Introduction
Over a decade ago the world decided to
approach malaria in a new way. The goal is the eradication of Malaria – and
that, by 2015, will no longer be a major cause of mortality nor a barrier to
social and economic development and growth anywhere in the world (www.rollbackmalaria.org). Malaria is
the world’s most prevalent infectious disease. Almost 40% of the world’s
population is at risk.1 In 2006, 247 million malaria cases caused
around a million deaths,2 of which children and pregnant women were
disproportionately affected. The African continent feels the greatest burden
from this neglected disease, with 45 countries in the sub-Sahara being endemic
for malaria and accounting for 86% of cases worldwide.2
Malaria is caused by protozoan parasites of
the genus Plasmodium. Over 100
recognised species of Plasmodium
exist, infecting a wide range of vertebrate hosts including primates, rodents,
birds and reptiles. The deadliest human malaria parasite is Plasmodium falciparum, resulting in the
most severe clinical symptoms of the disease and causing 90% of all malaria
deaths. Along with P. falciparum, P. vivax, P. ovale and P. malariae
are the four main species that are known to infect humans. There are
significant differences between the species; ranging from liver stage
progression, parasite replication time within the host, and the timing in
appearance of gametocytes in the bloodstream.3,4 Each species causes
a unique set of complications in terms of disease. P. falciparum infections are responsible for the most severe form
of malaria and can result in cerebral malaria and pregnancy-related malaria.
Malaria caused by P. vivax is
becoming an increasing problem,5 accounting for as much as 40% of
the total disease burden.6 Relapse can also be a problem with P. vivax infections. The development of
dormant hypnozoite forms in the liver can last up to 20 years and cause
subsequent reinfections in the blood.7
Plasmodium parasites are transmitted by female
mosquitoes of the genus Anopheles, of
which only 60 species are able to transmit the disease. Vector control remains
a central aspect of any malaria eradication strategy. So much so that in some
highly endemic countries vector control measures has led to reductions in
deaths from malaria.2 Historically, emphasis was put on reducing the
numbers of mosquitoes by combinations of environmental hygiene and insecticide
spraying. None was more important than dichlorodiphenyl-trichloroethane (DDT).
DDT use today is rare, highlighting the big importance that mosquito resistance
has to any and future vector control strategies. The development of resistance
to DDT was a primary cause of the collapse of previous malaria control
programmes in the latter half of the late century.8 Currently, there
is a near-complete dependence on pyrethroids for vector control, and the
development of new techniques for vector control need to be increased.9
This article gives a brief overview of the
current state of antimalarial drug development, paying close attention to the
history and current problems of drug treatment, and highlighting possible
future drugs in phase I clinical trials.
Antimalarials
and Resistance
Antimalarials present the most important
part of any integrated approach needed to combat the disease. Antimalarials
have direct benefits to patients and a general decrease in disability-adjusted
life years (DALYs) for the population in general. Today, parasite resistance to
all but one case of antimalarials exists in most endemic countries.10
Resistance has prompted the wide-scale shift in first-line treatments against
malaria, under recommendation by the World Health Organisation (WHO). However,
many countries continued to use ineffective mono-therapy treatments, due to, in
part, the disparity in costs between the more conventional chloroquine and
sulfadoxine-pyrimethamine based therapies and the recommended Artemisinin
combination drugs.11 However, the increase of international funding
commitments,10,12 resulting in increased malaria control programmes
has gone some way to rectify this problem.
Drug resistance is the major cause of
malaria treatment failure. However, influencing the rapid rise of drug
resistance are factors such as non-compliance or non-adherence to drug regimen,
nutritional status of patients, incorrect drug usage, counterfeit drugs, and
misdiagnosis of patients.13 Further clouding the issue is the
distinction between and outcome of drug resistance, treatment failure, and
reinfection.14 The mechanisms, molecular and biochemical, underlying
resistance of Plasmodium species to
the various antimalarial drugs has been greatly studied to date.15,16
The genetic events that confer antimalarial drug resistance are specific for
each drug and consist of mutations or single gene copy number mutations in
genes related to drug target (Table I).
Quinoline antimalarials have been widely
used for the treatment of malaria. Among these are mefloquine, quinine,
pyronaridine, halofantrine, primaquine, and chloroquinine. The cheapest and
more widely available antimalarial was quinine, the first known effective
anti-malarial drug – an extract from the bark of the tree Cinchona calisaya – was used as an antimalarial agent as early as
1632,17 and by the 19th century it was still the only
known antimalarial agent. For decades first-line treatment of malaria involved
chloroquine (CQ), the first synthetic antimalarial compound introduced after
the second world war18 following US government-sponsored clinical
trials which showed that CQ had prominent effects as an anti-malarial drug.19
Today, CQ is given as treatment for uncomplicated malaria or severe malaria.20
Parasite resistance to CQ is widespread.
CQ-resistant P. falciparum (CRPF) emerged
from four independent foci. Firstly, in Southeast Asia around the
Thai-Cambodian border, where CRPF infections were identified in 1957 and spread
quickly to Thailand.21 Two
other foci were identified in 1960
in South America, in Venezuela and in the Magdalena
Valley, Colombia.22 In 1976,
two confirmed cases of CRPF infection were reported from Port Moresby in Papua
New Guinea72 and probably represent the emergence of the fourth
independent focus of CRPF infection. In Africa, CRPF was first found in 1978.23 Resistance spread from the African coastal
areas inland and by 1983 had been observed in Sudan, Uganda, Zambia, and
Malawi. In 1973, Thailand was the first country to replace CQ as a first-line
drug. The spread of CQ resistance was the main factor causing the increased
child mortality rates observed in Africa since the last decade of the last
century.24
CQ resistance is multigenetic and results
in a reduced parasite accumulation of the drug,25,26 with reduced
concentrations of the drug in the digestive vacuole of the parasite. CQ enters
the food vacuole and targets the polymerisation of toxic haem, binding and thus
preventing its polymerisation to haemozoin.27,28 Resulting in the
increase of toxic haem leading to enhanced oxidative stress, membrane damage
and eventually parasite death.29 One mechanism of resistance is
associated with polymorphisms in a 36 kb segment of the parasite's chromosome
7, which contains a polymorphic gene encoding a unique 330 kDa protein, cg2.30 However, association
of cg2 with chloroquine resistance in
field isolates is incomplete.31 Genetic crosses identified a role of
the P. falciparum
chloroquine-resistance transporter (PfCRT), a carrier protein located in the
membrane of the digestive vacuole of the blood-stage parasite.32,33,34
Multiple polymorphisms in the gene are associated with chloroquine resistance
both in vitro and in vivo. However, PfCRT is not the sole
molecular determinant of chloroquine resistance. Mutations in the homolog of
the major multidrugtransporter P.
falciparum multidrug resistance gene (PfMDR) seems to modulate the extent
of chloroquine resistance conferred by mutations in PfCRT.35
Furthermore, the pfmdr1 gene has been shown to be involved in mefloquine
resistance and cross-resistance to halofantrine.36,37
Sulfadoxine-pyrimethanine (SP), a class of
antifolates, is another drug used to treat uncomplicated malaria.20 Its
widespread use in many countries as a first-line antimalarial treatment was
prompted by the emergence of CQ resistance. However, resistance developed
rapidly; SP was introduced in Thailand in 1967 and resistance was reported
within the same year.23,38 Antifolates (including
pyrimethamine-sulfadoxine, chlorproguanil-dapsone, and proguanil-atovaquonel)
represent the more traditional second-line treatment option for malaria, but
again, resistance is widespread.39 These classes of drugs have a
mode of action through either inhibiting the formation of dihydropteroate
catalyzed by dihydropteroate synthase (DHPS) by competing for the active site
of DHPS;40 or by inhibition of dihydrofolate reductase (DHFR), thus
preventing the NADPH-dependent reduction of dihydrofolate to tetrahydrofolate
by DHFR. Mechanisms of resistance seem to be associated with several point
mutations in the respective genes.41,42 A specific combination of
these mutations is heavily associated with treatment failure.43
However, treatment outcomes become increasingly more difficult to predict as
the level of mutation falls off .14
In 1972, Chinese scientists discovered Qing hao su – sesquiterpere lactone
artemisinin – isolated from the leaves of the sweet wormwood Artemisia annua. Artemisinin-based
combination therapies (ACTs) are now generally considered as the best current
treatment for uncomplicated falciparum malaria for a number of reasons.2
The most important being that no real mode of resistance has yet been
implicated with Artemisinin itself. Most likely because a shorter half-life
allows rapid clearance from the body, which avoids persistence of the drug at
sub-lethal concentrations, and as a result will avoid the emergence of
resistant parasites. Currently, several
treatment options are available – as mandated by the WHO2 –
artemether-lumefantrine, artesunate + amodiaquine, artesunate + mefloquine, and
artenusate + sulfadoxine-pyrimethamine. It is hoped that by combining
antimalarial drugs with different modes of action parasite resistance can
either be prevented or its onset delayed considerably, allowing completion of
full dose regimens to end in high cure rates and an eventual decrease of
disease transmission, benefiting patients and the larger community. Today, more
potent derivatives of its active chemical have been developed. These include
artemether, artemotil, and artesunate. The problem of the appearance of
resistance to artemisinin, is a problem health professionals, policy makers and
research scientists are well aware of.44 To that effect, ACTs are
now the recommended strategy both for clinical care and for the avoidance of
drug resistance.2 To date, there has been no in vivo cases of resistance reported, however, in vitro susceptibility was found to vary with mutations in pfmdr1 and pfcrt (the two genes proposed to modulate sensitivity to CQ).45
Furthermore, cases of drug resistance induced experimentally are few and of a
moderate level, and even then, have been proven to be transient.46
The mode of action of artemisinin and its derivatives is proving to be
complicated and has not been completely elucidated, however, it seems to stem
from alkylation of molecules by radicals produced from the reductive cleavage
of the intact peroxide by ferroheme ferrous-protoporphyrin IX.31,47
ACTs represent the present best hope for
treatment of malaria. If the history of the malaria parasite has taught us
anything then it’s that onset of parasite resistance is a distinct
inevitability, which brings up the question of where will the next generation
of antimalarials come from? Charles Ledger “gave
quinine to the world” even before the causative agent or the disease was
known, the wars in Europe and Vietnam led to the development of chloroquine,
mefloquine and halofantrine, and ancient China has brought the blue-green herb
that is currently the first line of defence against the world’s most prevalent
disease. The next generation of antimalarials are some way off from becoming a
clinical reality. Most antimalarial drugs developed thus far have been
identified and developed using conventional drug discovery techniques.48
The future will bring many progressive leaps in the kind of techniques employed
by researchers to increase the beneficial output of new compounds.
Pharmacogenetic-pharmacokinetic relations and parameters, pathogen and host
genomic and proteomic information, as well as randomised trials and replication
will all prove fruitful when applied to antimalarial drugs, not only in
understanding the resistance factors at play but also in understanding the
clinical success and failure of present and future antimalarial treatments.49
Drugs
in Phase I Clinical Trials
Aminoquinoline antimalarial (AQ-13) has
proved active in vitro against P. falciparum malaria parasites
resistant to CQ and other antimalarials, as well as being active in a model of
human infection with P. vivax,
CQ-resistant P. falciparum in the
squirrel monkey, a model of human infection with CQ-resistant P. falciparum, and in two in vivo monkey models of human malaria (P. cynomolgi in the rhesus monkey Macaca
mulatta). Its performance in human subjects is being investigated in Phase 1
(safety/toxicity and pharmacokinetic) studies.50,51,52 Furthermore,
AQ-13 has proven to be of similar safety to that of CQ in preclinical studies
performed by SRI International (IND 55,670). The trial on AQ-13 was
appropriately designed as a randomized controlled Phase I study, allowing the
assessment of safety and physiological outcomes after treatment as compared to
an existing and widely used drug, CQ. A key limitation inherent to such studies
is the small number of participants studied. This means that the study cannot
prove that AQ-13 is safe, or even as safe as CQ, but rather simply that the
findings do not raise immediate safety concerns.53
With malaria parasites often being
resistant to CQ and SP, chlorproguanil-dapsone is a potential alternative. The
objective of the clinical trial was to compare chlorproguanil-dapsone with
other antimalarial drugs for treating uncomplicated falciparum malaria.54
Recent trials have shown that chlorproguanil-dapsone (with 1.2 mg
chlorproguanil) as a single dose had fewer treatment failures than chloroquine
(1 trial), but more treatment failures and people with parasitaemia at day 28
than sulfadoxine-pyrimethamine (3 trials). Two trials compared the three-dose
chlorproguanil-dapsone (with 2 mg chlorproguanil) regimen with
sulfadoxine-pyrimethamine in new attendees. There were fewer treatment failures
with chlorproguanil-dapsone by day 7 (1 trial). Neither trial reported total
failures by day 28. A
further trial was carried out in participants selected because they had
previously failed sulfadoxine-pyrimethamine. Adverse event reporting was
inconsistent between trials, but chlorproguanil-dapsone was associated with
more adverse events leading to discontinuation of treatment compared with
sulfadoxine-pyrimethamine (1 trial). It was also associated with more red blood
cell disorders. Randomized controlled trials that follow up to day 28, record
adverse events, and use an intention-to-treat analysis are required to inform
any policy decisions. In all, it seems that there is insufficient data about the
effects of the current standard chlorproguanil-dapsone regimen (three-dose, 2
mg chlorproguanil). However, chlorproguanil-dapsone has been withdrawn in 2008
following demonstration of post-treatment haemolytic anaemia in G6PD deficient
patients in a Phase III trial of chlorproguanil-dapsone and
chlorproguanil-dapsone-artesunate versus artemether-lumefantrine.55,56
Significant reductions of haemoglobin levels in patients with G6PD deficiency
have been observed with both CD and CDA.
Mefloquine, a quinolinemethanol
antimalarial, is effective as therapy and prophylaxis for all species of
malaria infecting humans, including multi-drug resistant P.falciparum. Mefloquine is a chiral molecule with two asymmetric
carbon centres, which means it has four different stereoisomers. The drug is
currently manufactured and sold as a racemate of the (R,S)- and
(S,R)-enantiomers by Hoffman-LaRoche, a Swiss pharmaceutical company.
Mefloquine's clinical utility has been impaired by its association with
neuropsychiatric side effects.57 The pharmacological basis of these
side effects are not known but two of the most reported hypotheses relate to
its action on (i) the adenosine receptor58 and (ii) its effect on
the cholinesterase enzyme.59 For both these mechanisms, there is a
significant stereoselective activity of the two enantiomers.60
Studies show that the (-) isomer is 50-100 fold more potent towards adenosine
receptors compared with the (+) isomer.61 In addition,
(-)-mefloquine has considerably more anti-cholinesterase activity.62
It has therefore been hypothesised that (+)-mefloquine may have a better
central nervous system (CNS) safety profile compared with either the racemate
or (-)-mefloquine.63 The Phase I clinical trial consisted of a
randomized, ascending dose, double-blind, active and placebo-controlled,
parallel group study in healthy male and female volunteers designed to
investigate this hypothesis and to describe the comparative pharmacokinetics of
the racemate and the single enantiomer.64
Ferroquine (FQ)+Artesunate(AS),65 a unique
organometallic compound, is a novel antimalarial drug designed to overcome the
chloroquine (CQ) resistance problem currently in phase I clinical trials. FQ
has been revealed to be equally active on CQ-sensitive and CQ-resistant P. falciparum laboratory strains and
field isolates, and is also curative on rodent malaria parasites. AS, a class
of the artemisinin group of drugs that treat malaria, is a semi-synthetic
derivative of artemisinin that is water-soluble and may therefore be given by injection.66
Ferroquine and artesunate combination therapies have been the subject of Phase
I clinical trials.67 Combinations of the two drugs were used to
assess the safety of different doses of ferroquine with artesunate in adult
African patients with uncomplicated malaria and to assess activity in reducing
parasitemia and the pharmacokinetics of ferroquine and its metabolites.
Future
Prospects
Malaria is preventable and curable,
however, in the absence of quick and effective treatment, symptoms of the
disease progress and death results.68 Accurate diagnosis is needed
in all cases as well as accurate surveillance in all endemic areas.69
To curb the incidence of treatment failure, the spread of resistance, WHO
recommends confirmation of malaria through parasite-based diagnosis in all
patients prior to commencing treatment. Prompt parasitologic confirmation by
microscopy or alternatively by rapid diagnostic tests (RDTs) are recommended in
all patients suspected of malaria before treatment is started. Thus,
diminishing unnecessary use of ACTs and provide critical and accurate
surveillance data to manage programmes and monitor impact. However,
misdiagnosis and over-diagnosis of malaria still occurs.70 One
reason is simply due to the fact that early symptoms of malaria are
non-specific.
Bringing research agendas and control
programmes together is one of the greatest challenges to fighting any
infectious disease. For malaria endemic countries, strengthening the existing
health systems is crucial. Prevention, diagnosis and treatment needs to be
followed up with accurate surveillance. The last few years have seen a great
development in new treatments and new strategies, mainly because of the failure
of old regimes due to parasite resistance.
The unique biochemical aspects of the
parasite continue to be exploited in the hope of drug design. Parasite Genome
Initiatives are ongoing efforts of full genomic sequencing to facilitate full
understanding of how parasites develop, survive and reproduce in their respective
hosts, of parasite-host and parasite-immune system interactions and of the
factors that determine behaviour, pathogenicity, drug resistance and antigenic
variation. Parasite genome sequencing together with effective genetic
manipulation (gene knock-out and gene silencing) provides a valuable means of
mimicking loss of function attributable to therapeutic intervention (albeit
with the caveat that pharmacological agents cannot mimic the zero activity
state produced by conventional gene knock-out experiments).
Already, this year has seen significant
advancements in the world of malaria research. GlaxoSmithKline has made
available, in the public domain, thousands of compounds – confirmed-hit
structures – to the general scientific community. The genome for Artemisia annua – the herb producing the
active ingredient in the most effective treatment for malaria – has been
mapped.71 Immediately highlighting genes and markers that could pave
the way for higher yield varieties, which is another step in the road to full
eradication of this debilitating disease.
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