002 Chemotherapy of Malaria

“Corso di Laurea in Medicina e Chirurgia”
Insegnamento di Farmacologia 1 – IV anno – Programma di Chemioterapia AA 2019-2020

Luca.Pani@unimore.it @Luca__Pani
1. General Principles of Antimicrobial Therapy

2. Chemotherapy of Malaria
3. Chemotherapy of Protozoal Infections: Amebiasis, Giardiasis, Trichomoniasis, Trypanosomiasis, Leishmaniasis, and
Other Protozoal Infections
4. Chemotherapy of Helminth Infections
5. Sulfonamides, Trimethoprim-Sulfamethoxazole, Quinolones, and Agents for Urinary Tract Infections
6. Penicillins, Cephalosporins, and Other β-Lactam Antibiotics
7. Aminoglycosides
8. Protein Synthesis Inhibitors and Miscellaneous Antibacterial Agents
9. Chemotherapy of Tuberculosis, Mycobacterium avium Complex Disease, and Leprosy
10. Antifungal Agents
11. Antiviral Agents (Nonretroviral)
12. Treatment of Viral Hepatitis (HBV/HCV)
13. Antiretroviral Agents and Treatment of HIV Infection
“Corso di Laurea in Medicina e Chirurgia”
Insegnamento di Farmacologia 1 – IV anno – Lecture 002
AA 2019-2020
Chemotherapy of Malaria
Luca Pani, MD
Professor of Pharmacology and Clinical Pharmacology - University of Modena and Reggio Emilia, Modena, Italy
Professor of Clinical Psychiatry – Univ. of Miami – Miami, USA
Former CHMP, SAWP Member, European Medicine Agency (EMA), London – UK
Former Director General, Italian Medicines Agency (AIFA), Rome – IT
Luca.Pani@unimore.it @Luca__Pani
Disclaimer and Disclosure
The opinions expressed in this presentation are my personal views and may not be understood or quoted as
being made on behalf of or reflecting the position of any of the Institutions or Companies for which I have
worked or I collaborate with.
The mention of commercial products, their sources, or their use in connection with material reported herein is
not to be constructed as either an actual or implied endorsement of such products to any Public Department
or Health and/or Payer Services.
Apart from my Academic roles, I am the VP for Regulatory Strategy and Market Access Innovation for
VeraSci, USA, Chief Scientific Officer of EDRA-LSWR Publishing Company, Italy and of Inpeco SA Total Lab
Automation Company, Switzerland.
I do not bear any direct or indirect financial interest in products quoted in this talk.
These slides are both original or have been modified from presentations/videos from The Pharmacotherapy
of Malaria by Joseph M. Vinetz in Goodman & Gilman's: The Pharmacological Basis of Therapeutics, XIII Ed.;
2017, Copyright ©2019 McGraw-Hill Education. All rights reserved (Edizione Italiana, Zanichelli Editore, 2019)
This presentation is updated to October 12th, 2019.
Remember few general but
important principles
Inhibitory sigmoid Changes in sigmoid Emax model with
Emax curve. increases in drug resistance.
An increase in resistance may show changes in IC50: In A, the IC50 increases from 70 (orange line) to 100 (green line)
to 140 (blue line). An increase in resistance may also show a decrease in Emax: In B, efficacy decreases from full
response (orange line) to 70% (green line).
Diagrammatic depiction of a multicompartment model.
Ka, absorption constant; Vc, central compartment volume; VL, volume of lung compartment;
Vp, peripheral compartment volume.
Antimicrobial therapy–disease progression timeline.
Effect of different dose schedules on shape of the concentration-time curve. The same total dose of a drug was administered as a single dose
(panel A) and in three equal portions every 8 h (panel B). The total AUC for the fractionated dose in B is determined by adding AUC0–8h,
AUC8–16h, and AUC16–24h, which totals to the same AUC0–24h in A. The time that the drug concentration exceeds MIC in B is also determined
by adding T1 > MIC, T2 > MIC, and T3 > MIC, which results in a fraction greater than that for A.
Abbreviations
ACT: artemisinin-based combination therapy 5HT: serotonin
AV: atrioventricular IND: investigational new drug (application)
CDC: Centers for Disease Control and Prevention pfCRT: Plasmodium falciparum chloroquine
CNS: central nervous system resistance transporter
CSA: chondroitin sulfate A pfMRP: Plasmodium facliparum multidrug
CSF: cerebrospinal fluid resistance-associated protein
cytbc1: cytochrome bc1
DEET: N, N′-diethylmetatoluamide
ECG: electrocardiogram
FDA: Food and Drug Administration
GI: gastrointestinal
G6PD: glucose-6-phosphate dehydrogenase
The Global Impact of Malaria
Malaria remains among the top five causes of death among
children younger than 5 years, affects about a quarter of a
billion people, and causes almost 900,000 deaths annually
(GBD_2013_Collaborators, 2015). Malarial transmission
occurs in regions of Africa, Latin and South America, Asia, the
Middle East, the South Pacific, and the Caribbean. This
disease is caused by infection with protozoan parasites of the
genus Plasmodium. Five Plasmodium spp. are known to
infect humans: P. falciparum, P. vivax, P. ovale, P. malariae,
and P. knowlesi. Plasmodium falciparum and P. vivax cause
most malarial infections worldwide. Plasmodium falciparum
accounts for the majority of the burden of malaria in sub-
Saharan Africa and is associated with the most severe
disease. Plasmodium vivax accounts for half of the malaria
burden in South and East Asia and more than 80% of the
malarial infections in the Americas and has been
underappreciated as a cause of severe malaria (Baird, 2013).
The Global Impact of Malaria (Eastern Hemisphere)
The Global Impact of Malaria (Western Hemisphere)
Over the past half-century, malaria parasites
worldwide—primarily P. falciparum and P. vivax—have
become increasingly resistant to antimalarial drugs,
including chloroquine (Djimde et al., 2001; Warhurst,
2001); mefloquine (White et al., 2014); quinine (White et
al., 2014); sulfadoxine/pyrimethamine (Artimovich
et al., 2015; Plowe et al., 1995, Sibley et al., 2001); and
atovaquone (Garcia-Bustos et al., 2013; Kessl et al.,
2007).
In response, new, multiprong international public-
private partnerships as well as other funding agencies
and sources have emerged to create new pipelines that
advance drug candidates from discovery to clinical
development (Hemingway et al., 2016; Wells et al., 2010,
2015).
Malaria Life Cycle Animation: Human Host
Biology of Malaria Infection
Malarial infection is initiated when a female
anopheline mosquito injects Plasmodium
sporozoites during a blood meal (Miller et al., 1998).
After entering the dermis, sporozoites enter the
bloodstream and, within minutes, arrive at the
liver, where they infect individual hepatocytes via
cell surface receptor-mediated events (Sinnis et al.,
2013).
This process initiates the asymptomatic prepatent
period, or exoerythrocytic stage of infection, which
typically lasts about 1 week. (%)
During this period, the parasite undergoes asexual replication
within hepatocytes, resulting in production of liver-stage
schizonts.
When an infected hepatocyte ruptures, tens of thousands of
merozoites are released into the bloodstream and infect red
blood cells.
After the initial exoerythrocytic stage, P. falciparum and P.
malariae are no longer found in the liver.
Plasmodium vivax and P. ovale, however, can maintain a
quiescent hepatocyte infection as a dormant form of the parasite
known as the hypnozoite and can reinitiate symptomatic disease
long after the initial symptoms of malaria are recognized and
treated.
Erythrocytic forms cannot reestablish infection of hepatocytes. %
Transmission of human-infecting malarial parasites is
maintained in human populations by the persistence
of hypnozoites (several months to a few years for P.
vivax and P. ovale), by antigenic variation in P.
falciparum (probably months), and by the putative
antigen variation in P. malariae (for as long as several
decades).
The asexual erythrocytic stages of malarial parasites

are responsible for the clinical manifestations of
malaria. This part of the Plasmodium life cycle is
initiated by merozoite recognition of red blood cells
and mediated by cell surface receptors that facilitate
invasion of red blood cells. %
Once inside a red blood cell, the merozoite develops into a ring
form, which becomes a hemoglobin-metabolizing trophozoite
(feeding stage) that matures into an asexually dividing blood-
stage schizont.
Schizont rupture at the end of the growth-and-division cycle
releases 8–32 merozoites that invade new red blood cells. The
erythrocytic replication cycle lasts for 24 h (for P. knowlesi), 48 h
(for P. falciparum, P. vivax, and P. ovale), and 72 h (for P.
malariae).
Although most invading merozoites develop into schizonts, a
small proportion becomes gametocytes, the form of the parasite
infective to mosquitoes. Gametocytes are ingested by the
mosquito during an infectious blood meal; on reaching the
midgut of the mosquito, the gametocytes transform into gametes
that fertilize to become zygotes %
Zygotes mature into ookinetes that invade the mosquito midgut wall
and transform into oocysts.
Numerous rounds of asexual replication occur in the oocyst to
generate sporozoites over 10–14 days.
Fully developed sporozoites rupture from oocysts and invade the
mosquito salivary glands, from which they can initiate a new infection
during subsequent mosquito blood meals.
Thus, the infection cycles from mosquito to human to mosquito. %
Malaria Life Cycle Animation: Mosquito Host
Plasmodium falciparum has a family of binding proteins that recognize
a variety of host cell molecules that this parasite species uses to invade
all stages of erythrocytes (Lim et al., 2015; Weiss et al., 2016); high
parasitemia may result from this mechanism.
In contrast, P. vivax selectively binds to the Duffy chemokine receptor
protein as well as reticulocyte-specific proteins (Chitnis et al., 2008;
Paul et al., 2015).
Plasmodium falciparum assembles cytoadherence proteins (e.g.,
PfEMP1) (Weiss et al., 2016), encoded by a highly variable family of var
genes into structures called knobs that are presented on the
erythrocyte surface (Hviid et al., 2015; Ukaegbu et al., 2015). Knobs
allow the P. falciparum–parasitized erythrocyte to bind to postcapillary
vascular endothelium to avoid spleen-mediated clearance and allow
the parasite to grow in a low-O2, high-CO2 microenvironment. %
Clinical Manifestation of Malaria Infection
The cardinal signs and symptoms of malaria are high, spiking fevers
(with or without periodicity), chills, headaches, myalgias, malaise, and
GI symptoms (White et al., 2014). Severe headache, a characteristic
early symptom in malaria caused by all Plasmodium spp., often heralds
the onset of disease, even before fever and chills. Plasmodium
falciparum causes the most severe disease and may lead to organ
failure and death. Placental malaria, of particular danger for
primigravidae, is due to P. falciparum adherence to CSA in the
placenta. This often leads to severe complications, including
miscarriage. When treated early, symptoms of malarial infection
usually improve within 24–48 h. New insights into malaria clinical
presentations indicate that—in the endemic setting where
nonsterilizing clinical immunity is the rule, not the exception—the
cardinal symptoms of malaria may be atypical or absent (Chen et al.,
2016).. %
Acute illness due to P. vivax infection may appear severe
due to high fever and prostration. Indeed, the pyrogenic
threshold of this parasite is lower than that of P. falciparum.
Nonetheless, P. vivax malaria generally has a low mortality
rate. Plasmodium vivax malaria is characterized by relapses
caused by the reactivation of latent tissue forms. Clinical
manifestations of relapse are the same as those of primary
infection. In recent years, severe P. vivax malaria from
Oceania and India possess important similarities to severe
malaria caused by P. falciparum. These include
neurological symptoms (diminished consciousness,
seizure) and pulmonary edema. Rare but life-threatening
complications can occur, including splenic rupture, acute
lung injury, and profound anemia. Other Plasmodium have
a slight different clinic (not covered here) %
Asymptomatic P. falciparum and P. vivax infections are
common in endemic regions and represent important
potential reservoirs for malaria transmission. Although
different studies are not entirely consistent in the definition
of asymptomatic, generally this state implies a lack of fever,
headache, and other systemic complaints, within a defined
time period prior to a positive test for malaria parasitemia.
Migration of asymptomatic individuals to areas where
malaria is not present but vector mosquitoes are is an
important mechanism for the introduction or reintroduction
of malaria, in addition to facilitating the spread of drug-
resistant isolates. Novel approaches to preventing
transmission from asymptomatic reservoirs—whether
through new drugs or vaccines—will be essential for future
malaria control, elimination, and eradication strategies.%
Classification of Antimalaria Agents
The various stages of the malarial

parasite life cycle in humans differ in
their drug sensitivity.
Thus, antimalarial drugs can be

classified based on their activities
during this life cycle as well as by their
intended use for either
chemoprophylaxis or treatment.
The spectrum of antimalarial drug

activity leads to several generalizations.
1) The first relates to chemoprophylaxis: Because no
antimalarial drug kills sporozoites, it is not truly possible
to prevent infection; drugs can only prevent the
development of symptomatic malaria caused by the
asexual erythrocytic forms, either in the bloodstream or
as produced within and released by hepatocytes prior to
erythrocyte invasion.
2) The second relates to the treatment of an established
infection: No single antimalarial is effective against all
hepatic and intraerythrocytic stages of the life cycle that
may coexist in the same patient. Complete elimination of
the parasite infection, therefore, may require more than
one drug.
The patterns of clinically useful antimalarial agents fall into three general categories:
1. Agents (artemisinins, chloroquine, mefloquine, quinine and quinidine, pyrimethamine, sulfadoxine, and
tetracycline) that are not reliably effective against primary or latent liver stages. Instead, their action is
directed against the asexual blood stages responsible for disease. These drugs will treat, or prevent,
clinically symptomatic malaria.
2. Drugs (typified by atovaquone and proguanil) that target not only the asexual erythrocytic forms but also
the primary liver stages of P. falciparum. This additional activity shortens to several days the required
period for postexposure chemoprophylaxis.
3. Primaquine, an eight-amino quinoline that is effective against primary and latent liver stages as well as
gametocytes. Primaquine is used most commonly to eradicate the intrahepatic hypnozoites of P. vivax and
P. ovale that are responsible for relapsing infections. Tafenoquine, an eight-amino quinolone, is a long half-
life analogue of primaquine, has a similar spectrum of action as primaquine, and is in advanced clinical
trials (Llanos-Cuentas et al., 2014).
Susceptibilty to Drugs of Malarial Parasites at Various
Developmental Stages
Aside from their antiparasitic activity, the utility
of antimalarials for chemoprophylaxis or therapy
depends on their pharmacokinetics and safety.
Quinine and primaquine, which have significant
toxicity and relatively short half-lives, generally
are reserved for the treatment of established
infection and are not used for chemoprophylaxis
in a healthy traveler.
By contrast, chloroquine, which is relatively free
from toxicity and has a long t1/2, is convenient
for chemoprophylactic dosing (in those few
areas still reporting chloroquine-sensitive
malaria).
Specific Antimalaria Agents (in alphabetical order)
Artemisinin and its three major semisynthetic derivatives in
clinical use, dihydroartemisinin, artemether, and
artesunate, are potent and fast-acting antimalarials. They
are optimized for the treatment of severe P. falciparum
malaria and are also effective against the asexual
erythrocytic stages of P. vivax. Increasingly, the standard
treatment of malaria employs artemisinin-based
combination therapies (ACTs) to increase treatment efficacy
and reduce selection pressure for the emergence of drug
resistance. Recent reports of P. falciparum artemisinin
“resistance” do not indicate true resistance but reflect
delayed parasite clearance time on the order of hours. True
resistance to artemisinin has not been reported, and no
infection from this parasite has been reported to survive
ACT
Artemisinin (also known as Qinghaosu) is the active compound responsible for
antimalarial activities of the wormwood plant Artemisia annua. This
compound was identified through a largescale research effort initiated in
China during the 1960s to discover new antimalarial drugs; the plant was
already known for the treatment of ‘intermittent fevers’ from a Chinese
medical textbook dated 340 A.D. By 1975, the molecular formula of
artemisinin and its chemical structure was known, and in 1979 it was reported
that several thousand malaria cases, including chloroquine-resistant cases,
had been successfully treated in China using different artemisinin
formulations. Chemically, artemisinin is a sesquiterpene lactone with a
peroxide bond, that is required for the antimalarial effect of artemisinin and
synthetic or semi-synthetic derivates. The production of artemisinin, which is
necessary to obtain its derivates, currently relies on plant extraction and
suffers from availability shortage and price instability. Consequently, efforts
are being made to enhance plant yields and to develop alternative profitable
production methods, such as microbial biotechnologies or full synthesis of
peroxide-containing molecules active against Plasmodium spp.
Schematic view of postulated artemisinins’ modes of
action and resistance factors in P. falciparum. Iron, in the
context of a heme molecule or not, is believed to interact
with the peroxide bond of artemisinins (ART), ultimately
resulting in active carbon centered radicals. Activated ART
within the mitochondria might induce the membrane
depolarization of this organelle, through the production of
reactive oxygen species (ROS). Proteins, in which
mutations (red dots) have been shown to increase (arrow)
or to decrease (inhibition line) in vitro sensitivity to ART,
are indicated. These are PfATPase6, the digestive vacuole
transporters PfMDR1 and PfCRT, the deubiquitinating
enzyme UBP-1, and the putative apicoplast transporter G7.
Additionally, a quiescence mechanism has recently been
proposed to mediate resistance to ART. Putative targets or
target mechanisms are labeled in orange and putative
resistance factors in yellow.
The electron transport chain (ETC) of mitochondria has also
been involved in the bioactivation of artemisinins.
Hemoglobin (Hb) catabolism within the digestive vacuole
produces heme molecules, which need to be assembled as
inert haemozoin. Activated artemisinins might interfere with
this process or react with various proteins within the digestive
vacuole, including PfTCTP. Inactivation of the endoplasmic
reticulum (ER) PfATPase6 calcium pump, through direct
interaction with ART, has also been proposed, as well as
alkylation of various parasite proteins in the parasite
cytoplasm. Artemisinins cause a significant reduction of the
parasite burden, with a 4-log10 reduction in the parasite
population for each 48-h cycle of intraerythrocytic invasion,
replication, and regress. Only three to four cycles (6–8 days) of
treatment are required to remove all the parasites from the
blood. In addition, artemisinins possess some
gametocytocidal activity, leading to a decrease in malarial
parasite transmission.
The clinical significance of P. falciparum artemisinin
“resistance/delayed clearance” remains unclear
(Fairhurst, 2015), but this mutation potential could
threaten the future utility of this drug class.
Moreover, in the presence of mutations that confer
resistance to partner drugs (e.g., the ACT partner drug
piperaquine), clinically significant ACT failure is
substantial, with recrudescence rates reported to
exceed 50% (Amaratunga et al., 2016; Spring et al.,
2015).
Resistance of non–P. falciparum malaria parasites to
artemisinin class drugs has not been reported.
ADME
The semisynthetic artemisinins have been formulated for oral
(dihydroartemisinin, artesunate, and artemether); intramuscular
(artesunate and artemether); intravenous (artesunate); and
rectal (artesunate) routes. Bioavailability after oral dosing
typically is 30% or less. Peak serum levels occur rapidly with
artemisinins and in 2–6 h with intramuscular artemether. Both
artesunate and artemether have modest levels of plasma
protein binding, ranging from 43% to 82%. These derivatives are
extensively metabolized and converted to dihydroartemisinin,
which has a plasma t1/2 of 1–2 h. Drug bioavailability via rectal
administration is highly variable among individual patients. With
repeated dosing, artemisinin and artesunate induce their own
CYP-mediated metabolism, primarily via CYPs 2B6 and 3A4,
which may enhance clearance by as much as 5-fold.
Therapeutic Uses
Given their rapid and potent activity against
even multidrug-resistant parasites, the
artemisinins are valuable for the treatment of
severe P. falciparum malaria.
The artemisinins generally are not used alone
because of their limited ability to eradicate
infection completely.
Artemisinins are highly effective for the first-
line treatment of malaria when combined
with other antimalarials.
Artemisinins should not be used for
chemoprophylaxis because of their short t1/2
values.
Toxicity and Contraindications
In pregnant rats and rabbits, artemisinins can cause
increased embryo lethality or malformations early
postconception. Preclinical toxicity studies have identified
the brain (and brainstem), liver, and bone marrow as the
principal target organs. However, no systematic neurological
changes have been attributed to treatment in patients 5 years
of age or older. Patients may develop dose-related and
reversible decreases in reticulocyte and neutrophil counts
and increases in transaminase levels. About 1 in 3000 patients
develops an allergic reaction. Although studies of artemisinin
treatment during the first trimester have found no evidence of
adverse effects on fetal development, it is recommended that
ACTs not be used during the first trimester of pregnancy or for
the treatment of children 5 kg or less.
ACT Partner Drugs
Partner drugs for ACT are chosen for potency and t1/2
that substantially exceeds that of the artemisinin
partner.
The primary ACT regimens that are well tolerated in
adults and children 5 kg or more are artemether-
lumefantrine, artesunate-amodiaquine, and
dihydroartemisinin-piperaquine.
In the U.S., artemether-lumefantrine is probably the
drug of choice for all malaria cases if oral drug
treatment is appropriate.
Pyronaridine remains in clinical trials and is not
licensed.
Atovaquone
A fixed combination of atovaquone with proguanil
hydrochloride is available in the U.S. for malaria
chemoprophylaxis and for the treatment of
uncomplicated P. falciparum malaria in adults and
children.
Atovaquone is a lipophilic analogue of ubiquinone
(coenzyme Q), the electron acceptor for the
parasite’s cytbc1 complex. Cytbc1, situated on the
inner mitochondrial membrane, supplies oxidized
ubiquinone for dihydroorotate dehydrogenase, an
essential enzyme in pyrimidine biosynthesis in the
parasite.
Atovaquone
The selective toxicity of atovaquone for the
Plasmodium genus and not the human host may
stem from structural differences in the amino
terminal regions of plasmodial and human
cytochrome b (Capper et al., 2015).
The drug is highly active against P. falciparum
asexual blood-stage parasites and the liver stages
of P. falciparum, but not against P. vivax liver-
stage hypnozoites.
Synergy between proguanil and atovaquone
results from the ability of nonmetabolized
proguanil to enhance the mitochondrial toxicity of
atovaquone.
Atovaquone
Resistance to atovaquone alone in P.
falciparum develops easily and is conferred
by single, nonsynonymous nucleotide
polymorphisms in the cytochrome b gene
located in the mitochondrial genome.
Addition of proguanil markedly reduces the
frequency of appearance of atovaquone
resistance.
However, once atovaquone resistance is
present, the synergy of the partner drug
proguanil diminishes.
Atovaquone
The drug is highly active against P. falciparum asexual
blood-stage parasites and the liver stages of P. falciparum,
but not against P. vivax liver-stage hypnozoites.
Synergy between proguanil and atovaquone results from
the ability of nonmetabolized proguanil to enhance the
mitochondrial toxicity of atovaquone.
Resistance to atovaquone alone in P. falciparum develops
easily and is conferred by single, nonsynonymous
nucleotide polymorphisms in the cytochrome b gene
located in the mitochondrial genome. Addition of proguanil
markedly reduces the frequency of appearance of
atovaquone resistance. However, once atovaquone
resistance is present, the synergy of the partner drug
proguanil diminishes.
Atovaquone ADME
Atovaquone absorption is slow and variable after an oral
dose; absorption improves when the drug is taken with a
fatty meal.
More than 99% of the drug is bound to plasma protein; CSF
levels are less than 1% of those in plasma. Profiles of drug
concentration versus time often show a double peak, the first
at 1–8 h, the second 1–4 days after a single dose; this pattern
suggests enterohepatic circulation. Humans do not
metabolize atovaquone significantly.
The drug is excreted in bile, and more than 94% of the drug is Atovaquone plasma concentration–time profile
recovered unchanged in feces. Atovaquone has a reported after a single dose in 13 healthy individuals.
elimination t1/2 from plasma of 2–3 days in adults and 1–2
days in children.
Atovaquone Therapeutic Uses
A tablet containing a fixed dose of 250 mg atovaquone
and 100 mg proguanil hydrochloride, taken orally, is
highly effective and safe in a 3-day regimen for
treating mild-to-moderate attacks of chloroquine- or
sulfadoxine-pyrimethamine–resistant P. falciparum
malaria. The same regimen followed by a primaquine
course is effective in treatment of P. vivax malaria.
Atovaquone-proguanil is a standard agent for malaria
chemoprophylaxis. Experience in prevention of non–
P. falciparum malaria is limited. Plasmodium vivax
infection may occur after drug discontinuation,
indicating imperfect activity against exoerythrocytic
stages of this parasite.
Atovaquone Toxicity
Atovaquone may cause side effects (abdominal pain,
nausea, vomiting, diarrhea, headache, rash) that
require cessation of therapy.
Vomiting and diarrhea may decrease drug absorption,
resulting in therapeutic failure.
However, re-administration of this drug within an
hour of vomiting may still be effective in patients with
P. falciparum malaria.
Atovaquone occasionally causes transient elevations
of serum transaminase or amylase.
Atovaquone Precautions and Contraindications
Although atovaquone is generally considered to be

safe, it needs further evaluation in children weighing
less than 11 kg, pregnant women, and lactating
mothers.
Atovaquone may compete with certain drugs for
binding to plasma proteins. Therapy with rifampin
reduces plasma levels of atovaquone substantially;
the mechanism of this effect is not clear.
Coadministration with tetracycline is associated with
a 40% reduction in plasma concentration of
atovaquone.
Proguanil
The antimalarial activity of proguanil (chloroguanide) is ascribed
to cycloguanil, a cyclic triazine metabolite (structurally related to
pyrimethamine) and selective inhibitor of the bifunctional
plasmodial dihydrofolate reductase–thymidylate synthetase that
is crucial for parasite de novo purine and pyrimidine synthesis.
Antimalarial Action and Resistance
In drug-sensitive P. falciparum malaria, proguanil exerts activity
against both the primary liver stages and the asexual red blood
cell stages, thus adequately controlling the acute attack and
usually eradicating the infection. Proguanil is also active against
acute P. vivax malaria, but because the latent tissue stages of P.
vivax are unaffected, relapses may occur after the drug is
withdrawn.
Proguanil
Proguanil treatment does not destroy gametocytes, but oocytes
in the gut of the mosquito can fail to develop normally.
Cycloguanil selectively inhibits the bifunctional dihydrofolate
reductase–thymidylate synthetase of sensitive plasmodia,
causing inhibition of DNA synthesis and depletion of folate
cofactors. A series of amino acid changes near the dihydrofolate
reductase–binding site have been identified that cause
resistance to cycloguanil, pyrimethamine, or both. The presence
of Plasmodium dihydrofolate reductase is not required for the
intrinsic antimalarial activity of proguanil or chlorproguanil;
however, the molecular basis for this alternative activity is
unknown. In contrast to cycloguanil, resistance to the parent
drug, proguanil, either alone or in combination with atovaquone,
is not well documented.
Proguanil ADME
Proguanil is slowly but adequately absorbed from the GI tract. After a
single oral dose, peak plasma concentrations are attained within 5 h.
The mean plasma elimination t1/2 is about 180–200 h or longer. The
drug’s activation and metabolism involve the CYP2C subfamily; about
3% of whites are deficient in this oxidation phenotype, contrasted with
about 20% of Asians and Kenyans. Proguanil is oxidized to two major
metabolites, the active cycloguanil and an inactive 4-chlorophenyl
biguanide. On a daily dosage regimen of 200 mg-daily, plasma levels of
cycloguanil in extensive metabolizers exceed the therapeutic range,
whereas cycloguanil levels in poor metabolizers do not. Proguanil
itself does not accumulate appreciably in tissues during long-term
administration, except in red blood cells, where its concentration is
about three times that in plasma. In humans, 40%–60% of the
absorbed proguanil is excreted in urine, either as the parent drug or as
the active metabolite.
Proguanil Therapeutic Uses
Proguanil as a single agent is not available in the U.S. but has
been prescribed as chemoprophylaxis in England and Europe for
individuals traveling to malarious areas in Africa.
Strains of P. falciparum resistant to proguanil emerge rapidly in
areas where the drug is used exclusively, but breakthrough
infections may also result from deficient conversion of proguanil
to its active antimalarial metabolite.
Proguanil is effective and tolerated well in combination with
atovaquone, once daily for 3 days, to treat drug-resistant strains
of P. falciparum or P. vivax (see section on atovaquone). P.
falciparum readily develops clinical resistance to monotherapy
with either proguanil or atovaquone; however, resistance to the
combination is uncommon unless the strain is initially resistant
to atovaquone.
Proguanil Toxicity and Side Effects
In chemoprophylactic doses of 200–300 mg daily, proguanil
causes relatively few adverse effects, except occasional nausea
and diarrhea.
Large doses (≥1 g daily) may cause vomiting, abdominal pain,
diarrhea, hematuria, and the transient appearance of epithelial
cells and casts in the urine.
Doses as high as 700 mg twice daily have been taken for more
than 2 weeks without serious toxicity.
Proguanil is safe for use during pregnancy.
It is remarkably safe when used in conjunction with other
antimalarial drugs.
Quinoline and Related Compounds

Quinine is the chief alkaloid of cinchona, the powdered bark of
the South American cinchona tree.
Quinine and its many derivatives have been the mainstay of
malarial treatment for four centuries.
Structure-activity analysis of the cinchona alkaloids provided
the basis for the discovery of more recent antimalarials, such
as mefloquine.
Asexual malarial parasites flourish in host erythrocytes by
digesting hemoglobin; this generates free radicals and iron-
bound heme as highly reactive byproducts.
Chloroquine ADME
Chloroquine is well absorbed from the GI tract and rapidly
from intramuscular and subcutaneous sites. This drug
extensively sequesters in tissues, particularly liver, spleen,
kidney, lung, and, to a lesser extent, brain and spinal cord.
Chloroquine binds moderately (60%) to plasma proteins. The
actions of hepatic CYPs produce two active metabolites,
desethylchloroquine and bisdesethylchloroquine. Renal
clearance of chloroquine is about half of its total systemic
clearance.
Unchanged chloroquine and desethylchloroquine account for
more than 50% and 25% of the urinary drug products,
respectively, and their renal excretion is increased by urine
acidification.
Chloroquine ADME
To avoid potentially lethal toxicity, parenteral
chloroquine is given either slowly by constant intravenous
infusion or in small divided doses by the subcutaneous or
intramuscular route.
Chloroquine is safer when given orally because the rates
of absorption and distribution are more closely matched.
Peak plasma levels are achieved in about 3–5 h.
The t1/2 of chloroquine increases from a few days to weeks
as plasma levels decline. The terminal t1/2 ranges from 30
to 60 days, and traces of the drug can be found in the
urine for years after a therapeutic regimen.
Chloroquine Therapeutic Uses
Chloroquine is highly effective against the erythrocytic
forms of P. vivax, P. ovale, P. malariae, P. knowlesi, and
chloroquine-sensitive strains of P. falciparum. For
infections caused by P. ovale and P. malariae, it remains
the agent of choice for chemoprophylaxis and treatment.
For P. falciparum, ACTs have largely replaced chloroquine.
The utility of chloroquine has declined across most
malaria-endemic regions of the world because of the
spread of chloroquine-resistant P. falciparum. Except in
areas where resistant strains of P. vivax are reported,
chloroquine is effective in chemoprophylaxis or treatment
of acute attacks of malaria caused by P. vivax, P. ovale, and
P. malariae.
Chloroquine Toxicity and Side Effects Sudden cardiac arrest in a patient
Taken in proper doses and for recommended total taking chloroquine
durations, chloroquine is safe, but its safety margin
is narrow; a single dose of 30 mg/kg may be fatal.
Acute chloroquine toxicity is encountered most
frequently when therapeutic or high doses are
administered too rapidly by parenteral routes.
Cardiovascular effects include hypotension,
vasodilation, suppressed myocardial function,
cardiac arrhythmias, and eventual cardiac arrest.
Confusion, convulsions, and coma may also result
from overdose. Chloroquine doses of more than 5 g
given parenterally usually are fatal. Prompt The ECG after initial resuscitation. It shows complete AV block with
treatment with mechanical ventilation, a left bundle-branch block QRS morphology escape rhythm and
the QTc interval is 0.696 ms.
epinephrine, and diazepam may be lifesaving.
Chloroquine Toxicity and Side Effects
Doses of chloroquine used for oral therapy of the
acute malarial attack may cause GI upset, headache,
visual disturbances, and urticaria. Pruritus also occurs
most commonly among dark-skinned persons.
Prolonged treatment with suppressive doses
occasionally causes side effects such as headache,
blurring of vision, diplopia, confusion, convulsions,
lichenoid skin eruptions, bleaching of hair, widening
of the QRS interval, and T-wave abnormalities. These
complications usually disappear soon after the drug is
withheld. Rare instances of hemolysis and blood
dyscrasias have been reported. This drug has also
been reported to interfere with the immunogenicity of
certain vaccines.
Chloroquine Toxicity and Side Effects
Irreversible retinopathy and ototoxicity can result from
high daily doses (>250 mg) of chloroquine or
hydroxychloroquine leading to cumulative total doses of
more than 1 g/kg. Retinopathy presumably is related to
drug accumulation in melanin-containing tissues and can
be avoided if the daily dose is 250 mg or less. Prolonged
therapy with high doses of chloroquine or
hydroxychloroquine also can cause toxic myopathy,
cardiopathy, and peripheral neuropathy. These reactions
improve if the drug is withdrawn promptly. Rarely,
neuropsychiatric disturbances, including suicide, may be
related to overdose. The utility of chloroquine has declined
across most malaria-endemic regions of the world because
of the spread of chloroquine-resistant P. falciparum.
Chloroquine Precautions and Contraindications
Chloroquine is not recommended for treating individuals with
epilepsy or myasthenia gravis and should be used cautiously, if
at all, in the presence of advanced liver disease or severe GI,
neurological, or blood disorders.
The dose should be reduced in renal failure. In rare cases,
chloroquine can cause hemolysis in patients with G6PD
deficiency.
Chloroquine should not be prescribed for patients with
psoriasis or other exfoliative skin conditions. It should not be
used to treat malaria in patients with porphyria cutanea tarda;
however, it can be used in lower doses for treatment of
manifestations of this form of porphyria. Chloroquine inhibits
CYP2D6 and thus can interact with a variety of different drugs.
Chloroquine Precautions and Contraindications
It attenuates the efficacy of the yellow fever vaccine when
administered at the same time. It should not be given with
mefloquine because of increased risk of seizures.
Chloroquine opposes the action of anticonvulsants and
increases the risk of ventricular arrhythmias when
coadministered with amiodarone or halofantrine.
By increasing plasma levels of digoxin and cyclosporine,
chloroquine can increase the risk of toxicity from these
agents.
Patients receiving long-term, high-dose therapy should
undergo ophthalmological and neurological evaluations
every 3–6 months
Quinine
Oral quinine is FDA-approved for the treatment of
uncomplicated P. falciparum malaria. Quinidine, a
stereoisomer of quinine, is more potent as an antimalarial
and more toxic than quinine. Quinine acts against asexual
erythrocytic forms and has no significant effect on hepatic
forms of malarial parasites. This drug is more toxic and less
effective than chloroquine against malarial parasites
susceptible to both drugs. Compared to artemisinin class
therapy, quinine produces poorer clinical outcomes.
However, quinine, along with its stereoisomer quinidine, is
especially valuable for the parenteral treatment of severe
illness owing to drug-resistant strains of P. falciparum.
Because of its toxicity and short t1/2, quinine is generally not
used for chemoprophylaxis.
Quinine
The antimalarial mechanism of quinine is presumably
similar to that of chloroquine.
The basis of P. falciparum resistance to quinine is
complex.
Patterns of P. falciparum resistance to quinine correlate
in some strains with resistance to chloroquine yet in
others correlate more closely with resistance to
mefloquine and halofantrine.
A number of transporter genes may confer resistance to
quinine.
Quinine ADME
Quinine is readily absorbed when given orally or
intramuscularly. Oral absorption occurs mainly from the
upper small intestine and is more than 80% complete,
even in patients with marked diarrhea. After an oral dose,
plasma levels reach a maximum in 3–8 h and, after
distributing into an apparent volume of about 1.5 L/kg,
decline with a t1/2 of about 11 h. The pharmacokinetics of
quinine may change with severe malarial infection: The
apparent volume of distribution and the systemic
clearance of quinine decrease, such that the average
elimination t1/2 increases to 18 h. The high levels of
plasma α1-acid glycoprotein produced in severe malaria
may prevent toxicity by binding quinine and thereby
reducing the free fraction of drug. %
Quinine ADME
Concentrations of quinine are lower in erythrocytes
(33%–40%) and CSF (2%–5%) than in plasma, and the
drug readily reaches fetal tissues.
The cinchona alkaloids are metabolized extensively,
especially by hepatic CYP3A4; thus, only about 20% of an
administered dose is excreted in an unaltered form in the
urine.
The major metabolite of quinine, 3-hydroxyquinine,
retains some antimalarial activity and can accumulate
and possibly cause toxicity in patients with renal failure.
Renal excretion of quinine itself is more rapid when the
urine is acidic.
Quinine and Quinidine Therapeutic Uses
Quinine and quinidine have long been treatments of
choice for drug-resistant and severe P. falciparum
malaria. However, the advent of oral and intravenous
artemisinin therapy has changed this situation. Standard
of care for severe illness, and only until artemisinin
therapy can be started, is the prompt use of loading
doses of intravenous quinine (or quinidine, where
intravenous quinine is not available) can be lifesaving.
Oral medication to maintain therapeutic concentrations
is then given as soon as tolerated and is continued for 5–7
days. Especially for treatment of infections with
multidrug-resistant strains of P. falciparum, slower-acting
blood schizonticides such as tetracyclines or clindamycin
are given concurrently to enhance quinine efficacy.
Quinine and Quinidine Therapeutic Uses
Different formulation of Quinine and Quinidine exist. The
therapeutic range for “free” quinine is 0.2 and 2.0 mg/L.
Regimens needed to achieve this target vary based on
patient age, severity of illness, and the responsiveness of
P. falciparum to the drug.
Dosage regimens for quinidine are similar to those for
quinine, although quinidine binds less to plasma proteins
and has a larger apparent volume of distribution, greater
systemic clearance, and shorter terminal elimination t1/2
than quinine.
The CDC recommends a dose of quinidine of 10 mg
salt/kg initially, followed by 0.02 mg salt/kg/min.
Quinine and Quinidine Toxicity and Side Effects
The fatal oral dose of quinine for adults is about 2–8 g.
Quinine is associated with a triad of dose-related toxicities
when given at full therapeutic or excessive doses:
cinchonism, hypoglycemia, and hypotension.
Mild forms of cinchonism (consisting of tinnitus, high-tone
deafness, visual disturbances, headache, dysphoria,
nausea, vomiting, and postural hypotension) occur
Many Civil War commanders required that their soldiers take
frequently and disappear soon after the drug is withdrawn. quinine prophylactically. A woodcut from the March 11,
1865, Harper’s Weekly shows quinine rations being distributed
Hypoglycemia is also common and can be life threatening if to Union troops.
Science History Institute
not treated promptly with intravenous glucose.
Hypotension is rare and most often is associated with
excessively rapid intravenous infusions of quinine or
quinidine.
Prolonged medication or high single doses also may
produce GI, cardiovascular, and skin manifestations. GI
symptoms (nausea, vomiting, abdominal pain, and
diarrhea) result from the local irritant action of quinine,
but the nausea and emesis also have a central basis.
Cutaneous manifestations may include flushing,
sweating, rash, and angioedema, especially of the face.
Quinine and quinidine, even at therapeutic doses, may
cause hyperinsulinemia and severe hypoglycemia
through their powerful stimulatory effect on pancreatic
beta cells. Quinine rarely causes cardiac complications
unless therapeutic plasma concentrations are exceeded.
QTc prolongation is mild and does not appear to be
affected by concurrent mefloquine treatment.
Acute overdosage also may cause serious and even fatal
cardiac dysrhythmias, such as sinus arrest, junctional
rhythms, atrioventricular block, and ventricular
tachycardia and fibrillation. Quinidine is even more
cardiotoxic than quinine. Cardiac monitoring of patients
on intravenous quinidine is advisable where possible.
Severe hemolysis can result from hypersensitivity to
these cinchona alkaloids. Hemoglobinuria and asthma
from quinine may occur more rarely. “Blackwater fever”—
the triad of massive hemolysis, hemoglobinemia, and
hemoglobinuria leading to anuria, renal failure, and in
some instances death—is a rare hypersensitivity reaction
to quinine therapy that can occur during treatment of
malaria.
Quinine occasionally may cause milder hemolysis,
especially in people with G6PD deficiency. Thrombotic
thrombocytopenic purpura also is rare but can occur
even in response to ingestion of tonic water, which has
about 4% the therapeutic oral dose per 12 oz (“cocktail
purpura”). Other rare adverse effects include
hypoprothrombinemia, leukopenia, and agranulocytosis.
Research in model systems indicated that quinine can
inhibit a number of transport proteins, including Tat2p,
which transports tryptophan, the precursor of 5HT.
Quinine also competitively inhibits the rate-limiting step
in 5HT biosynthesis, tryptophan hydroxylase. Whether
these data relate to adverse effects of quinine in humans
remains to be determined.
Islahudin et al., 2014; Khozoie et al., 2009
Mefloquine
Mefloquine emerged from the Walter Reed Malaria
Research Program as safe and effective against drug-
resistant strains of P. falciparum. Mefloquine is a highly
effective blood schizonticide. Mefloquine associates with
intraerythrocytic hemozoin, suggesting similarities to the
mode of action of chloroquine.
However, increased pfmdr1 copy numbers are associated
with both reduced parasite susceptibility to mefloquine
and increased PfMDR1-mediated solute import into the
digestive vacuole of intraerythrocytic parasites,
suggesting that the drug’s target resides outside this
vacuolar compartment.
Mefloquine ADME
Mefloquine is taken orally because parenteral preparations
cause severe local reactions. The drug is absorbed rapidly
but with marked variability. Probably owing to extensive
enterogastric and enterohepatic circulation, plasma levels of
mefloquine rise in a biphasic manner to their peak in about
17 h. Mefloquine has a variable and long t1/2, 13–24 days,
reflecting its high lipophilicity, extensive tissue distribution,
and extensive binding (about 98%) to plasma proteins. The
slow elimination of mefloquine fosters the emergence of
drug-resistant parasites. Mefloquine is extensively
metabolized in the liver by CYP3A4; this CYP can be inhibited
by ketoconazole and induced by rifampicin. Excretion of Concentration - time curve for mefloquine in plasma (▲) and
saliva (■) after administration of single oral dose of mefloquine
mefloquine is mainly by the fecal route; about 10% of (20 mg/kg body weight) in healthy volunteers.
mefloquine appears unchanged in the urine.

Mefloquine Therapeutic Uses
Mefloquine should be reserved for the
prevention and treatment of malaria
caused by drug-resistant P. falciparum and
P. vivax; it is no longer considered first line
treatment of malaria.
The drug is especially useful as a
chemoprophylactic agent for travelers
spending weeks to years in areas where
these infections are endemic.
In areas where malaria is due to multiply
drug-resistant strains of P. falciparum,
mefloquine is more effective when used in
combination with an artemisinin
compound.
Mefloquine Toxicity and Side Effects
At chemoprophylactic dosages, while oral mefloquine is
generally well tolerated, the U.S. FDA has added a “black
box” warning to mefloquine labeling, noting the drug’s
potential to cause severe, possibly permanent,
neurological and psychiatric adverse effects.
Vivid dreams are common; significant neuropsychiatric
signs and symptoms can occur in 10% or more of people
receiving treatment doses; serious adverse events
(psychosis, seizures) are rare. Short-term adverse effects
of treatment include nausea, vomiting, and dizziness.
Dividing the dose improves tolerance. The full dose
should be repeated if vomiting occurs within the first
hour.
Mefloquine Toxicity and Side Effects
After treatment of malaria with mefloquine, CNS
toxicity can be as high as 0.5%; symptoms include
seizures, confusion or decreased sensorium, acute
psychosis, and disabling vertigo.
Such symptoms are reversible on drug
discontinuation. Mild-to-moderate toxicities (e.g.,
disturbed sleep, dysphoria, headache, GI
disturbances, and dizziness) occur even at
prophylactic dosages.
Adverse effects usually manifest after the first to
third doses and often abate even with continued
treatment. Cardiac abnormalities, hemolysis, and
agranulocytosis are rare.
Mefloquine Contraindications and Drug Interactions
At very high doses, mefloquine is teratogenic in rodents.
Studies have suggested an increased rate of stillbirths with
mefloquine use, especially during the first trimester.
Pregnancy should be avoided for 3 months after mefloquine
use because of the prolonged t1/2 of this agent.
This drug is contraindicated for patients with a history of
seizures, depression, bipolar disorder and other severe
neuropsychiatric conditions, or adverse reactions to
quinoline antimalarials.
Although this drug can be taken safely 12 h after a last dose
of quinine, taking quinine shortly after mefloquine can be
hazardous because the latter is eliminated so slowly.
Mefloquine Contraindications and Drug Interactions
Treatment with or after halofantrine or within 2 months of
prior mefloquine administration is contraindicated.
Controlled studies suggest that mefloquine does not impair
performance in persons who tolerate the drug; nonetheless,
some advise against the use of mefloquine for patients in
occupations that require focused concentration, dexterity,
and cognitive function.
Primaquine
Primaquine, in contrast to other antimalarials, acts on
exoerythrocytic tissue stages of Plasmodium spp. in
the liver to prevent and cure relapsing malaria.
Patients should be screened for G6PD deficiency prior
to therapy with this drug.
The mechanism of action of the 8-aminoquinolines has
not been elucidated. Primaquine acts against primary
and latent hepatic stages of Plasmodium spp. And
prevents relapses in P. vivax and P. ovale infections.
This drug and other 8 aminoquinolines also display
gametocytocidal activity against P. falciparum and
other Plasmodium species. However, primaquine is
inactive against asexual blood-stage parasites.
Primaquine Therapeutic Uses
Primaquine is used primarily for terminal chemoprophylaxis
and radical cure of P. vivax and P. ovale (relapsing) infections
because of its high activity against the latent tissue forms
(hypnozoites) of these Plasmodium species.
The compound is given together with a blood schizonticide,
usually chloroquine, to eradicate erythrocytic stages of these
plasmodia and reduce the possibility of emerging drug
resistance.
For terminal chemoprophylaxis, primaquine regimens should
be initiated shortly before or immediately after a subject leaves
an endemic area. Radical cure of P. vivax or P. ovale malaria can
be achieved if the drug is given either during an asymptomatic
latent period of presumed infection or during an acute attack.
Primaquine Therapeutic Uses
Simultaneous administration of a
schizonticidal drug plus primaquine
is more effective than sequential
treatment in promoting a radical
cure.
Limited studies demonstrated
efficacy in prevention of P.
falciparum and P. vivax malaria
when primaquine was taken as
chemoprophylaxis.
Primaquine is generally well
tolerated when taken for up to 1
year.
Primaquine Toxicity and Side Effects
Primaquine has few side effects when given in the usual
therapeutic doses.
Primaquine can cause mild-to-moderate abdominal distress in
some individuals.
Taking the drug at mealtime often alleviates these symptoms.
Mild anemia, cyanosis (methemoglobinemia), and leukocytosis
are less common.
High doses (60–240 mg daily) worsen the abdominal symptoms.
Methemoglobinemia can occur even with usual doses of
primaquine and can be severe in individuals with congenital
deficiency of NADH methemoglobin reductase (NADH-
cytochrome b5 reductase [diaphorase 1]).
Primaquine Toxicity and Side Effects
Chloroquine and dapsone may synergize with primaquine
to produce methemoglobinemia in these patients.
Granulocytopenia and agranulocytosis are rare
complications of therapy and usually are associated with
overdosage. Other rare adverse reactions are
hypertension, arrhythmias, and symptoms referable to
the CNS.
Therapeutic or higher doses of primaquine may cause
acute hemolysis and hemolytic anemia in humans with
G6PD deficiency.
Primaquine is the prototype of more than 50 drugs,
including antimalarial tafenoquine and sulfonamides,
that causes hemolysis in G6PD-deficient individuals.
Sulfonamides, Sulfones Tetracyclines and Clindamycin
The sulfonamides and sulfones are p-aminobenzoic acid
analogues that competitively inhibit Plasmodium
dihydropteroate synthase and act as slow-acting blood
schizonticides and are more active against P. falciparum than P.
vivax.
Tetracycline and doxycycline are useful in malaria treatment, as
is clindamycin. These agents are slow-acting blood
schizonticides that can be used alone for short-term
chemoprophylaxis in areas with chloroquine- and mefloquine-
resistant malaria (only doxycycline is recommended for malaria
chemoprophylaxis).
For details of these agents see the specific lectures on them
Decision Algorithm for the Treatment
of Malaria (1 of 2)
Atovaquone-proguanil, mefloquine,
artemether-lumefantrine, tetracycline, and
doxycycline are not indicated during
pregnancy (pregnancy category C).
Tetracycline and doxycycline are not
indicated in children younger than 8 years.
(Modified from Centers for Disease Control and Prevention. Malaria. n.d.
http://www.cdc.gov.access.library.miami.edu/malaria/resources/pdf/algorithm.pdf. Accessed Oct 13, 2019.)
Decision Algorithm for the Treatment of Malaria (2 of 2)
Chemoprophylaxis for Prevention of Malaria in Nonimmune
Individuals
Individuals
Individuals
Individuals
Agents for Presumptive Self-Treatment of Malaria*
* If used for presumptive self-treatment, medical care should be sought as soon as possible. Source: Modified from
www.cdc.gov/travel; accessed May 26, 2016.
Agents for Presumptive Self-Treatment of Malaria*
* If used for presumptive self-treatment, medical care should be sought as soon as possible. Source: Modified from
www.cdc.gov/travel; accessed May 26, 2016.
Treating the Mosquito rather than the Human
Recent technological developments seem likely to
revolutionize mosquito control and mosquito susceptibility
to malarial parasites.
Isaacs et al. (2011) engineered resistance to infection by P.
falciparum in mosquitoes by having the mosquitoes express
single-chain antibodies that targeted antigens on the
parasite’s surface and inhibited the parasite’s capacity to
invade the midgut and salivary glands of the mosquito,
effects that would reduce or eliminate the capacity of the
mosquito to infect humans in the course of a blood meal.
The development of gene editing using CRISPR/cas9* has
opened up a new avenue for high-efficiency expression of
resistance genes for treating the spread and prevalence of
malaria. %
*Clustered Regularly Interspaced Short Palindromic Repeats; Cas9 = CRISPR Associated Protein 9
Others have described a “mutagenic chain reaction” based on CRISPR/cas9 that can spread a mutation from one chromosome to its
homologous chromosome, converting heterozygous mutations to homozygosity in most germline and somatic cells in Drosophila.
This gene drive system works in mosquitoes as well (Gantz et al., 2015), introducing antiplasmodium effector genes into the germline and
thence into the progeny with very high frequency.
Other CRISPR/cas9 endonuclease constructs have driven genes in the malarial vector Anopheles gambiae, targeting female reproduction and
holding the promise of reducing the mosquito population in malarious areas to levels that will not support transmission of the disease. %
It seems likely that this gene editing–gene drive
technology will be applicable to other vector-borne
diseases. As Hammond et al. (2016) noted, “The
success of gene drive technology for vector control will
depend on the choice of suitable promoters to
effectively drive homing during […] gametogenesis, the
phenotype of the disrupted genes, the robustness of the
nuclease during homing and the ability of the target
population to generate compensatory mutations”.
CRISPR/cas9 gene drives have not yet been released
into the wild. Indeed, the use of these techniques in
the field must be approached with caution and must
await a full understanding of the ecological
consequences and the ethical and regulatory issues.

002 Chemotherapy of Malaria

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“Corso di Laurea in Medicina e Chirurgia”

Insegnamento di Farmacologia 1 – IV anno – Programma di Chemioterapia AA 2019-2020

1. General Principles of Antimicrobial Therapy

The asexual erythrocytic stages of malarial parasites

The various stages of the malarial

Thus, antimalarial drugs can be

The spectrum of antimalarial drug

Although atovaquone is generally considered to be

Quinoline and Related Compounds

mefloquine appears unchanged in the urine.

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