gametocytes were measured or noted, the ARCO® and other artemisinin-based combinations had a
negative impact on the gametocytogenesis.
All the studies demonstrated that ARCO®, artemether-lumefantrine, artesunate-amodiaquine, and
dihydroartemisinin-piperaquine combinations were equally effective in the treatment of uncomplicated
malaria, particularly Plasmodium falciparum malaria, while further studies are needed for Plasmodium
vivax and mixed parasite species infections. One study showed low response with ARCO® in the
treatment of mixed infections, an observation needing further verification. The pooled data however,
demonstrated that a single dose administration of ARCO® is highly efficacious, both in adults and
children. It was also noted that all patients responded satisfactorily to the shorter (a single dose or
1-day treatment) course of ARCO®. The cure rates however, were similar in all treatments on day-28;
extension of observations beyond 28 days did not result in better outcomes nor was there any
significant differences in cure rates whether ARCO® was given as a single dose (8 tablets for adults or
on a body-weight basis for children) or in two divided doses over 24 h (1-day treatment regime).
3.2.2. Safety profile
The safety data provided in relation to individual patients were primarily clinical. Where laboratory
data was available, the laboratory evaluation schedules were not consistent between the studies,
making comparative interpretation of safety data difficult. Because the trial methodology included in
the pooled analysis had not been prospectively standardized, there existed substantial inter-trial
differences in defining, assessing, reporting, and classifying adverse events. Furthermore, reliably
distinguishing drug side effects from clinical symptoms of malaria infection is often difficult and much
of the reporting is largely dependent upon a subjective assessment performed at the time of the event.
The safety data obtained for this analysis were from individual patient data case record forms, which
were archived at the Centre for clinical studies at Kunming Pharmaceutical Corporation.
A total of 16 different adverse events, with varying frequencies and intensities, were recorded in the
pooled analysis of 952 adult patients who received artemisinin-naphthoquine combination for
Pharmaceuticals 2010, 3
uncomplicated malaria. The five most common adverse events were, in order of frequency, headache,
nausea, vomiting, dizziness, and abdominal pain. However, it was difficult to discern which of the
adverse events were malaria related and which were due to drug treatment because almost all of these
events were reported during the first 24-hrs following the commencement of treatment. No adult or
paediatric patients discontinued the treatment or any part of the treatment prematurely due to adverse
A meaningful comparison of safety profiles between different treatments including artemisinin-
based products is beyond the scope of this analysis. It should be noted however, that most of the safety
data presented were derived from patients treated with ARCO® and extrapolation from this data to
different populations and settings should be made with caution. Despite the methodological limitations
of this analysis, the overall safety profile of ARCO® treatment in these series of studies appeared to be
benign. The total incidence of drug-related adverse events considered by clinicians and/or principal
investigators was estimated to be low (≤5%). The majority of the adverse events reported has been of
gastrointestinal-related in nature and were self-limiting. In general, safety profile of ARCO® treatment
appears to be excellent. However, the data from this analysis do not suggest that there are no additional
concerns about ARCO® use as a therapeutic agent in a wider context but pharmacovigilance is
important for its continued deployment.
Artemisinin-naphthoquine combination (ARCO®) is a new generation ACT. An analysis of the
pooled data from several studies in different countries indicates that this combination is quite safe and
equally effective (efficacious) as other ACTs recommended by World Health Organization (WHO)
which include artemether-lumefantrine (AL), artesunate-amodiaquine (AS + AQ), artesunate-
mefloquine (AS + MQ), artesunate plus sulphadoxine-pyrimethamine (AS + SP) and dihydro-
artemisinin-piperaquine (DHA + PPQ) combinations for treatment of uncomplicated falciparum
malaria . Whether or not a single dose or a 1-day treatment with ARCO® will ever be considered
for malaria treatment one day (from a drug resistance point of view) on a wide scale remains to be
debated but these series of studies undertaken in different countries provide additional information on
the potency and/or efficacy of ARCO® in different environmental and epidemiological
conditions/settings. These and other studies further affirms that ACTs including ARCO®, represent a
promising approach to drug-resistant malaria treatment [31-38], and a shorter regimens may offer
certain advantages in settings where acceptability or adherence to complex therapeutic dosing
regimens is an on-going challenge. Treatment failures with ACTs due to lack of proper adherence to
best practices or due to lack of poor knowledge with multiple dosing and complex regimens have been
reported [4,39,40]. The declining efficacy of artemisinin (or perhaps insufficient dose of the drug) may
affect the efficacy of partner medicines after long term utilization. Naphthoquine, the partner drug in
ARCO® easily develops resistance if given as single dose. Resistance to the artemisinin’s partner
medicines may compromise the efficacy of the ACT. Therefore, the efficacy of ARCO® needs careful
monitoring after its introduction and widescale use, particularly in multidrug resistant areas. At present
however, there is seemingly no doubt that a single dose or a 1-day treatment with the combined
Pharmaceuticals 2010, 3
artemisinin and naphthoquine for uncomplicated falciparum malaria provided high efficacy in adult
populations, as well as in the trialed children population.
The safety of ARCO® is comparable to other ACTs; it is relatively safe, both from the laboratory
and clinical aspects. The naphthoquine component may have some effects on certain hepatic functions
but a review of data in a number of studies that assessed laboratory indices did not reveal any major
deviations in hepatic functions that may implicate exclusively drug-induced hepatic dysfunctions .
Almost all biological indices returned to within normal range values post-treatment. Many of the
reported post-treatment events were likely to be related to the underlying malaria infection rather than
the drug(s) used in the treatment. Abnormalities in laboratory test reported in the therapeutic trials
were limited to elevations of transaminases and frequency of abnormalities varied across studies
treated with ACTs including ARCO®. No patients were intentionally discontinued prematurely as a
result of severe adverse experiences during the therapy and monitoring periods, however, there were
patients who withdrew or failed to fulfill the study protocols who remained to be accounted for in
several of the studies.
The pooled data from multi-national therapeutic studies presented here provides scientific evidence
for clinical use of ARCO® (artemisinin-naphthoquine combination) as a new generation ACT. The
findings are consistent with observations made with other ACTs [32-38]. In general, malaria therapy
with artemisinin-based combinations has been shown to reduce malaria transmission, as well as
reducing malaria-related morbidity and mortality [41-43]. The reduction of malaria transmission may
be attributed partly to the anti-gametocytocidal effects of artemisinin component of artemisinin-based
combinations. Rapid intervention with artemisinin-based combination treatment in uncomplicated or
severe malaria can also impact on mortality, particularly among children. This intervention would
likely to result in survival benefit and better outcome. Shorter therapeutic dosing regimens such as
offered by ARCO®, may be an advantage in that the health workers can administer the drug as directly
observed treatment. With the shorter treatment duration, the potential to be deployed for home
management of malaria at community levels needs to be evaluated. However, the impact of shorter
dosing regimens on morbidity and mortality due to falciparum malaria remains to be ascertained.
Only one study in these series compared the efficacy of a single dose ARCO® versus multiple doses
DHA-PPQ on vivax malaria; both treatments provided equivalent cure rates (99% vs. 97% for ARCO®
and DHA-PPQ, respectively) on 42-day follow-up. Data is limited on the role of ARCO® in other
malaria parasite species including Plasmodium vivax malaria.
Artemisinin-naphthoquine combination (ARCO®) compares favourably with existing ACTs, so may
be the next new generation ACT. Review of available data concludes that, from the clinical efficacy
and safety point of view, ARCO® offers no advantages over existing ACTs except for the fact that this
combination may be given as a single dose than three daily doses or three twice daily doses. It will be
more useful particularly in situations where noncompliance to the currently practiced 3-day course of
ACTs is common.
Pharmaceuticals 2010, 3
5. Identified Research Gaps
While the therapeutic assessment of ARCO® demonstrated high level of efficaciousness and safety,
the following gaps in our knowledge exist.
Malaria affects children more than adults. There is however, insufficient information available on the
pharmacokinetics of ARCO® in children, particularly in children between 6 months to 5 years of age.
Women who are pregnant are relatively more vulnerable to malaria than non-pregnant women.
Denying this population the most effective antimalarial drugs available would not save lives. It may be
that the embryonic toxicity of ACTs in human pregnancies has been over-emphasized . There is
therefore, an immediate need to establish safety perimeters within which ACTs including ARCO® can
safely be prescribed in pregnancies, particularly in the first trimester of pregnancy.
5.3. Therapeutic Dosing Regimen and Pharmacokinetics
ARCO® tablets were co-formulated to deliver optimal blood levels for individual drugs in a single
dose administration of eight tablets. Any variations, such as two divided doses (1-day treatment) or
scaling-down of number of tablets on body-weight basis must be supported and guided by
pharmacokinetic data to avoid sub-therapeutic levels. Substantially little pharmacokinetic data is
available to support and guide different dosage schedules, so further studies are needed in these areas
to optimize therapy for different dosing schedules.
Acknowledgements and Contributions
The authors would like to thank Kunming Pharmaceutical Corporation (KPC) for permission to use
archived data for review and analysis. One of the authors (SH) provided data and did the preliminary
analysis without which this short review would not have been possible. FWH did the final review
analysis of the data and drafted the manuscript. We also would like to thank Luddy Salonda for
independent proofreading the manuscript.
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