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Advances in Environmental Biology, 6(2): 534-542, 2012
ISSN 1995-0756
This is a refereed journal and all articles are professionally screened and reviewed
ORIGINAL ARTICLE
Current Trends in Malaria and Tuberculosis Chemotherapy
Jonah Sydney Aprioku
Department of Pharmacology, Faculty of Basic Medical Sciences, University of Port Harcourt, Port Harcourt,
Nigeria.
Jonah Sydney Aprioku: Current Trends in Malaria and Tuberculosis Chemotherapy
ABSTRACT
Over the past few decades, research on chemotherapy has developed several agents and treatment
approaches/protocols for the treatment of microbial infections, including Plasmodium and Mycobacterium
infections. However, failure in the successful treatment of both infections (i.e., malaria and tuberculosis) has
posed great challenges to humans. This is majorly due to the development of resistance to available drugs. In
addition, malaria is endemic in the sub Sahara and the incidence of tuberculosis (TB) is also very high and
worsens rapidly due to the high prevalence of human immunodeficiency virus (HIV) infection, making the
treatment of both conditions even more difficult in such regions. Effective management of these diseases is very
important, due to their adverse socio-economic impacts globally and especially in the sub Sahara. This article
briefly discusses the history and general principles of antimicrobial chemotherapy. The paper also summarizes
the current status and some new advances in the chemotherapy of malaria and tuberculosis.
Key words: Antimicrobial, chemotherapy, drug resistance, Plasmodium, Mycobacterium, nanotechnology.
Historical perspective of chemotherapy:
The term chemotherapy was introduced in 1907
by the German biochemist, Paul Ehrlich to refer to
antiparasitic therapy in describing his important early
studies on Trypanosoma brucei, the tsetse fly-borne
parasite that causes African trypanosomiasis
commonly called sleeping sickness. Chemotherapy
now refers more broadly to the use of any chemical
compound that selectively acts on microbes (bacteria,
fungi, parasites, virus etc) or cancer. One of the early
chemicals developed by Ehrlich which was both
remarkably nontoxic to humans and remarkably toxic
against a number of treponemal diseases (including
syphilis and yaws) was the arsenical compound,
Salvarsan arsphenamine, which was also called the
“magic bullet”.
Selective toxicity of chemicals has been
exploited and widely employed as a technique for
defense among animals and plants since the ancient
days. Many fungi and bacteria make toxic substances
that kill or suppress the growth of competing
microorganisms or facilitate infection of a host.
Some plants make a vast array of toxins for their
self-defense. Humans first discovered this process in
1929 with Alexander Fleming’s chance observation
of the antibacterial effect of a substance (penicillin)
secreted by Penicillium notatum mould (now called
Penicillium chrisogenum) mould [12,33]. Penicillin
was subsequently purified and produced in large
quantities and introduced for clinical use by Howard
Florey in 1940. Following the successful synthesis of
penicillin by scientists, many other potential natural
antibacterial compounds were discovered and
synthesized, including tetracycline, streptomycin and
the cephalosporins, which were collectively called
“antibiotics” to refer to antibacterial substances
produced by various species of microorganisms
(bacteria, fungi, and actinomycetes) that suppress the
growth of other microorganisms. Following chemical
analysis and other studies resulting in the elucidation
of the structures of these natural antibiotics,
semisynthetic derivatives of the natural products
were developed by chemists. These semisynthetic
drugs and other classes of related drugs were safer
and more effective than the naturally produced drugs,
as the new semisynthetic or wholly synthetic drugs
had improved pharmacokinetic properties, greater
stability and extended spectrums of action. The
meaning of the term “antibiotics” has now been
extended to also include synthetic antimicrobial
agents, such as sulfonamides and quinolones.
Furthermore, rational development of several
compounds that can interfere with microbial
biological process/replication has also been greatly
facilitated with increasing knowledge of molecular
mechanisms of microbial biology/replication.
Currently, antimicrobial agents are readily available
and are among the most commonly used and misused
of all drugs. The emergence of microbial drug
Corresponding Author
Jonah Sydney Aprioku, Department of Pharmacology, Faculty of Basic Medical Sciences,
University of Port Harcourt, Port Harcourt, Nigeria.
E-mail: [email protected] 535
Adv. Environ. Biol., 6(2): 534-542, 2012
There are principles that guide the use of
antimicrobial agents in order to minimize potentially
toxic and the promotion of selection of resistant
microorganisms.
bactericidal activity occurs respectively. The static
versus cidal designation may also depend on both the
pharmacological properties of the drug and such
clinical factors as immune system function, inoculum
size, drug concentration in tissue and duration of
therapy. A cidal drug may prove to be merely static if
an inappropriately low dose or short treatment course
is prescribed. A static drug may be cidal if given in
high doses for prolonged courses to exquisitely
sensitive pathogens.
Once pathogen identity and antimicrobial
susceptibility data are available, antimicrobial agents
with a narrower spectrum are used to replace initial
broad spectrum agents, in order to reduce toxicity
and prevent the emergence of antimicrobial
resistance.
Selection of an antimicrobial agent:
Pharmacological factors:
The practice of choosing a particular
antimicrobial therapy without proper evaluation of
the disease is irrational and potentially dangerous.
Optimal and judicious selection of antimicrobial
agents for the therapy of infectious diseases requires
good clinical judgment and knowledge of
microbiological factors and the pharmacology of the
antimicrobial agent to be used [26].
Evaluation of the pharmacology of the drug is
another important principle of antimicrobial
chemotherapy. This includes its pharmacokinetics,
pharmacodynamics,
selective
drug
toxicity,
resistance
and
possible
drug
interactions.
Consideration of these factors is needed to make a
proper selection, dosage and route of administration
of antimicrobial drug [26].
Microbiological factors:
Current status and new developments of malaria
chemotherapy:
resistance is one major consequence of the
widespread, indiscriminate and irrational use of
antibiotics in humans [31,18,44]. This often results
from exposure to very low concentrations of
antimicrobials, which may provide a path whereby
human pathogens could eventually evolve high-level
antimicrobial drug resistance [34,18]. Thus,
inappropriate use of antibiotics accelerates the
development of resistance in pathogens [56,18,44].
Principles of antimicrobial chemotherapy:
Good knowledge of the most likely
microorganism to cause a specific infection in a
given host and the clinical presentations of the
infection may suggest the identity of the infecting
microorganism(s) [16,26]. Such knowledge is
required in initiating an initial empirical therapy for
microbial infections in some class of patients,
especially in the critically ill or hospitalized patients,
who require broad-spectrum antimicrobial agents
[26,41,32]. After initiation of empirical therapy,
identification of the infecting pathogen is required to
be done using a microscope in the laboratory in order
to make definitive diagnosis. Furthermore, because
sensitivity of microorganisms to antimicrobial drugs
varies widely among different bacterial strains and
even within a particular specie, microorganisms
sensitivity tests is very essential in antimicrobial
therapy.
Sensitivity of a microorganism to specific
antimicrobial agents (antimicrobial susceptibility
testing) is done by in vitro laboratory tests, and is
used to predict efficacy in vivo and make appropriate
drug selection [51,26]. The most commonly used are
the agar- or broth-dilution tests which provide
quantitative information and disk-diffusion tests,
which provide qualitative information. The dilution
tests are used to measure the minimum inhibitory
concentration (MIC) or minimum bactericidal
concentration (MBC), which represents the lowest
concentration of the agent at which bacteriostatic or
Malaria results from infection with Plasmodium
falciparum, Plasmodium vivax, Plasmodium ovale or
Plasmodium malariae, but a large majority of the
clinical cases and mortalities is caused by
Plasmodium falciparum [7,13,37]. Recently, a fifth
human parasite has been identified to be P. knowlesi,
which has the long-tailed and pig-tailed macaque
monkeys as the natural hosts [57,68].
P. falciparum is the leading cause of disease in
most parts of the world, producing about 250 million
new infections, with a mortality estimate of about 1
million deaths each year; and approximately 85% of
these deaths are among children, and most occur in
Africa [74]. Half of the world's population is at risk
from malaria, however, the disease is endemic in
sub-Saharan Africa and children below the age of
five suffer the greatest burden of the disease
[3,60,73]. In Nigeria, nearly 110 million of clinical
cases of malaria are diagnosed per year, about 50%
of the adult population experiencing at least one
malaria episode per year and young children having
2-4 attacks of malaria annually [17]. Despite efforts
to control the disease, malaria is among the top three
deadly communicable diseases and the most deadly
tropical disease [53]. The consequences of the
disease are further compounded by extremely low
living conditions in poor nations.
The current line of malaria therapy
recommended by the World Health Organization is
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Adv. Environ. Biol., 6(2): 534-542, 2012
diagnostic testing in all cases of suspected malaria
and treatment based on clinical symptoms alone is
only reserved for settings where diagnostic tests are
not available [74].
Diagnosis:
Early diagnosis and prompt treatment are
fundamental components of the WHO global strategy
for malaria control [71,74]. Current confirmatory
qualitative
methods
include
parasitological
confirmation by microscopy or rapid diagnostic test
(RDTs). In most malaria endemic countries of subSaharan Africa, the standard for laboratory
confirmation of a clinical malaria diagnosis is a
peripheral blood film, examined microscopically.
However, some limitations of the microscopic-based
diagnosis of malaria including low sensitivity,
labour-intensiveness, requirement for trained
personnel (expertise) and quality equipment, is now
making RDT to become preferable, especially
because of its higher sensitivity both in clinical and
research settings [36.39,4,74].
Microscopy:
Thick and thin smears of sample blood are
usually prepared on separate frosted slides and
stained using standard staining method ("Field's
stain" or "Giemsa stain"). The Field's stain method is
more often used because the method provides a
readable film within few minutes compared to the
"Giemsa stain”. Blood slides are then read under a
microscope, each film graded as positive (asexual
malaria parasites seen) or negative (no malaria
parasites seen) based on the inspection of 200 fields
of the thick smear. The parasite density is estimated
assuming 8,000 white blood cells/μl [69]. The thin
smear is useful in species identification.
Rapid diagnostic test:
RDTs are handheld cassettes detecting
Plasmodium parasites by an antibody-antigen
reaction. They are available in several formats and
designed to detect one or more antigens including
Plasmodium falciparum specific histidine rich
protein 2 (PfHRP-2), P. falciparum specific parasite
lactate dehydrogenase (Pf-pLDH), Plasmodium vivax
specific parasite lactate dehydrogenase (Pv-pLDH)
or antigen common to the four Plasmodium species:
pan-pLDH or aldolase [5,39]. RDT generally
involves blotting a small volume of blood (2-20μl)
on a nitrocellulose strip containing monoclonal
antibodies, which react with parasite specific
antigens available in the blood of infected patients to
give visible, diagnostic and control bands [36]. Test
is considered positive when the antigen and control
lines are visible in their respective windows and
negative when only the control band is visible.
RDTs have high sensitivity and specificity
(>90%) at a parasitaemia >100 asexual parasites/μl
[39,4]. The accuracy (sensitivity and specificity) of
RDTs is mostly dependent on the parasite species,
transmission intensity, parasite density, amount of
circulating antigens, local polymorphisms of target
antigen and persistence of antigens after treatment.
RDTs can also serve as a source of parasite DNA, as
sufficient DNA could be successfully extracted from
malaria rapid diagnostic tests (RDTs), used and
collected as part of routine case management services
in health facilities, and thus forming the basis for
molecular analyses, surveillance and quality control
(QC) testing of RDTs [27].
Current drug treatment:
Correct use of an effective antimalarial drug will
not only shorten the duration of malaria illness but
also reduce the incidence of complications and the
risk of death. Antimalarial drug resistance has
spread and intensified over the last 15–20 years,
leading to a dramatic decline in the efficacy of most
antimalarial drugs including aminoquinolines,
halofantrine,
sulfadoxine-pyrimehtamine
etc
[6,10,76,50,55].
Currently, the drugs with significant effects on
the parasite are the artemisinin and its derivatives.
Artemisinin and its derivatives are the most rapidly
acting of all the current antimalarial drugs and they
are highly efficacious against multi-drug resistant P.
falciparum [25,42]. Development of resistance to
artemisinin monotherapy [35], has prompted the use
of artemisinin-based combination treatments (ACTs),
involving the use of an artemisinin compound with
other antimalarial agents [66,42,74]. ACTs have been
demonstrated to have better parasite clearance and
efficacy than single artemisinin therapies and
combination therapy offers hope for preserving the
efficacy of antimalarial drugs [1,11,42]. The World
Health Organization has recommended these
regimens/combinations as: artesunate-sulfadoxinepyrimethamine
(artesunate-SP),
artesunateamodiaquine,
artemether-lumefantrine
and
artesunate-mefloquine. A fifth combination has
recently been added- dihydroartemisinin-piperaquine
[74]. The ACTs are presently recommended and used
as the first line antimalarial agents in malaria
chemotherapy [42,74]. In order to reduce the drug
resistance, the WHO has also recommended the
removal
of oral
artemisinin
monotherapy
formulations from the circulation because their use is
thought to hasten the development of parasite
resistance.
Artemisinins:
Artemisinin (qinghaosu) was discovered in 1972
by Chinese scientists as the active principle of the
leaves of a Chinese medicinal plant known as
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Adv. Environ. Biol., 6(2): 534-542, 2012
Artemisia annua L. [29]. It is a sesquiterpene
trioxane lactone with a peroxide bridge linkage. It
acts against the asexual stages and gametocytes
thereby having potent schizontocidal activity and
able to reduce the rate of malaria transmissibility in
places of high malaria incidence.
Modification of artemisinin has yielded
artemether and arteether (oil soluble derivatives) and
dihydroartemisinin (DHA), sodium artesunate and
artelinic acid (water soluble derivatives). Artemisinin
and its derivatives (except DHA) are all metabolized
to DHA, which is the biological active metabolite of
the drugs at variable rates [40,22,21]
The artemisinin derivatives have more potent
blood schizontocidal activities than the parent
compound and are the most rapidly effective
antimalarial drugs known [35]. Artemisinins have
also been shown to have anti-inflammatory [64,77]
and antiproliferative effects against a wide range of
cancer cell lines [28,65,30].
Recent studies have indicated that antiretroviral
protease inhibitors may affect outcome in malarial
disease. The human immunodeficiency virus (HIV)-l
protease inhibitors saquinavir, ritonavir and indinavir
directly inhibit the growth of Plasmodium falciparum
in vitro at clinically relevant concentrations [58]. By
these findings, drug-drug interactions that occur
between antiretrovirals and some antimalarials in
malaria and HIV coinfection can be avoided.
Concurrent administration of SP and nevirapine and
zidovudine have been shown to cause serious adverse
drug reactions and diagnostically challenging drug
toxicities [8]. These findings are particularly
important due to the existing high rate of malaria and
HIV-1 coinfection in sub-Saharan Africa and the
effort to employ highly active antiretroviral therapy
for effective management and prevention of
HIV/AIDS in this region.
Mechanism of action:
NITD609, is an experimental drug which has
been shown to be effective against the two most
common parasites responsible for malaria (P.
falciparum and P. vivax) and also against a range of
drug-resistant strains in mice with malaria [52].
NITD609, observed to be a potential drug candidate
among 12,000 chemicals that were screened using an
ultra-high throughput robotic screening technique,
has been identified to be structurally and chemically
different from all other currently used antimalarials
and belongs to a class of drugs called spiroindolones
[78]. The compound has been reported to target
malaria parasite protein different from proteins
attacked by the conventional malaria drugs and also
to have unique pharmacokinetic profile [52,78].
NITD609 is currently undergoing clinical trials and if
the results obtained in the mice are reproducible after
the clinical trials, then NITD609 has the promise to
be a breakthrough in malaria treatment.
Artemisinins are selectively distributed into P.
falciparum infected erythrocytes, where they cause
malaria parasite’s death through generation of free
radicals [63]. The peroxide bond (endoperoxide
bridge) of artemisinin is activated by iron (II)-heme
produced during hemoglobin degradation in
erythrocytes. This results in the generation of toxic
reactive oxygen species (ROS) responsible for
parasites death [49,75]. However, some studies have
also reported that artemisinins endoperoxide
cleavage do not require activation by heme iron
[46,30].
Adverse effects:
Artemisinins have been reported to be relatively
safe, however there are concerns on some recently
reported adverse effects. Apart from the reported
minor cardiovascular effects observed during clinical
trials,
artemisinin
compounds
have
been
demonstrated to cause neurotoxicity, especially in the
vestibular, motor and auditory brain stem nuclei in
animal studies [20]. Furthermore, artemisinins have
been recently shown to affect testicular function
[43,2] and female reproductive function [67,47] in
animal models. These effects appear to be due to
sustainable high levels of the drugs and their
metabolites and calls for caution in prolonged or
repetitive treatment with artemisinin and its
derivatives, which may occur in areas of high
transmission.
New drugs for malaria treatment:
Antiretrovirals:
NITD609:
Current status and new developments of tuberculosis
chemotherapy:
Tuberculosis (TB) is a pervasive disease of the
respiratory system, caused by Mycobacterium
tuberculosis. It is a leading chronic bacterial
infection and constitutes a major public health
challenge [19]. The spread of multidrug resistance
TB (MDR-TB) and the appearance of extensively
drug-resistant TB (XDR-TB) pose new challenges
for its prevention, treatment and control [48].
Approximately, two billion people are currently
infected
with
Mycobacterium
tuberculosis
representing about 30% of the global population. The
infection is endemic in developing countries, where
higher mortality has been reported [45,14]. The most
effective pharmacotherapy is a multidrug
combination of active anti-tuberculosis agents.
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Adv. Environ. Biol., 6(2): 534-542, 2012
Current drug treatment:
Drug-resistant TB:
Anti-tuberculosis drugs are grouped into firstline, second-line or third-line drugs, according to
their potencies and efficacies.
There are different forms of drug-resistant TB
and each regimen requires different drug
combination for their effective treatment:
First-line drugs:
Multidrug-resistant (MDR-TB):
The first-line drugs used in treating TB are:
isoniazid (INH), rifampin (RMP), pyrazinamide
(PZA), ethambutol (EMB) and streptomycin (SM).
These drugs are administered orally and are shown to
have excellent potency against M. tuberculosis [23].
Multidrug-resistant TB is a form of TB in which
the bacteria become resistant to INH and RMP, but
may or may not be resistant to other agents. Less
patient compliance and poor adherence to
administration schedules due to the prolonged
pharmacotherapy and associated pill burden remain
the main reasons for therapeutic failure and
development of MDR strains [9]. Treatment takes
longer usually with any of the first-line drugs and
mostly second-line drugs, which are more expensive
and have more side-effects [38,72].
Second-line drugs:
The second-line drugs used for the treatment of
TB are: aminoglycosides (e.g., amikacin and
kanamycin); polypeptides (e.g., capreomycin,
viomycin and enviomycin; fluroquinolones (e.g.,
ciprofloxacin, levofloxacin and moxifloxacin);
thioamides (e.g., ethionamide and prothioamide) and
cycloserine [23,45].
Third-line drugs:
The third-line drugs for treating TB include
rifabutin, linezolid, thioidazine, arginine, Vitamin D,
macrolides (e.g., clarithromycin) and thioacetazone
[23,45].
Anti-TB drug regimens:
Combination of the above drugs for effective
tuberculosis treatment is dependent on the form of
tuberculosis.
Extensively drug-resistant (XDR-TB):
XDR-TB is a more aggressive form of MDR-TB
in which the bacteria are resistant to the first-line
drugs (INH and RMP) and any fluoroquinolone, and
at least one of three injectable second-line drugs:
capreomycin, kanamycin and amikacin [9,72]. As
with MDR-TB, XDR-TB can be either transmitted or
developed, for example, if MDR-TB drugs are
misused or mismanaged. Treatment options for
XDR-TB are fewer, more expensive and less
effective with many unpleasant side effects.
Treatment requires the use of two or more new drugs
in addition to initial regimen containing INH and
RMP.
Novel technologies applied to the treatment of TB:
Latent and active TB:
There are two forms of TB: latent TB and active
TB. In latent TB, the bacteria are dormant in body
and this phase can last for up to decades and can also
develop into active TB. The usual treatment of latent
TB is one anti-tuberculosis drug (usually isioniazid)
giving daily for 6-12 months in HIV-negative people.
This has greatly reduced the subsequent risk of
developing active TB [59].
In active TB, the bacteria multiply and spread in
the body, thereby causing tissue damage. The most
effective pharmacotherapy is a multidrug
combination of INH, RMP, PZA and EMB for an
initial 2-month intensive treatment (initial intensive
phase). This is followed by a continuation phase,
usually 4-month treatment with RMP and INH
exclusively [70,45]. During the initial intensive
phase of treatment, the agents destroy almost all
bacilli in the three physiological categories, while
any residual dormant bacilli or replicating rifampinresistant mutants are eliminated during the
continuation phase.
Despite potentially curative pharmacotherapies
being available for over 50 years, the therapeutic
outcome has not been satisfactory because of length
of drug treatment and the pill burden, which affect
patient lifestyle. Furthermore, the oral route, through
which most anti-TB drugs are administered,
represents
many
pharmacokinetic
problems,
including bioavailability [14]. Current concern is to
therefore to design novel antibiotics that will
overcome drug resistance, shorten the treatment
course and reduce drug interactions with the aim of
improving patient healthcare.
New technologies such as the design of carrierbased drug delivery systems (nanotechnology) are
under investigation for treating TB. Nanotechnology
appears as one of the promising approaches for the
development of more effective chemotherapeutic
agents for TB treatment and other conditions
[24,54,61].
This
technology
involves
the
development
of
novel
microparticulate,
encapsulation and various other carrier-based drug
delivery systems for incorporating the principal anti-
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Adv. Environ. Biol., 6(2): 534-542, 2012
TB agents. Biodegradable polymers and liposomes
are used as carriers to trap specific amounts of the
drugs and administered either intravenously or
subcutaneously [56]. The drugs are then released
gradually overtime as they diffuse out into the body
in sufficient amounts that are lethal to the M.
tuberculosis parasite, which ultimately reduces the
dose and duration of treatment.
7.
8.
Conclusion:
Microbial infections are known to cause diseases
that have high mortality rates, including malaria,
tuberculosis and HIV/AIDS. Every human is exposed
to these unfriendly microbes, while over 40% of the
global population is infected with one pathogenic
microorganism or the other, which poses great
concerns in public health. Effective treatment of
these diseases has not been very successful due to the
development of resistance by microorganisms to the
available chemotherapeutic drugs. This impacts
severe adverse socio-economic effects on the society,
because of the debilitating health consequences from
such diseases. Misuse and irrational use of
chemotherapeutic agents is a major cause of
development of drug resistance by P. falciparum and
M. tuberculosis and other microorganisms. As
pharmacologists and other scientists discover and
design novel drugs and treatment approaches for P.
falciparum and M. tuberculosis infections, there is
hope that they will be more effectively eradicated in
the future, if the drugs are used properly.
9.
10.
11.
12.
13.
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