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Spring 2021

A brief historical overview of the antimalarials chloroquine and A brief historical overview of the antimalarials chloroquine and

artemisinin: An investigation into their mechanisms of action and artemisinin: An investigation into their mechanisms of action and

discussion on the predicament of antimalarial drug resistance discussion on the predicament of antimalarial drug resistance

Ekaterina Ellyce San Pedro

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A Brief Historical Overview of the Antimalarials Chloroquine and Artemisinin: An

Investigation into their Mechanisms of Action and Discussion on The Predicament of

Antimalarial drug resistance

By Ellyce San Pedro

Abstract:

Malaria is a problem that has affected humanity for millenia. As a result, two important

antimalarial drugs, chloroquine and artemisinin, have been developed to combat Malaria.

However, problems with antimalarial resistance have emerged. The following review discusses

the history of Malaria and the synthesis of chloroquine and artemisinin. It discusses both drugs’

mechanisms of action and Plasmodium modes of resistance. It also further discusses the

widespread predicament of antimalarial drug resistance, which is being combated by

artemisinin-based combination therapy. Lastly, a case study is discussed concerning the

reintroduction of chloroquine in areas where it has previously failed due to resistance.

Introduction:

Malaria or in Italian, “Mal ‘aria’” (Hempelmann & Krafts, 2013) has plagued humanity

for millenia. From the ancient Egyptians in 1550 B.C. (Fagan, 2000) to the present day, historical

records detail a deadly disease that results in symptoms such as shaking, fever, fatigue and death

(CDC 2021). In the present day, Malaria has persisted, resulting in around 409,000 deaths in

2019 alone (CDC 2021). Prior to the modern day, Malaria’s origins were considered mysterious

and miasmic in nature. But with the help of modern technology, great clinical advancements

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have been made in decreasing its potency. In particular, the antimalarial drugs chloroquine and

artemisinin are today’s front-line defense against this dangerous disease.

Parasite Life Cycle:

Malaria is caused by a protozoan parasite. Malaria can be commonly contracted from

four specific sporozoan species: P. malariae, P. falciparum, P. vivax and P. ovale (Fagan, 2000).

The most common malarial infections are derived from the P. falciparum and P. vivax species

(Fagan, 2000).

The following parasite cycle can be used to generally describe the life cycles of the above

listed parasites. The parasite life cycle requires a human host and a mosquito host (CDC 2021).

The cycle begins when an infected female mosquito partakes in a human blood meal, which

allows the entry of sporozoites into the skin (CDC 2021). The sporozoite then moves into the

circulation (CDC 2021). Sporozoites are ambulatory parasites derived from a female anopheline

mosquito that infects humans and targets human hepatocytes (WHO 2015).

After sporozoite entry, a sporozoite infection of liver cells occurs. Sporozoites are

obligate intracellular parasites that develop within the host cell during the vertebrate stage of the

life cycle. The sporozoites then mature into schizonts (WHO 2015). Schizonts are mature

malarial parasites that reside in the host’s liver cells where they undergo nuclear division (WHO

2015). Upon their maturation, the schizonts burst and release merozoites (CDC 2021).

Merozoites are parasites that are released into the bloodstream when a liver cell bursts (WHO

2015). Upon formation, the merozoites proceed to invade erythrocytes. It is also important to

note, that as the parasite grows within the erythrocyte, it must digest the host cell’s hemoglobin

to acquire amino acids to support its metabolism and also to create more space in the host cell to

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grow. The sporogonic cycle or the sexual reproduction portion of the parasite life cycle occurs

when the parasites multiply within the mosquito (CDC 2021). This occurs when parasite gametes

are ingested by a mosquito in another blood meal. During the sporogonic cycle, the male

microgametes fuse with female macrogametes to produce a zygote (CDC 2021). These zygotes

will eventually mature into oocytes that will become sporozoites (CDC 2021). These sporozoites

will be released from the mosquito’s salivary glands (CDC 2021). This continues the parasite’s

life cycle as the mosquito continues taking blood meals.

Past Explanations for Malaria:

In the past, many explanations have been attributed to the cause of Malaria. Malaria was

first attributed to miasma. Miasma was thought to be a dangerous cloud of particles that caused

diseases (Hempelmann & Krafts, 2013). This led to the coinage of the Italian phrase “mal’aria”,

indicating bad air (Hempelmann & Krafts, 2013).

The idea of a malarial parasite was not introduced until microscopic staining techniques

were able to detect the presence of the parasites in blood (Hempelmann & Krafts, 2013). Dr.

Ronald Ross, a British army surgeon, was the first individual to prove that mosquitoes

transmitted Malaria (Hempelmann & Krafts, 2013). In 1897, Ross obtained mosquitoes and gave

them blood that had crescent-shaped cells (Murray, 1923). After feeding, Ross saw that there

were pigmented crystals in the stomach wall (Murray 1923). Ross realized that mosquitoes do

not normally produce the pigment known as hemozoin and he deduced that this pigment could be

related to Malaria (Murray, 1923). Prior to this in 1880, Dr. Alphonse Laveragen discovered that

Malaria was caused by a protozoan parasite (Nye, 2002). This discovery occurred when Dr.

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Laveragen, a military surgeon, visualized the malarial parasite through the use of blood smears

(Nye, 2002).

Past Treatments/Drugs Used to Treat Malaria:

Antimalarial drugs have had a colorful history. Alternatives to quinine (the derivative for

chloroquine), have included methylene blue dye, Prontosil and Atabrine (Lowe, 2020).

Unfortunately, these drugs were not highly effective. They have also had the unfortunate side

effect of turning patients into a whole spectrum of colors (Lowe, 2020). Methylene blue gave

patients a blue tint. Prontosil turned patients into a permanent shade of red (Lowe, 2020).

Atabrine gave individuals a yellow hue, while also causing depression, psychosis, seizures, and

other problems (Lowe, 2020). In terms of today’s antimalarial treatments, the CDC states that

common drugs that are used to treat Malaria include: atovaquone/Proguanil, and chloroquine

(CDC 2021). However, chloroquine and artemisinin remain as the two frontline drugs that are

most commonly used to combat the effects of Malaria.

Chloroquine - A History:

Chloroquine was discovered in 1934 by Johnann Hans Andersag (Lowe, 2020) from

cinchona trees that are located in South America. Chloroquine is a weak base drug and it belongs

to the family of 4-aminoquinolines (Coban, 2020). Quinolone was extracted in 1820 by

researchers Pelletier and Caventou (Lowe, 2020). Quinine was synthesized in 1944 (Lowe,

2020). Unlike its predecessors, chloroquine possesses strong antimalarial activity and does not

change the appearance of a patient's skin tones (Lowe, 2020).

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Chloroquine Mechanism of Action:

Chloroquine's mechanism of action is still not fully understood. However, there are

several suppositions that may explain how chloroquine functions in infected erythrocytes. An

early theory for chloroquine’s mechanism of action focused on chloroquine’s ability to bind

DNA and RNA (Coban, 2020). It was previously thought that chloroquine would bind to the host

cell’s DNA and RNA through hydrogen bonds and electrostatic forces (Coban, 2020). However,

DNA-chloroquine interactions required an excessively high concentration of chloroquine to

occur (Coban, 2020). This amount was much higher than needed to eliminate parasites, therefore

making it unlikely that this supposition was true (Coban, 2020).

The second and more substantial mechanism of action relies on chloroquine’s interactions

with free-heme in the infected erythrocyte. Chloroquine weakens the malarial parasite by

reducing its ability to synthesize hemozoin, a substance that is significant to Plasmodium

survival (Pilat et al, 2020).

In the absence of antimalarial drugs, the malarial parasite performs hemoglobin

degradation using proteases such as plasmepsins and falcipains (Coban, 2020). Plasmepsins and

falcipains are a part of Plasmodium-specific families of aspartic proteases and cysteine proteases.

These proteases catabolize hemoglobin to release peptides and nutrients that the parasite requires

to survive (Wicht et al, 2020). However, it has also been shown that many of these amino acids

are returned to the serum. Thus, hemoglobin degradation is also surmised to create space in the

infected erythrocyte for parasite growth (Krugliak et al, 2002).

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During the process of hemoglobin degradation, heme is released and converted into

alpha-hematin (ferriprotoporphyrin IX) which is toxic to the parasite (Coronado et al, 2015). The

parasite normally evades this problem by transforming alpha-hematin into hemozoin (or

beta-hematin), which is non-toxic to the parasite (Coronado et al, 2015).

Chloroquine inhibits hemozoin synthesis in the following manner. Chloroquine moves

from the cell cytosol into the digestive vacuole within the infected cell (Wicht et al, 2020). Upon

entrance into the digestive vacuole, the weak base chloroquine is protonated and becomes unable

to exit the digestive vacuole membrane (Wicht et al, 2020). The protonated chloroquine then

binds to the alpha-hematin and to the surfaces of already existing hemozoin crystals (Wicht et al,

2020). Once this binding occurs, hemozoin formation is inhibited and leads to swelling of the

digestive vacuole and the accumulation of toxic free alpha-hematin in the vacuole (Wicht et al,

2020). Additionally, chloroquine damages the digestive vacuole’s membrane and allows for the

release of proteases into the cell (Coban 2020).

Methods used to Determine Anti-Malarial Drug Resistance:

Anti-malarial drug resistance is the parasite’s ability to survive despite antimalarial drugs

(Basco, & Ringwald, 2000). Anti-malarial drug resistance is a problem that has appeared in

many areas of the world. Examples include P. falciparum resistance to chloroquine in Southeast

Asia, Colombia, and Papua New Guinea (Mita et al, 2009).

As such, several tools have been developed to survey antimalarial resistance. The three

most commonly used approaches are: in vivo studies, in vitro/ex vivo studies and molecular

assays. In vivo studies are used for determining how effective the drug is in patients. In vitro/ex

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vivo studies determine how susceptible a parasite is to the drug in question. Molecular assays are

used to find gene mutations that may be related to drug resistance (Nsanzabana et al, 2018).

In vivo studies are conducted by prescribing a specific dosage of the drug to patients who

are experiencing uncomplicated Plasmodium infections (Nsanzabana et al, 2018). After

treatment, a clinical follow up is conducted for a specific time period to assess if the treatment

was successful or not (Nsanzabana et al, 2018). In vitro/ex vivo studies use parasite samples that

have been acquired from patients or from cultures (Trager & Jensen, 1976). The parasites are

then cultured in either different concentrations of the anti-malarial drug or through exposure to

high concentrations of the antimalarial for a short interval of time to observe its effects

(Witkowski et al, 2013). Different methods that are used to measure parasite growth include:

microscopy, isotopic tests, ELISA, fluorescent markers, flow cytometry and RSA or ring-stage

survival assays (Nsanzabana et al, 2018). Molecular methods are also used to determine

polymorphisms that are related to anti-malarial drug resistance (Nsanzabana et al, 2018). This

technique involves the detection of (SNPs) single nucleotide polymorphisms (Nsanzabana et al,

2018), which can be determined in a variety of different ways.

Anti-Chloroquine Resistance

Selective pressure is defined as a factor involving natural selection that selects for one

group over another (Hilaris 2021). As previously mentioned, chloroquine and artemisinin have

been used as the drugs of choice to eliminate malarial parasites. However, this has also resulted

in the emergence of chloroquine and artemisinin resistance. This section will discuss chloroquine

resistance.

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Chloroquine has been used as the antimalarial drug of choice for decades since its

inception. Over time, it has been deemed as a safe and affordable antimalarial. This was the case

until resistance against chloroquine was seen in Southeast Asia and also in South America (Kim

et al, 2019).

There are also several theories for anti-chloroquine resistance. The most supported

mechanism is that chloroquine resistance is associated with a series of point mutations in the

PfCRT or the P. falciparum CQ-resistant transporter (Kim et al, 2019). The PfCRT is a

transporter whose structure includes 424 amino acids as well as 10 transmembrane helix domains

(Wicht et al, 2020). These components create a negatively charged chamber that faces the

digestive vacuole (Wicht et al, 2020). The cavity is significant because it is believed to attract

positively charged drugs for transport out of the cytosol. In this case, it is believed to transport

the positively-charged chloroquine out of the cytosol (Wicht et al, 2020). Once chloroquine is

removed from the digestive vacuole, the parasite can continue to detox by synthesizing the

nontoxic hemozoin.

The important mutation involved changes a lysine to a threonine at the 76th position

(Wicht et al, 2020). The K76T mutation is important because this mutation arises with the

presence of other mutations that are highly specific to region or location (Wicht et al, 2020). The

structure of the PfCRT showed that the mutations C72S, N326D , K76T, A220S, I356L and

A220S are inside the drug-binding chamber (Wicht et al, 2020). This is important because four

of these mutations are necessary for chloroquine resistance (Wicht et al, 2020).

Artemisinin - A History:

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Artemisinin was created in 1972 amidst controversy in the east (History of antimalarials

2021). In 1955, The United States and Vietnam were at war (History Channel Editors, 2017). But

Vietnam was also fighting a war on a second front. Vietnam was struggling against Malaria. As

such, Vietnam turned to its ally, China for aid (Faurant, 2011). In response, on May 23, 1967,

Mao Tse-tung began the 523 research program, which led to the discovery and development of

artemisinin (Faurant, 2011). Youyou Tu from the Chinese Academy of Medical Sciences led the

project (Krungkai & Krungkai, 2016). During the project, the team investigated and researched

2,000 traditional Chinese recipes and 380 herbal extracts in a bid to find a compound that

possessed strong antimalarial properties (Krungkai & Krungkai, 2016).

Artemisinin was founded from ancient Chinese medicine (Krungkai & Krungkai, 2016).

An ancient text described sweet wormwood as a treatment for Malaria and it was identified as an

effective anti-malarial (Faurant, 2011). However, at first there was confusion between the forms

of quinghao or huanghuahao, wherein quinghao or artemisinin emerged as the effective version

(White et al, 2015).

Artemisinin was also developed against the backdrop of the Chinese Cultural revolution

in 1967 (Faurant, 2011). After artemisinin was developed, the relationship between China and

Vietnam soured. For a time, artemisinin’s significance was lost.

Artemisinin Mechanism of Action:

Artemisinin is believed to function by utilizing free heme-bound iron to catalyze

parasite-toxic free radicals. (Krungkai & Krungkai, 2016). Upon entry into the digestive vacuole,

artemisinin is activated when its endoperoxide bridge is cleaved by iron protoporphyrin IX or

alpha-hematin (Wicht et al, 2020). As discussed above, iron protoporphyrin IX or Fe2+ heme is a

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byproduct of the parasite-digested hemoglobin (Wicht et al, 2020). Artemisinin’s endo-peroxide

bridge is then reduced from Fe2+ to the ferrous iron Fe3+ (Krungkai & Krungkai, 2016). The

Fe2+-heme-artemisinin carbon-centered radicals then cause damage to the parasite by damaging

its proteins, lipids and other components (Wicht et al, 2020).

There are two theories for the activation of artemisinin, the mitochondrial and the

heme-degradation pathway (Muangphrom et al, 2016). As stated above, artemisinin activation

occurs when the endoperoxide bridge has been cleaved. In the mitochondrial pathway,

artemisinin is activated by the mitochondria and is associated with lipid peroxidation due to the

synthesis of reactive oxygen species. It is also thought to cause the depolarization of plasma

membranes and mitochondria (Muangphrom et al, 2016). The heme-mediated pathway is a bit

more complex because it involves two proposed activation models, the reductive scission model

and the open peroxide model (Muangphrom et al, 2016).

In the Reductive Scission Model it has been proposed that oxygen centered radicals

change conformation to create carbon centered radicals (O’Neil et al, 2010). Ferrous heme was

also seen to bind to artemisinin and to eventually cause a cleavage of the peroxide bridge that

created oxygen centered radicals that would change shape to create carbon centered radicals

(O’Neil et al, 2010).

In the Open Peroxide model, it is suggested that protonation drives ring opening (O’Neil

et al, 2010). It is suggested that iron works as a Lewis acid by promotion of the ionic

bioactivation of artemisinin (O’Neil et al, 2010). It has also been suggested that non-peroxide

oxygen aids with ring opening to create hydroperoxide (O’Neil et al, 2010). The oxygen atom

stabilizes positive charges and reduces the energy that is needed for ring opening. Cleavage of

the endoperoxide bridge and inclusion of water creates an unsaturated hydroperoxide that

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modifies proteins using direct oxidation (O’Neil et al, 2010). This degradation of hydroperoxide

creates a hydroxyl radical that oxidizes certain amino acids (O’Neil et al, 2010 ). The open

peroxide model could possibly create several ROS or reactive oxygen species that affect

antimalarial activity (O’Neil et al, 2010).

Other targets of artemisinin include the creation of reactive oxygen species through

activation of the mitochondrial electron transport chain (Krungkai & Krungkai, 2016).

Artemisinin Resistance and K-13:

Artemisinin has been highly effective in treating Malaria. Artemisinin resistance was first

reported in 2009 in falciparum malaria patients located on the Thai-Cambodian border (Krungkai

& Krungkai, 2016). More cases of artemisinin resistance were seen in 2014, where it was

reported that resistance was spreading from Vietnam to Myanmar (Krungkai & Krungkai, 2016).

One of the main players in artemisinin resistance is the Kelch-13 protein. The Kelch-13

protein or K-13 protein is important for the development of the parasite in the erythrocytic cycle

(Wicht et al, 2020). The K-13 protein is important because it controls the endocytosis of

hemoglobin into the digestive vacuole (Birnbaum et al, 2020). Digested hemoglobin is partially

used for the synthesis of amino acids that are used to create the parasite’s proteins, and its

digestion results in the creation of toxic, alpha-hematin (Krugliak et al, 2001). Alpha-hematin is

important because it activates artemisinin through the cleavage of its endoperoxide bridge.

Mutations that resulted in decreased levels of K-13 were seen to reduce the endocytosis of

hemoglobin, which resulted in reduced levels of alpha-hematin or Fe(II)PPIX for artemisinin

activation, leading to artemisinin resistance (Birnbaum et al, 2020). More research also showed

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that disruption of the pathway through the interruption of falcipain 2a or the addition of E64 (a

protease inhibitor) can increase the parasite’s resistance to artemisinin (Wicht et al, 2020).

K-13 has also been seen to change the cell cycle in K-13 C580T clinical isolates during

the ring-to-trophozoite stage, leading to additional reduction of alpha-hematin for artemisinin

activation (Wicht et al, 2020). It has also been theorized to disrupt proteins and cause

dysregulation of PfPK4 phosphorylation (Wicht et al, 2020). It has also been suggested that

K-13 uses the UPR or unfolded protein response to dispose of damaged proteins as a way to

respond to cell stress (Wicht et al, 2020). However, there is also evidence that K-13 mutations do

not cause resistance through the modulation of proteasomal activity (Wicht et al, 2020). K-13

mutations have also been linked to the mitochondria of the parasite. (Wicht et al, 2020).

ART Resistance Non-Related to K-13:

K-13 is not the only gene that has been associated with artemisinin resistance. Other

antimalarial suspects include: UBP-1, V3275F mutation in pfubp1 and the T381 mutation (Wicht

et al, 2020). The UBP-1 is thought to be significant in artemisinin resistance because of a linkage

group selection analysis of a genetic cross that involved Plasmodium chabaudi between a

selected artemisinin-resistant parent and an artemisinin-sensitive parent (Wicht et al, 2020).

According to Wicht et al, the V3275F mutation for pfubp1 was correlated with resistance in

vitro, but not in in vivo experiments. It is also important to note that the UBP-1 and the V3275F

mutation have not been found to be correlated with reduced clearance of P. falciparum

infections after artemisinin treatment (Wicht et al, 2020). The T381 mutation is considered to be

more compelling because of a GWAS related to the China-Myanmar border that entailed the P.

falciparum’s weakness to artemisinin (Wicht et al, 2020).

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Combination Therapy as a Solution to Anti-Malarial Drug Resistance

As discussed above, new solutions are necessary to overcome anti-malarial drug

resistance in Asia, Africa and other areas of the world (Nyunt & Plowe, 2007). Combination

drugs therapies are therefore used to block and deal with drug resistance (Nyunt & Plowe, 2007).

Combination therapy was suggested in 1955 (ter Kile et al, 2007) and has been supported by

multiple studies, including those by Peters (Covell et al, 1955), White and Olliaro (Nyunt &

Plowe, 2007) and White et al (Nyunt & Plowe, 2007).

An early test of this theory was the combination of chloroquine and pyrimethamine in the

1950s and 1960s (Nyunt & Plowe, 2007). This test failed when resistance evolved in response to

chloroquine and pyrimethamine usage (Nyunt & Plowe, 2007). This combination was also used

in Asia and in Africa, but only led to anti-malarial resistance (Nyunt & Plowe, 2007).

Today’s new approach is to use drugs that have different mechanisms of action (Nyunt &

Plowe, 2007). The mainstay of this theory is artemisinin in ACTs or artemisinin-based

combination therapies (Nyunt & Plowe, 2007). Artemisinins have long been considered to be the

most potent antimalarial drug. Combining different drugs with artemisinin has led to high

efficacy rates, even with antimalarials that were not considered as potent as artemisinin (Van der

Pljim et al, 2021). In this treatment, a large percentage of parasites are eliminated by artemisinin

and the remaining parasites are dealt with by the partner drug (Van der Pljim et al, 2021). As

such, ACTs are considered a significant treatment against Malaria in areas where other drugs

have been compromised by drug resistance (Nyunt & Plowe, 2007).

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Other combination therapies recommended by WHO include artesunate-mefloquine and

artesunate-amodiaquine, among others (Nyunt & Plowe, 2007). However, in these

combinations, sometimes the non-artemisinin based drug has a longer half life and is somewhat

compromised by resistance (Nyunt & Plowe, 2007). This implies that the non-ART partner drug

is at risk of resistance during the time period after treatment, when new parasites can emerge

from the liver (Nyunt & Plowe, 2007). Unfortunately, this means that resistance may still occur

and may be accelerated in regions where anti-malarial drug treatment is common (Nyunt &

Plowe, 2007). To combat this problem, it is highly important to choose ideal partner drugs and to

use them in the correct time frame (Nyunt & Plowe, 2007) .

Phenomenon of older anti-malarial drugs being brought back to fight against Malaria.

The previous discussion has involved different types of chloroquine and artemisinin

resistance, which has reduced the efficacy of these antimalarial drugs in certain regions of the

world. In 1993, physicians in Mawai had to replace chloroquine with pryimethamine and

sulfadoxine due to chloroquine resistance (Laufer et al, 2006). At the time, chloroquine efficacy

had been reduced to less than 50% (Laufer et al, 2006). However, by 2001, chloroquine resistant

falciparum Malaria became undetectable (Laufer et al, 2006). It was hypothesized that

chloroquine could return as an effective anti-malarial drug in Malawi (Laufer et al, 2006).

In the study, a randomized clinical trial was held with 210 individuals that had

uncomplicated Plasmodium falciparum Malaria (Laufer et al, 2006). The individuals were

treated with either chloroquine or sulfadoxine-pyrimethamine to test for antimalarial efficacy of

the drugs (Laufer et al, 2006). The results showed that treatment failure occurred in 1/80 cases

that were assigned to chloroquine (Laufer et al, 2006). In other words, the cumulative efficacy of

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chloroquine had risen to 99% compared with the less than 50% efficacy rate of chloroquine in

1993 (Laufer et al, 2006). In comparison, sulfadoxine-pyrimethamine treatment had failed in

71/87 cases (Laufer et al, 2006). The cumulative efficacy of sulfadoxine-pyrimethamine was

21% (Laufer et al, 2006).

It was previously suggested that reduction of chloroquine useage could result in the

return of a chloroquine-sensitive P. falciparum parasite. This was hypothesized to be due to a

mutation in the PfCRT gene that confers chloroquine resistance but also comes at the expense of

a fitness cost to the parasite. Specifically, chloroquine resistance could be linked to defective

hemoglobin catabolism, which could eventually eliminate or reduce the presence of the

chloroquine-resistant parasite in the absence of drug pressure (Lewis et al, 2014).

The point mutation in the PfCRT gene is associated with chloroquine-resistant falciparum

Malaria (Laufer et al, 2006). This marker was measured before and after reducing the use of

chloroquine. Results showed that from 1992-2000 the marker for PfCRT decreased as the use of

chloroquine was reduced (Laufer et al, 2006). In 2001, the marker was not seen. This is in

contrast to countries that still use chloroquine and have infections where more than 90% of the P.

falciparum infections are due to chloroquine-resistant parasites (Laufer et al, 2006). This

strongly suggests that chloroquine can and should be used again as an effective anti-malarial in

the Malawi region and this method can possibly be used in other locations to help reduce

drug-resistant malaria.

Conclusion:

Over the centuries, Malaria and humanity have had an interesting and colorful

relationship. Artemisinin and chloroquine are antimalarial drugs that have been developed in

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response to malarial pressure. Antimalarial resistance has developed in both drugs, which poses

problems for preventing and treating antimalarial resistance. As such, ACT’s or artemisinin

based combination therapies have been used to offset antimalarial resistance. Additionally, it

may be possible to reuse chloroquine or other antimalarials in areas where there was previous

antimalarial resistance to the drug that has been eliminated.

However, new therapies will still be needed to treat Malaria in the future. The new

frontier of antimalarial treatment may be rooted in gene therapy through the concept of drug

targeting of single lethal pairs for drug resistant malaria (Lee et al, 2013). If tangible, it may be

possible to eliminate Plasmodium cells while also protecting human cells against elimination

(Lee et al, 2013), In the future, this type of treatment may lead to the reduction of unpleasant

symptoms for patients as well as the possible future elimination of Malaria.

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