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Five species of the plasmodium parasite can infect humans; the most serious forms of the
disease are caused by Plasmodium falciparum. Malaria caused by Plasmodium vivax,
Plasmodium ovale and Plasmodium malariae causes milder disease in humans that is not
generally fatal. A fifth species, Plasmodium knowlesi, is a zoonosis that causes malaria
in macaques but can also infect humans.
A wide variety of antimalarial drugs are available to treat malaria. In the last 5 years
treatment of P. falciparum infections in endemic countries has been transformed by the
use of combinations of drugs containing an artemisinin derivative. Severe malaria is
treated with intravenous or intramuscular quinine or, increasingly, the artemisinin
derivative artesunate. Several drugs are also available to prevent malaria in travellers to
malaria-endemic countries (prophylaxis). Resistance has developed to several
antimalarial drugs, most notably chloroquine.
Malaria transmission can be reduced by preventing mosquito bites with mosquito nets
and insect repellents, or by mosquito control measures such as spraying insecticides
inside houses and draining standing water where mosquitoes lay their eggs.
Although many are under development, the challenge of producing a widely available
vaccine that provides a high level of protection for a sustained period is still to be met
Persistent in
Species Appearance Periodicity
liver?
Plasmodium
tertian no
falciparum
Severe malaria is almost exclusively caused by P. falciparum infection and usually arises
6–14 days after infection. Consequences of severe malaria include coma and death if
untreated—young children and pregnant women are especially vulnerable. Splenomegaly
(enlarged spleen), severe headache, cerebral ischemia, hepatomegaly (enlarged liver),
hypoglycemia, and hemoglobinuria with renal failure may occur. Renal failure may cause
blackwater fever, where hemoglobin from lysed red blood cells leaks into the urine.
Severe malaria can progress extremely rapidly and cause death within hours or days. In
the most severe cases of the disease fatality rates can exceed 20%, even with intensive
care and treatment. In endemic areas, treatment is often less satisfactory and the overall
fatality rate for all cases of malaria can be as high as one in ten. Over the longer term,
developmental impairments have been documented in children who have suffered
episodes of severe malaria.
Chronic malaria is seen in both P. vivax and P. ovale, but not in P. falciparum. Here, the
disease can relapse months or years after exposure, due to the presence of latent parasites
in the liver. Describing a case of malaria as cured by observing the disappearance of
parasites from the bloodstream can, therefore, be deceptive. The longest incubation
period reported for a P. vivax infection is 30 years. Approximately one in five of P. vivax
malaria cases in temperate areas involve overwintering by hypnozoites (i.e., relapses
begin the year after the mosquito bite).
Causes
Malaria parasites
The parasite's primary (definitive) hosts and transmission vectors are female mosquitoes
of the Anopheles genus, while humans and other vertebrates are secondary hosts. Young
mosquitoes first ingest the malaria parasite by feeding on an infected human carrier and
the infected Anopheles mosquitoes carry Plasmodium sporozoites in their salivary
glands. A mosquito becomes infected when it takes a blood meal from an infected
human. Once ingested, the parasite gametocytes taken up in the blood will further
differentiate into male or female gametes and then fuse in the mosquito gut. This
produces an ookinete that penetrates the gut lining and produces an oocyst in the gut wall.
When the oocyst ruptures, it releases sporozoites that migrate through the mosquito's
body to the salivary glands, where they are then ready to infect a new human host. This
type of transmission is occasionally referred to as anterior station transfer. The
sporozoites are injected into the skin, alongside saliva, when the mosquito takes a
subsequent blood meal.
Only female mosquitoes feed on blood, thus males do not transmit the disease. The
females of the Anopheles genus of mosquito prefer to feed at night. They usually start
searching for a meal at dusk, and will continue throughout the night until taking a meal.
Malaria parasites can also be transmitted by blood transfusions, although this is rare
The life cycle of malaria parasites in the human body. A mosquito infects a person
by taking a blood meal.
First, sporozoites enter the bloodstream, and migrate to the liver.
They infect liver cells (hepatocytes), where they multiply into merozoites, rupture
the liver cells, and escape back into the bloodstream.
Then, the merozoites infect red blood cells, where they develop into ring forms, then
trophozoites (a feeding stage), then schizonts (a reproduction stage), then back into
merozoites.
Sexual forms called gametocytes are also produced, which, if taken up by a
mosquito, will infect the insect and continue the life cycle.
Within the red blood cells, the parasites multiply further, again asexually, periodically
breaking out of their hosts to invade fresh red blood cells. Several such amplification
cycles occur. Thus, classical descriptions of waves of fever arise from simultaneous
waves of merozoites escaping and infecting red blood cells.
Some P. vivax and P. ovale sporozoites do not immediately develop into exoerythrocytic-
phase merozoites, but instead produce hypnozoites that remain dormant for periods
ranging from several months (6–12 months is typical) to as long as three years. After a
period of dormancy, they reactivate and produce merozoites. Hypnozoites are responsible
for long incubation and late relapses in these two species of malaria.
The parasite is relatively protected from attack by the body's immune system because for
most of its human life cycle it resides within the liver and blood cells and is relatively
invisible to immune surveillance. However, circulating infected blood cells are destroyed
in the spleen. To avoid this fate, the P. falciparum parasite displays adhesive proteins on
the surface of the infected blood cells, causing the blood cells to stick to the walls of
small blood vessels, thereby sequestering the parasite from passage through the general
circulation and the spleen. This "stickiness" is the main factor giving rise to hemorrhagic
complications of malaria. High endothelial venules (the smallest branches of the
circulatory system) can be blocked by the attachment of masses of these infected red
blood cells. The blockage of these vessels causes symptoms such as in placental and
cerebral malaria. In cerebral malaria the sequestrated red blood cells can breach the blood
brain barrier possibly leading to coma.
Although the red blood cell surface adhesive proteins (called PfEMP1, for Plasmodium
falciparum erythrocyte membrane protein 1) are exposed to the immune system, they do
not serve as good immune targets because of their extreme diversity; there are at least 60
variations of the protein within a single parasite and effectively limitless versions within
parasite populations. The parasite switches between a broad repertoire of PfEMP1 surface
proteins, thus staying one step ahead of the pursuing immune system.
Some merozoites turn into male and female gametocytes. If a mosquito pierces the skin
of an infected person, it potentially picks up gametocytes within the blood. Fertilization
and sexual recombination of the parasite occurs in the mosquito's gut, thereby defining
the mosquito as the definitive host of the disease. New sporozoites develop and travel to
the mosquito's salivary gland, completing the cycle. Pregnant women are especially
attractive to the mosquitoes, and malaria in pregnant women is an important cause of
stillbirths, infant mortality and low birth weight, particularly in P. falciparum infection,
but also in other species infection, such as P. vivax.
Blood smear from a P. falciparum culture (K1 strain). Several red blood cells have ring
stages inside them. Close to the center there is a schizont and on the left a trophozoite.
Since Charles Laveran first visualised the malaria parasite in blood in 1880, the mainstay
of malaria diagnosis has been the microscopic examination of blood.
Fever and septic shock are commonly misdiagnosed as severe malaria in Africa, leading
to a failure to treat other life-threatening illnesses. In malaria-endemic areas, parasitemia
does not ensure a diagnosis of severe malaria because parasitemia can be incidental to
other concurrent disease. Recent investigations suggest that malarial retinopathy is better
(collective sensitivity of 95% and specificity of 90%) than any other clinical or laboratory
feature in distinguishing malarial from non-malarial coma.
Although blood is the sample most frequently used to make a diagnosis, both saliva and
urine have been investigated as alternative, less invasive specimens.
Symptomatic diagnosis
Areas that cannot afford even simple laboratory diagnostic tests often use only a history
of subjective fever as the indication to treat for malaria. Using Giemsa-stained blood
smears from children in Malawi, one study showed that when clinical predictors (rectal
temperature, nailbed pallor, and splenomegaly) were used as treatment indications, rather
than using only a history of subjective fevers, a correct diagnosis increased from 21% to
41% of cases and unnecessary treatment for malaria was significantly decreased.
From the thick film, an experienced microscopist can detect parasite levels (or
parasitemia) down to as low as 0.0000001% of red blood cells. Diagnosis of species can
be difficult because the early trophozoites ("ring form") of all four species look identical
and it is never possible to diagnose species on the basis of a single ring form; species
identification is always based on several trophozoites.
OptiMAL-IT will reliably detect falciparum down to 0.01% parasitemia and non-
falciparum down to 0.1%. Paracheck-Pf will detect parasitemias down to 0.002% but
will not distinguish between falciparum and non-falciparum malaria. Parasite nucleic
acids are detected using polymerase chain reaction. This technique is more accurate than
microscopy. However, it is expensive, and requires a specialized laboratory. Moreover,
levels of parasitemia are not necessarily correlative with the progression of disease,
particularly when the parasite is able to adhere to blood vessel walls. Therefore more
sensitive, low-tech diagnosis tools need to be developed in order to detect low levels of
parasitaemia in the field.
Prevention
Methods used to prevent the spread of disease, or to protect individuals in areas where
malaria is endemic, include prophylactic drugs, mosquito eradication, and the prevention
of mosquito bites. The continued existence of malaria in an area requires a combination
of high human population density, high mosquito population density, and high rates of
transmission from humans to mosquitoes and from mosquitoes to humans. If any of these
is lowered sufficiently, the parasite will sooner or later disappear from that area, as
happened in North America, Europe and much of Middle East. However, unless the
parasite is eliminated from the whole world, it could become re-established if conditions
revert to a combination that favors the parasite's reproduction. Many countries are seeing
an increasing number of imported malaria cases due to extensive travel and migration.
The distribution of funding varies among countries. Countries with large populations do
not receive the same amount of support. The 34 countries that received a per capita
annual support of less than $1 included some of the poorest countries in Africa.
Brazil, Eritrea, India, and Vietnam have, unlike many other developing nations,
successfully reduced the malaria burden. Common success factors included conducive
country conditions, a targeted technical approach using a package of effective tools, data-
driven decision-making, active leadership at all levels of government, involvement of
communities, decentralized implementation and control of finances, skilled technical and
managerial capacity at national and sub-national levels, hands-on technical and
programmatic support from partner agencies, and sufficient and flexible financing.
Prophylactic drugs
Several drugs, most of which are also used for treatment of malaria, can be taken
preventively. Generally, these drugs are taken daily or weekly, at a lower dose than
would be used for treatment of a person who had actually contracted the disease. Use of
prophylactic drugs is seldom practical for full-time residents of malaria-endemic areas,
and their use is usually restricted to short-term visitors and travelers to malarial regions.
This is due to the cost of purchasing the drugs, negative side effects from long-term use,
and because some effective anti-malarial drugs are difficult to obtain outside of wealthy
nations.
Quinine was used starting in the 17th century as a prophylactic against malaria. The
development of more effective alternatives such as quinacrine, chloroquine, and
primaquine in the 20th century reduced the reliance on quinine. Today, quinine is still
used to treat chloroquine resistant Plasmodium falciparum, as well as severe and
cerebral stages of malaria, but is not generally used for prophylaxis.
10
The use of prophylactic drugs where malaria-bearing mosquitoes are present may
encourage the development of partial immunity.
Treatment
Active malaria infection with P. falciparum is a medical emergency requiring
hospitalization. Infection with P. vivax, P. ovale or P. malariae can often be treated on an
outpatient basis. Treatment of malaria involves supportive measures as well as specific
antimalarial drugs. When properly treated, someone with malaria can expect a complete
recovery.
Counterfeit drugs
Sophisticated counterfeits have been found in several Asian countries such as Cambodia,
China, Indonesia, Laos, Thailand, Vietnam and are an important cause of avoidable death
in those countries. WHO have said that studies indicate that up to 40% of artesunate
based malaria medications are counterfeit, especially in the Greater Mekong region and
have established a rapid alert system to enable information about counterfeit drugs to be
rapidly reported to the relevant authorities in participating countries. There is no reliable
way for doctors or lay people to detect counterfeit drugs without help from a laboratory.
Companies are attempting to combat the persistence of counterfeit drugs by using new
technology to provide security from source to distribution.
Epidemiology
11
Malaria causes about 250 million cases of fever and approximately one million deaths
annually. The vast majority of cases occur in children under 5 years old; pregnant women
are also especially vulnerable. Despite efforts to reduce transmission and increase
treatment, there has been little change in which areas are at risk of this disease since
1992. Indeed, if the prevalence of malaria stays on its present upwards course, the death
rate could double in the next twenty years. Precise statistics are unknown because many
cases occur in rural areas where people do not have access to hospitals or the means to
afford health care. As a consequence, the majority of cases are undocumented.
Although co-infection with HIV and malaria does cause increased mortality, this is less
of a problem than with HIV/tuberculosis co-infection, due to the two diseases usually
attacking different age-ranges, with malaria being most common in the young and active
tuberculosis most common in the old. Although HIV/malaria co-infection produces less
severe symptoms than the interaction between HIV and TB, HIV and malaria do
contribute to each other's spread. This effect comes from malaria increasing viral load
and HIV infection increasing a person's susceptibility to malaria infection.
Malaria is presently endemic in a broad band around the equator, in areas of the
Americas, many parts of Asia, and much of Africa; however, it is in sub-Saharan Africa
where 85– 90% of malaria fatalities occur. The geographic distribution of malaria within
large regions is complex, and malaria-afflicted and malaria-free areas are often found
close to each other. In drier areas, outbreaks of malaria can be predicted with reasonable
accuracy by mapping rainfall. Malaria is more common in rural areas than in cities; this is
12
History
Malaria has infected humans for over 50,000 years, and Plasmodium may have been a
human pathogen for the entire history of the species. Close relatives of the human malaria
parasites remain common in chimpanzees. References to the unique periodic fevers of
malaria are found throughout recorded history, beginning in 2700 BC in China. The term
malaria originates from Medieval Italian: mala aria—"bad air"; and the disease was
formerly called ague or marsh fever due to its association with swamps and marshland.
Malaria was once common in most of Europe and North America, where it is no longer
endemic, though imported cases do occur.
Scientific studies on malaria made their first significant advance in 1880, when a French
army doctor working in the military hospital of Constantine in Algeria named Charles
Louis Alphonse Laveran observed parasites for the first time, inside the red blood cells of
people suffering from malaria. He, therefore, proposed that malaria is caused by this
organism, the first time a protist was identified as causing disease. For this and later
discoveries, he was awarded the 1907 Nobel Prize for Physiology or Medicine. The
malarial parasite was called Plasmodium by the Italian scientists Ettore Marchiafava and
Angelo Celli. A year later, Carlos Finlay, a Cuban doctor treating patients with yellow
fever in Havana, provided strong evidence that mosquitoes were transmitting disease to
and from humans. This work followed earlier suggestions by Josiah C. Nott, and work by
Patrick Manson on the transmission of filariasis.
However, it was Britain's Sir Ronald Ross working in the Presidency General Hospital in
Calcutta who finally proved in 1898 that malaria is transmitted by mosquitoes. He did
this by showing that certain mosquito species transmit malaria to birds and isolating
malaria parasites from the salivary glands of mosquitoes that had fed on infected birds.
For this work Ross received the 1902 Nobel Prize in Medicine. After resigning from the
Indian Medical Service, Ross worked at the newly-established Liverpool School of
Tropical Medicine and directed malaria-control efforts in Egypt, Panama, Greece and
Mauritius. The findings of Finlay and Ross were later confirmed by a medical board
headed by Walter Reed in 1900, and its recommendations implemented by William C.
Gorgas in the health measures undertaken during construction of the Panama Canal. This
public-health work saved the lives of thousands of workers and helped develop the
methods used in future public-health campaigns against this disease.
The first effective treatment for malaria came from the bark of cinchona tree, which
contains quinine. This tree grows on the slopes of the Andes, mainly in Peru. A tincture
13
In the early 20th century, before antibiotics became available, Julius Wagner-Jauregg
discovered that patients with syphilis could be treated by intentionally infecting them
with malaria; the resulting fever would kill the syphilis spirochetes, and quinine would
then be administered to control the malaria. Although some patients died from malaria,
this was considered preferable to the almost-certain death from syphilis.
Although the blood stage and mosquito stages of the malaria life cycle were identified in
the 19th and early 20th centuries, it was not until the 1980s that the latent liver form of
the parasite was observed. The discovery of this latent form of the parasite finally
explained why people could appear to be cured of malaria but still relapse years after the
parasite had disappeared from their bloodstreams.
ANTIMALARIAL DRUGS
14
Some agents are used for more than one application. It is therefore more practical to
group antimalarials by chemical structure since this is associated with important
properties of each drug, such as mechanism of action.
Quinine has a long history stretching from Peru, and the discovery of the cinchona tree,
and the potential uses of its bark, to the current day and a collection of derivatives that are
still frequently used in the prevention and treatment of malaria. Quinine is an alkaloid
that acts as a blood schizonticidal and weak gametocide against Plasmodium vivax and
Plasmodium malariae. As an alkaloid, it is accumulated in the food vacuoles of
Plasmodium species, especially Plasmodium falciparum. It acts by inhibiting the
hemozoin biocrystallization, thus facilitating an aggregation of cytotoxic heme. Quinine
is less effective and more toxic as a blood schizonticidal agent than chloroquine; however
it is still very effective and widely used in the treatment of acute cases of severe P.
falciparum. It is especially useful in areas where there is known to be a high level of
resistance to chloroquine, mefloquine and sulfa drug combinations with pyrimethamine.
Quinine is also used in post-exposure treatment of individuals returning from an area
where malaria is endemic.
The treatment regimen of quinine is complex and is determined largely by the parasite's
level of resistance and the reason for drug therapy (i.e. acute treatment or prophylaxis).
The World Health Organization recommendation for quinine is 8 mg/kg three times daily
for 3 days in areas where the level of adherence is questionable and for 7 days where
parasites are sensitive to quinine. In areas where there is an increased level of resistance
to quinine 8 mg/kg three times daily for 7 days is recommended, combined with
doxycycline, tetracycline or clindamycin. Doses can be given by oral, intravenous or
intramuscular routes. The recommended method depends on the urgency of treatment and
the available resources (i.e. sterilised needles for IV or IM injections).
15
Chloroquine
Chloroquine was until recently the most widely used anti-malarial. It was the original
prototype from which most other methods of treatment are derived. It is also the least
expensive, best tested and safest of all available drugs. The emergence of drug resistant
parasitic strains is rapidly decreasing its effectiveness; however it is still the first-line
drug of choice in most sub-Saharan African countries. It is now suggested that it is used
in combination with other antimalarial drugs to extend its effective usage.
A slightly different drug called nivaquine or chloroquine phosphate has also been
invented. Popular drugs that make use of this compound are Chloroquine FNA, Resochin
and Dawaquin.
- 40mg/ml
- I.M. injection only. (NEVER I.V.) For more serious cases, i.e. if the patient is vomiting, fitting,
not fully conscious, temp. over 39.5 degrees or severe diarrhea.
16
3–5 ¼
5–7 ¼
8–9 ¾
10 – 14 1
15 – 19 1½
20 – 24 2
25 – 29 2½
30 - 39 3
Children and adults should receive 25 mg of chloroquine per kg given over 3 days. A
pharmacokinetically superior regime, recommended by the WHO, involves giving an
initial dose of 10 mg/kg followed 6–8 hours later by 5 mg/kg, then 5 mg/kg on the
following 2 days. For chemoprophylaxis: 5 mg/kg/week (single dose) or 10 mg/kg/week
divided into 6 daily doses is advised. It should be noted that chloroquine is only
recommended as a prophylactic drug in regions only affected by P. vivax and sensitive P.
falciparum strains. Chloroquine has been used in the treatment of malaria for many years
and no abortifacient or teratogenic effects have been reported during this time, therefore
it is considered very safe to use during pregnancy. However, itching can occur at
intolerable level.
Amodiaquine
17
3 – 5.9 ½ (50mg)
6 – 9.9 1 (100mg)
10 – 14.9 1½ (150mg)
15 – 18.9 2 (200mg)
19 & over give chloroquine
The drug should be given in doses between 25 mg/kg and 35 mg/kg over 3 days in a
similar method to that used in Chloroquine administration. Adverse reactions are
generally similar in severity and type to that seen in Chloroquine treatment. In addition,
bradycardia, itching, nausea, vomiting and some abdominal pain have been recorded.
Some blood and hepatic disorders have also been seen in a small number of patients.
Pyrimethamine
Sulphadoxine
Proguanil
18
Mefloquine
Mefloquine was developed during the Vietnam War and is chemically related to quinine.
It was developed to protect American troops against multi-drug resistant P. falciparum. It
is a very potent blood schizonticide with a long half-life. It is thought to act by forming
toxic heme complexes that damage parasitic food vacuoles. It is now used solely for the
prevention of resistant strains of P. falciparum despite being effective against P. vivax, P.
ovale and P. marlariae. Mefloquine is effective in prophylaxis and for acute therapy. It is
now strictly used for resistant strains (and is usually combined with Artesunate).
Chloroquine/Proguanil or sufha drug-pyrimethamine combinations should be used in all
other Plasmodia infections.
Mefloquine can only be taken for a period up to 6 months (due to side effects, ...). After
this, other drugs (such as those based on paludrine/nivaquine) again need to be taken.
19
Atovaquone is only available in combination with Proguanil under the name Malarone,
albeit at a price higher than Lariam. It is most commonly used in prophylaxis by
travellers.
Primaquine
Dosage:
Adult. For single dose on the first day of treatment for P. falciparum.
3 – 5.9 -
6 – 9.9 ½ (3.75mg)
10 – 14.9 1 (7.5mg)
15 – 18.9 1½ (11.25mg)
19 – 27.9 2 (15mg)
28 – 36.9 3 (22.5mg)
37 – 49.9 4 (30mg)
For the prevention of relapse in P. vivax and P. ovale 0.15 mg/kg should be given for 14
days. As a gametocytocidal drug in P. falciparum infections a single dose of 0.75 mg/kg
repeated 7 days later is sufficient. This treatment method is only used in conjunction with
another effective blood schizonticidal drug. There are few significant side effects
although is has been shown that Primaquine may cause anorexia, nausea, vomiting,
cramps, chest weakness, anaemia, some suppression of myeloid activity and abdominal
pains. In cases of over-dosage granulocytopenia may occur.
20
Artemesinin is a Chinese herb (Qinghaosu) that has been used in the treatment of fevers
for over 1,000 years, thus predating the use of Quinine in the western world. It is derived
from the plant Artemisia annua, with the first documentation as a successful therapeutic
agent in the treatment of malaria is in 340 AD by Ge Hong in his book Zhou Hou Bei Ji
Fang (A Handbook of Prescriptions for Emergencies). The active compound was isolated
first in 1971 and named Artemsinin. It is a sesquiterpene lactone with a chemically rare
peroxide bridge linkage. It is this that is thought to be responsible for the majority of its
anti-malarial action, although the target within the parasite remains controversial. At
present it is strictly controlled under WHO guidelines as it has proven to be effective
against all forms of multi-drug resistant P. falciparum, thus every care is taken to ensure
compliance and adherence together with other behaviours associated with the
development of resistance. It is also only given in combination with other anti-malarials.
• Artemisinin has a very rapid action and the vast majority of acute patients
treated show significant improvement within 1–3 days of receiving treatment. It
has demonstrated the fastest clearance of all anti-malarials currently used and acts
primarily on the trophozite phase, thus preventing progression of the disease.
Semi-synthetic artemisinin derivatives (e.g. artesunate, artemether) are easier to
use than the parent compound and are converted rapidly once in the body to the
active compound dihydroartemesinin. On the first day of treatment 20 mg/kg
should be given, this dose is then reduced to 10 mg/kg per day for the 6 following
days. Few side effects are associated with artemesinin use. However, headaches,
nausea, vomiting, abnormal bleeding, dark urine, itching and some drug fever
have been reported by a small number of patients. Some cardiac changes were
reported during a clinical trial, notably non specific ST changes and a first degree
atrioventricular block (these disappeared when the patients recovered from the
malarial fever).
21
Halofantrine
Halofantrine is a relatively new drug developed by the Walter Reed Army Institute of
Research in the 1960s. It is a phenanthrene methanol, chemically related to Quinine and
acts acting as a blood schizonticide effective against all plasmodium parasites. Its
mechanism of action is similar to other anti-malarials. Cytotoxic complexes are formed
with ferritoporphyrin XI that cause plasmodial membrane damage. Despite being
effective against drug resistant parasites, Halofantrine is not commonly used in the
treatment (prophylactic or therapeutic) of malaria due to its high cost. It has very variable
bioavailability and has been shown to have potentially high levels of cardiotoxicity. It is
still a useful drug and can be used in patients that are known to be free of heart disease
and are suffering from severe and resistant forms of acute malaria. A popular drug based
on halofantrine is Halfan. The level of governmental control and the prescription-only
basis on which it can be used contributes to the cost, thus Halofantrine is not frequently
used.
Doxycycline
Probably one of the more prevalent antimalarial drugs prescribed, due to its relative
effectiveness and cheapness, Doxycycline is a Tetracycline compound derived from
Oxytetracycline. The tetracyclines were one of the earliest groups of antibiotics to be
22
When treating acute cases and given in combination with Quinine; 100 mg/kg of
Doxycycline should be given per day for 7 days. In prophylactic therapy, 100 mg (adult
dose) of Doxycycline should be given every day during exposure to malaria.
The most commonly experienced side effects are permanent enamel hypoplasia, transient
depression of bone growth, gastrointestinal disturbances and some increased levels of
photosensitivity. Due to its effect of bone and tooth growth it is not used in children
under 8, pregnant or lactating women and those with a known hepatic dysfunction.
Tetracycline is only used in combination for the treatment of acute cases of P.Falciparum
infections. This is due to its slow onset. Unlike Doxycycline it is not used in
chemoprophylaxis. For Tetracycline, 250 mg is the recommended adult dosage (it should
not be used in children) for 5 or 7 days depending on the level of adherence and
compliance expected. Oesophageal ulceration, gastrointestinal upset and interferences
with the process of ossification and depression of bone growth are known to occur. The
majority of side effects associated with Doxycycline are also experienced.
Clindamycin
Clindamycin should be given in conjunction with Quinine as a 300 mg dose (in adults)
four times a day for 5 days. The only side effects recorded in patients taking Clindamycin
are nausea, vomiting and abdominal pains and cramps. However these can be alleviated
by consuming large quantities of water and food when taking the drug.
Pseudomembranous colitis (caused by Clostridium difficile) has also developed in
some patients; this condition may be fatal in a small number of cases.
Resistance to antimalarials
Anti-malarial drug resistance has been defined as: "the ability of a parasite to survive
and/or multiply despite the administration and absorption of a drug given in doses equal
to or higher than those usually recommended but within tolerance of the subject. The
23
Drug resistant parasites are often used to explain malaria treatment failure. However, they
are two potentially very different clinical scenarios. The failure to clear parasitemia and
recover from an acute clinical episode when a suitable treatment has been given and anti-
malarial resistance in its true form. Drug resistance may lead to treatment failure, but
treatment failure is not necessarily caused by drug resistance despite assisting with its
development. A multitude of factors can be involved in the processes including problems
with non-compliance and adherence, poor drug quality, interactions with other
pharmaceuticals, poor absorption, misdiagnosis and incorrect doses being given. The
majority of these factors also contribute to the development of drug resistance.
The generation of resistance can be complicated and varies between plasmodium species.
It is generally accepted to be initiated primarily through a spontaneous mutation that
provides some evolutionary benefit, thus giving an anti-malarial used a reduced level of
sensitivity. This can be caused by a single point mutation or multiple mutations. In most
instances a mutation will be fatal for the parasite or the drug pressure will remove
parasites that remain susceptible, however some resistant parasites will survive.
Resistance can become firmly established within a parasite population, existing for long
periods of time.
Plasmodium have developed resistance against antifolate combination drugs, the most
commonly used being sulfadoxine and pyrimethamine. Two gene mutations are thought
to be responsible, allowing synergistic blockages of two enzymes involved in folate
synthesis. Regional variations of specific mutations give differing levels of resistance.
24
Spread of resistance
There is no single factor that confers the greatest degree of influence on the spread of
drug resistance, but a number of plausible causes associated with an increase have been
acknowledged. These include aspects of economics, human behaviour, pharmokinetics,
and the biology of vectors and parasites.
1. The biological influences are based on the parasites ability to survive the presence
of an anti-malarial thus enabling the persistence of resistance and the potential for
further transmission despite treatment. In normal circumstances any parasites that
persist after treatment are destroyed by the host's immune system, therefore any
factors that act to reduce the elimination of parasites could facilitate the
development of resistance. This attempts to explain the poorer response
associated with immunocompromised individuals, pregnant women and young
children.
2. There has been evidence to suggest that certain parasite-vector combinations can
alternatively enhance or inhibit the transmission of resistant parasites, causing
'pocket-like' areas of resistance.
3. The use of anti-malarials developed from similar basic chemical compounds can
increase the rate of resistance development, for example cross-resistance to
chloroquine and amiodiaquine, two 4-aminoquinolones and mefloquine
conferring resistance to quinine and halofantrine. This phenomenon may reduce
the usefulness of newly developed therapies prior to large-scale usage.
4. The resistance to anti-malarials may be increased by a process found in some
species of plasmodium, where a degree of phenotypic plasticity was exhibited,
allowing the rapid development of resistance to a new drug, even if the drug has
not been previously experienced.
5. The pharmokinetics of the chosen anti-malarial are key; the decision of choosing
a long-half life over a drug that is metabolised quickly is complex and still
remains unclear. Drugs with shorter half-life's require more frequent
administration to maintain the correct plasma concentrations, therefore potentially
presenting more problems if levels of adherence and compliance are unreliable,
but longer-lasting drugs can increase the development of resistance due to
prolonged periods of low drug concentration.
6. The pharmokinetics of anti-malarials is important when using combination
therapy. Mismatched drug combinations, for example having an 'unprotected'
period where one drug dominates can seriously increase the likelihood of
selection for resistant parasites.
7. Ecologically there is a linkage between the level of transmission and the
development of resistance, however at present this still remains unclear.
25
Prevention of resistance
The prevention of anti-malarial drug resistance is of enormous public health importance.
It can be assumed that no therapy currently under development or to be developed in the
foreseeable future will be totally protective against malaria. In accordance with this, there
is the possibility of resistance developing to any given therapy that is developed. This is a
serious concern, as the rate at which new drugs are produced by no means matches the
rate of the development of resistance. In addition, the most newly developed therapeutics
tend to be the most expensive and are required in the largest quantities by some of the
poorest areas of the world. Therefore it is apparent that the degree to which malaria can
be controlled depends on the careful use of the current drugs to limit, insofar as it is
possible, any further development of resistance.
Provisions essential to this process include the delivery of fast primary care where staff
are well trained and supported with the necessary supplies for efficient treatment. This in
itself is inadequate in large areas where malaria is endemic thus presenting an initial
problem. One method proposed that aims to avoid the fundamental lack in certain
countries health care infrastructure is the privatisation of some areas, thus enabling drugs
to be purchased on the open market from sources that are not officially related to the
health care industry. Although this is now gaining some support there are many problems
related to limited access and improper drug use, which could potentially increase the rate
of resistance development to an even greater extent.
There are two general approaches to preventing the spread of resistance: preventing
malaria infections and, preventing the transmission of resistant parasites.
Preventing malaria infections developing has a substantial effect on the potential rate of
development of resistance, by directly reducing the number of cases of malaria thus
decreasing the requirement for anti-malarial therapy. Preventing the transmission of
resistant parasites limits the risk of resistant malarial infections becoming endemic and
can be controlled by a variety of non-medical methods including insecticide-treated bed
nets, indoor residual spraying, environmental controls (such as swamp draining) and
personal protective methods such as using mosquito repellent. Chemoprophylaxis is also
important in the transmission of malaria infection and resistance in defined populations
(for example travellers).
26
Combination therapy
The problem of the development of malaria resistance must be weighed against the
essential goal of anti-malarial care; that is to reduce morbidity and mortality. Thus a
balance must be reached that attempts to achieve both goals whilst not compromising
either too much by doing so. The most successful attempts so far have been in the
administration of combination therapy. This can be defined as, 'the simultaneous use of
two or more blood schizonticidal drugs with independent modes of action and different
biochemical targets in the parasite'. There is much evidence to support the use of
combination therapies, some of which has been discussed previously, however several
problems prevent the wide use in the areas where its use is most advisable. These include:
problems identifying the most suitable drug for different epidemiological situations, the
expense of combined therapy (it is over 10 times more expensive than traditional mono-
therapy), how soon the programmes should be introduced and problems linked with
policy implementation and issues of compliance.
The combinations of drugs currently prescribed can be divided into two categories: Non-
artemesinin and Quinine based combinations and, Artemesinin based combinations. It is
also important to distinguish fixed-dose combination therapies (in which two or more
drugs are co-formulated into a single tablet) from combinations achieved by taking two
separate antimalarials.
27
Artemesinin has a very different mode of action than conventional anti-malarials (see
information above), this makes is particularly useful in the treatment of resistant
infections, however in order to prevent the development of resistance to this drug it is
only recommended in combination with another non-artemesinin based therapy. It
produces a very rapid reduction in the parasite biomass with an associated reduction in
clinical symptoms and is known to cause a reduction in the transmission of gametocytes
28
29
Other combinations
There are several anti-malarial combinations currently being developed that are hoped to
be highly efficacious, cost-effective, safe and well tolerated. These are to be newly
developed compounds and not derivatives of currently used drugs, thus decreasing the
likelihood of resistance.
30
Experimental drugs
In 1996, Geoff McFadden became aware of the work of the biologist Ian Wilson, who
had discovered that the plasmodia responsible for causing malaria retained parts of
chloroplasts, an organelle usually found in plants, complete with their own functioning
genomes. This led Professor McFadden to the realisation that herbicides may be useful
lead compounds for the development of drugs against malaria. These "apicoplasts" are
thought to have originated through the endosymbiosis of algae and play a crucial role in
fatty acid bio-synthesis in plasmodia. To date, 466 proteins have been found to be
produced by apicoplasts and these are now being looked at as possible targets for novel
anti-malarial drugs.
Coartem
Coartem (artemether 20 mg/lumefantrine 120 mg) is an artemisinin-based
combination therapy (ACT) indicated for the treatment of acute uncomplicated
plasmodium falciparum malaria, the most dangerous form of the disease. Coartem
is produced by the Swiss pharmaceutical company, Novartis.
31
Access To Treatment
Coartem is provided without profit to developing countries using grants from the Global
Fund to Fight AIDS, Tuberculosis and Malaria, US President’s Malaria Initiative along
with other donors. These broad partnerships have provided millions of children and
adults with access to a high-quality treatment for malaria.
Novartis has lowered the price of Coartem by 50% since 2001, increasing access to
patients around the world. The first significant price reduction occurred in 2006, when
the price of Coartem decreased from an average of US $1.57 to US $1.00. In 2006, due to
an improved supply situation for the natural ingredient artemisinin, Novartis was able to
undertake the pharmaceutical industry’s most aggressive manufacturing scale-up of its
kind from 4 million treatments in 2004 to 62 million treatments in 2006. Novartis and its
partners invested heavily in expanding production capacity at their state-of-the-art
facilities in China, and Suffern, New York. This increase in production capacity ensured
that supplies of Coartem met demand which enabled Novartis to further decrease the
price of Coartem.
In April 2008, Novartis further reduced the public sector price of Coartem by
approximately 20%, to an average of US $0.80 (or US $0.37 for a child’s treatment
pack). This price reduction was made possible through production efficiency gains.
In January 2009, Novartis and Medicines for Malaria Venture (MMV) launched Coartem
Dispersible, the first ACT developed specifically for children suffering from malaria.
Coartem Dispersible contains the same amount of artemether and lumefantrine as
Coartem. A phase III study published in The Lancet showed that Coartem Dispersible
provides a high cure rate of 97.8%, which is comparable to that of Coartem (98.5%).
Investigators also reported that it had a good safety profile.
According to the WHO, there were 247 million cases of malaria in 2006, causing about
880,000 deaths, mostly among African children. In Africa alone, a child dies every 30
seconds from malaria. Before Coartem Dispersible, many parents and healthcare workers
crushed bitter-tasting antimalarial tablets for their children to swallow. The sweet-tasting
Coartem Dispersible tablets disperse quickly in small amounts of water, easing
administration and ensuring effective dosing.
32
Artemisinin
Pharmacokinetic data
Routes Oral
Artemisinin is a drug used to treat multi-drug resistant strains of falciparum malaria. The
compound (a sesquiterpene lactone) is isolated from the plant Artemisia annua. Not all
plants of this species contain artemisinin. Apparently it is only produced when the plant
is subjected to certain conditions, most likely biotic or abiotic stress. It can be synthesized
from artemisinic acid The drug is derived from a herb used in Chinese traditional
medicine, though it is usually chemically modified and combined with other medications.
Use of the drug by itself as a monotherapy is explicitly discouraged by the World Health
Organization as there have been signs that malarial parasites are developing resistance to
the drug. Combination therapies that include artemisinin are the preferred treatment for
malaria and are both effective and well tolerated in patients. The drug is also being
studied as a treatment for cancer.
History
33
It remained largely unknown to the rest of the world for about ten years, until results
were published in a Chinese medical journal. The report was met with skepticism at first,
because the Chinese had made unsubstantiated claims about having found treatments for
malaria before. In addition, the chemical structure of artemisinin, particularly the
peroxide, appeared to be too unstable to be a viable drug.
Artemisinin derivatives
Because artemisinin itself has physical properties such as poor bioavailability that limit
its effectiveness, semi-synthetic derivatives of artemisinin, including artemether and
artesunate, have been developed.
There are a number of derivatives and analogues within the artemisinin family:
To counter the present shortage in leaves of Artemisia annua, researchers have been
searching for a way to develop artemisinin artificially in the laboratory. A 2006 paper in
Nature presented a genetically engineered yeast that can synthesize a precursor called
artemisinic acid which can be chemically converted to artemisinin.
34
Artemisinins can be used alone, but this leads to a high rate of recrudescence (return of
parasites) and other drugs are required to clear the body of all parasites and prevent
recurrence. The World Health Organization is pressuring manufacturers to stop making
the uncompounded drug available to the medical community at large, saying it would be
a significant loss if the malaria parasite developed resistance to Artemisinin.
Artemisinins are not used for malaria prophylaxis (prevention) because of the extremely
short activity of the drug. To be effective, it would have to be administered multiple
times each day.
Cancer treatment
Artemisinin is undergoing early research and testing for the treatment of cancer,
primarily by researchers at the University of Washington. Artemisinin has a peroxide
lactone group in its structure. It is thought that when the peroxide comes into contact with
high iron concentrations (common in cancerous cells), the molecule becomes unstable
and releases reactive oxygen species. It has been shown to reduce angiogenesis and the
expression of vascular endothelial growth factor in some tissue cultures.
Resistance
A study published in 2008 by Noedl and colleagues in the New England Journal of
Medicine suggests a consensus among researchers that artemisinin is losing its potency in
Cambodia and increased efforts are required to prevent drug-resistant malaria from
35
Adverse effects
Artemisinins are generally well tolerated at the doses used to treat malaria. The side
effects from the artemisinin class of medications are similar to the symptoms of malaria:
nausea, vomiting, anorexia, and dizziness. Mild blood abnormalities have also been
noted. The only serious adverse effect is an allergic reaction. The drugs that are used in
combination therapies can contribute to the adverse effects that are experienced by those
undergoing treatment. Adverse effects in patients with acute falciparum malaria treated
with artemisinin derivatives tend to be higher.
Mechanism of action
There is no consensus regarding the mechanism through which artemisinin derivatives
kill the parasites. Their site of action within the parasite also remains controversial.
At the chemical level, one theory states that when the parasite that causes malaria infects
a red blood cell, it consumes hemoglobin within its digestive vacuole, liberating free
heme, an iron-porphyrin complex. The iron reduces the peroxide bond in artemisinin
generating high-valent iron-oxo species, resulting in a cascade of reactions that produce
reactive oxygen radicals which damage the parasite leading to its death.
Numerous studies have investigated the type of damage that oxygen radicals may induce.
For example, Pandey et al. have observed inhibition of digestive vacuole cysteine
protease activity of malarial parasite by artemisinin. These observations were supported
by ex vivo experiments showing accumulation of hemoglobin in the parasites treated with
artemisinin and inhibition of hemozoin formation by malaria parasites. Electron
microscopic evidence linking artemisinin action to the parasite's digestive vacuole has
been obtained showing that the digestive vacuole membrane suffers damage soon after
parasites are exposed to artemisinin.
Artemisinins have been reported to inhibit PfATP6, the parasite's SERCA-type enzyme
(calcium transporter), expressed in Xenopus oocytes. In this isolated system, resistance to
artemisinin is reported to be conferred by a single mutation in PfATP6. A study from
French Guiana in field isolates of malaria parasites identified an unrelated mutation in
PfATP6 that was associated with resistance to artemether. However this series of studies
does not constitute convincing evidence that PfATP6 is a site of action of artemisinins, or
that mutations in PfATP6 cause reduced artemisinin susceptibility. Robust evidence in
this context can be obtained by a transfection study, and it is notable that data from such a
study were presented at the Molecular Approaches to Malaria Conference (Lorne,
Australia) in February, 2008 yet remain unpublished. There is no evidence to suggest a
role for PfATP6 in mediating the artemisinin resistance that appears to be emerging in
Cambodia.
36
Dosing
The WHO approved adult dose of co-artemether (artemether-lumefantrine) for malaria is
4 tablets at 0, 8, 24, 36, 48 and 60 hours (six doses).This has been proven to be superior
to regimens based on amodiaquine. Artemesinin is not soluble in water and therefore
Artemisia annua tea was postulated not to contain pharmacologically significant amounts
of artemesinin. However, this conclusion was rebuked by several experts who stated that
hot water (85 oC), and not boiling water, should be used to prepare the tea. Although
Artemisia tea is not recommended as a substitute for the ACT (artemisinin combination
therapies) more clinical studies on artemisia tea preparation have been suggested.
Artesunate
Artesunate
Artesunate (INN) is part of the artemisinin group of drugs that treat malaria. It is a semi-
synthetic derivative of artemisinin that is water-soluble and may therefore be given by
injection. It is sometimes abbreviated AS.
Uses
Artesunate is used primarily as treatment for malaria; but it has also been shown to be
>90% efficacious at reducing egg production in Schistosoma haematobium infection.
Dosing
Intravenous dose of IV artesunate:
37
Synthesis
Artesunate is prepared from dihydroartemisinin (DHA) by reacting it with succinic acid
anhydride in basic medium. Pyridine as base/solvent, sodium bicarbonate in chloroform
and catalyst DMAP (N,N-dimethylaminopyridine) and triethylamine in 1,2-
dichloroethane have been used, with yields of up to 100%. A large scale process involves
treatment of DHA in dichloromethane with a mixture of pyridine, a catalytic amount of
DMAP and succinic anhydride. The dichloromethane mixture is stirred for 6–9 h to get
artesunate in quantitative yield. The product is further re-crystallized from
dichloromethane. alpha-Artesunate is exclusively formed (m.p 135–137˚C).
Drug resistance
Clinical evidence of drug resistance has appeared in Western Cambodia, where
artemesinin monotherapy is common. There are as yet no reports of resistance emerging
elsewhere
Quinine
Pharmacokinetic data
Bioavailability 76 to 88%
Protein ~70%
binding
38
Though it has been synthesized in the lab, the bark of the cinchona tree is the only
natural source of quinine. The medicinal properties of the cinchona tree were originally
discovered by the Quechua Indians of Peru and Bolivia; later, the Jesuits were the first to
bring the cinchona to Europe.
Quinine was the first effective treatment for malaria caused by Plasmodium falciparum,
appearing in therapeutics in the 17th century. It remained the antimalarial drug of choice
until the 1940s, when other drugs replaced it. Since then, many effective antimalarials
have been introduced, although quinine is still used to treat the disease in certain critical
situations. Quinine is available with a prescription in the United States and over-the-
counter, in very small quantities, in tonic water. Quinine is also used to treat lupus,
nocturnal leg cramps and arthritis.
Chemical structure
Quinine contains two major fused-ring systems: the aromatic quinoline and the bicyclic
quinuclidine.
History
Quinine is an effective muscle relaxant, long used by the Quechua Indians of Peru to halt
shivering due to low temperatures. The Peruvians would mix the ground bark of cinchona
trees with sweetened water to offset the bark's bitter taste, thus producing tonic water.
Quinine has been used in unextracted form by Europeans since at least the early 1600s.
Quinine was first used to treat malaria in Rome in 1631. During the 1600s, malaria was
endemic to the swamps and marshes surrounding the city of Rome. Malaria was
39
Synthetic quinine
Cinchona trees remain the only economically practical source of quinine. However, under
wartime pressure, research towards its synthetic production was undertaken. A formal
chemical synthesis was accomplished in 1944 by American chemists R.B. Woodward
and W.E. Doering. Since then, several more efficient quinine total syntheses have been
achieved, but none of them can compete in economic terms with isolation of the alkaloid
from natural sources. The first synthetic organic dye, mauveine, was discovered by
William Henry Perkin in 1856 while he was attempting to synthesize quinine.
Quinine is a basic amine and is therefore always presented as a salt. Various preparations
that exist include the hydrochloride, dihydrochloride, sulfate, bisulfate and gluconate.
This makes quinine dosing complicated since each of the salts has a different weight.
All quinine salts may be given orally or intravenously (IV); quinine gluconate may
also be given intramuscularly (IM) or rectally (PR). The main problem with the rectal
route is that the dose can be expelled before it is completely absorbed; this can be
corrected by giving a half dose again.
40
Adult Give I.M. quinine (600mg/10ml) every 8 hours. (Three times daily)
When the patients improves change to quinine tablet (300mg base) for 3 more days.
NB: If quinine is given I.V. it must be diluted in dextrose/saline and SLOWLY infuse over 4
hours.
Children:
__________________________________________
Weight (kg) Quinine I.M/ml Quinine tab.
b.d t.d.s
3 – 3.9 ½ ¼
4 – 5.9 1 ¼
6 – 9.9 2 ½
15 – 19.9 3 ½
20 – 24.9 4 1
25 – 29.9 5 2
30 – 39.9 6 2½
The preparations available in the UK are quinine sulfate (200 mg or 300 mg tablets) and
quinine hydrochloride (300 mg/ml for injection). Quinine is not licensed for IM or PR
use in the UK. The adult dose in the UK is 600 mg quinine dihydrochloride IV or 600 mg
quinine sulfate orally every eight hours. For nocturnal leg cramps, the dosage is 200–
300 mg at night.
41
Side-effects
It is usual for quinine in therapeutic doses to cause cinchonism; in rare cases, it may even
cause death (usually by pulmonary edema). The development of mild cinchonism is not a
reason for stopping or interrupting quinine therapy and the patient should be reassured.
Blood glucose levels and electrolyte concentrations must be monitored when quinine is
given by injection. The patient should ideally be in cardiac monitoring when the first
quinine injection is given (these precautions are often unavailable in developing countries
where malaria is endemic).
Cinchonism is much less common when quinine is given by mouth, but oral quinine is
not well tolerated (quinine is exceedingly bitter and many patients will vomit after
ingesting quinine tablets): Other drugs such as Fansidar (sulfadoxine (sulfonamide
antibiotic) with pyrimethamine) or Malarone (proguanil with atovaquone) are often used
when oral therapy is required. Quinine ethyl carbonate is tasteless and odourless, but is
only commercially available in Japan. Blood glucose, electrolyte and cardiac monitoring
are not necessary when quinine is given by mouth.
Quinine can cause paralysis if accidentally injected into a nerve. It is extremely toxic in
overdose, and the advice of a poisons specialist should be sought immediately.
Quinine in some cases can lead to constipation, erectile dysfunction and diarrhea.
The New York Times Magazine described a case, presenting with fever, hypotension,
and blood abnormalities mimicking septic shock.
Abortifacient
Despite popular belief, quinine is an ineffective abortifacient (in the US, quinine is listed
as Pregnancy category D. Pregnant women who take toxic doses of quinine will suffer
from renal failure before experiencing any kind of quinine-induced abortion. Indeed,
quinine is the only drug recommended by the WHO as firstline treatment for
uncomplicated malaria in pregnancy.
Disease interactions
Quinine can cause hemolysis in G6PD deficiency, but again this risk is small and the
physician should not hesitate to use quinine in patients with G6PD deficiency when there
is no alternative. Quinine can also cause drug-induced immune thrombocytopenic
purpura (ITP). Symptoms can be severe enough to require hospitalisation and platelet
transfusion, with several cases resulting in death.
42
Hearing impairment
Some studies have related the use of quinine and hearing impairment, in particular
high-frequency loss, but it has not been conclusively established whether such
impairment is temporary or permanent.
Dosing
Dihydroartemisinin is available as a fixed drug combination with piperaquine (each tablet
contains 40 mg of dihydroartemisinin and 320 mg of piperaquine; trade name Artekin,
manufactured by Holleykin Pharmaceuticals).
The adult dose is 1.6/12.8 mg/kg per dose (rounded up or down to the nearest half tablet)
given at 0 h, 8 h, 24 h, and 48 h. Alternatively, the same total dose may be given once
daily for three days.
43
Piperaquine is a bisquinoline antimalarial drug that was first synthesised in the 1960s,
and used extensively in China and Indochina as prophylaxis and treatment during the
next 20 years. A number of Chinese research groups documented that it was at least as
effective as, and better tolerated than, chloroquine against falciparum and vivax malaria,
but no pharmacokinetic characterisation was undertaken. With the development of
piperaquine-resistant strains of Plasmodium falciparum and the emergence of the
artemisinin derivatives, its use declined during the 1980s. However, during the next
decade, piperaquine was rediscovered by Chinese scientists as one of a number of
compounds suitable for combination with an artemisinin derivative. The rationale for
such artemisinin combination therapies (ACTs) was to provide an inexpensive, short-
course treatment regimen with a high cure rate and good tolerability that would reduce
transmission and protect against the development of parasite resistance. This approach
has now been endorsed by the WHO. Piperaquine-based ACT began as China-Vietnam 4
(CV4®: dihydroartemisinin [DHA], trimethoprim, piperaquine phosphate and
primaquine phosphate), which was followed by CV8® (the same components as CV4 but
in increased quantities), Artecom® (in which primaquine was omitted) and Artekin® or
Duo-Cotecxin® (DHA and piperaquine phosphate only). Recent Indochinese studies
have confirmed the excellent clinical efficacy of piperaquine-DHA combinations (28-day
cure rates >95%), and have demonstrated that currently recommended regimens are not
associated with significant cardiotoxicity or other adverse effects. The pharmacokinetic
properties of piperaquine have also been characterised recently, revealing that it is a
highly lipid-soluble drug with a large volume of distribution at steady
state/bioavailability, long elimination half-life and a clearance that is markedly higher in
children than in adults. The tolerability, efficacy, pharmacokinetic profile and low cost of
piperaquine make it a promising partner drug for use as part of an ACT.
44
Medicinal uses
Sweet Wormwood was used by Chinese herbalists in ancient times to treat fever, but had
fallen out of common use, but was rediscovered in 1970 when the Chinese Handbook of
Prescriptions for Emergency Treatments (340 AD) was found. This pharmacopeia
contained recipes for a tea from dried leaves, prescribed for fevers (not specifically
malaria).
Extractions
In 1971, scientists demonstrated that the plant extracts had antimalarial activity in
primate models, and in 1972 the active ingredient, artemisinin (formerly referred to as
arteannuin), was isolated and its chemical structure described. Artemisinin may be
extracted using a low boiling point solvent such as diethylether and is found in the
glandular trichomes of the leaves, stems, and inflorescences, and it is concentrated in the
upper portions of plant within new growth.
Parasite treatment
It is commonly used in tropical nations which can afford it, preferentially as part of a
combination-cocktail with other antimalarials in order to prevent the development of
parasite resistance.
Malaria treatment
45
Cancer treatment
The plant has also been shown to have anti-cancer properties. It is said to have the ability
to be selectively toxic to some breast cancer cells [Cancer Research 65:(23).Dec 1, 2005]
and some form of prostate cancer, there have been exciting preclinical results against
leukemia, and other cancer cells.
Mechanism
Other uses
In modern-day central China, specifically Hubei Province, the stems of this wormwood
are used as food in a salad-like form. The final product, literally termed "cold-mixed
wormwood" is a slightly bitter salad with strong acid overtones from the spiced rice
vinegar used as a marinade. It is considered a delicacy and is typically more expensive to
buy than meat.
46
Credit: NIAID
Glossary
47
48
INDICATION
Treatment of Acute Malaria
Fansidar is indicated for the treatment of acute, uncomplicated P. falciparum malaria for
those patients in whom chloroquine resistance is suspected. However, strains of P.
falciparum (see CLINICAL PHARMACOLOGY: Microbiology) may be encountered
which have developed resistance to Fansidar, in which case alternative treatment should
be administered.
Prevention of Malaria
Malaria prophylaxis with Fansidar is not routinely recommended and should only be
considered for travelers to areas where chloroquine-resistant P. falciparum malaria is
endemic and sensitive to Fansidar, and when alternative drugs are not available or are
contraindicated (see CONTRAINDICATIONS). However, strains of P. falciparum may
be encountered which have developed resistance to Fansidar.
The dosage should be swallowed whole, and not chewed, with plenty of fluids after a
meal.
49
Dosage:
Children.
3–5 ¼
6–9 ½
10 – 19 1
20 – 29 1½
30 – 49 2 (adult)
Prevention of Malaria
The malaria risk must be carefully weighed against the risk of serious adverse drug
reactions (see INDICATIONS AND USAGE). If Fansidar is prescribed for prophylaxis,
it is important that the physician inquires about sulfonamide intolerance and points out
the risk and the need for immediate drug withdrawal if skin reactions do occur.
The first dose of Fansidar should be taken 1 or 2 days before arrival in an endemic area;
administration should be continued during the stay and for 4 to 6 weeks after return.
SIDE EFFECTAS
For completeness, all major reactions to sulfonamides and to pyrimethamine are included
below, even though they may not have been reported with Fansidar (see WARNINGS
and PRECAUTIONS: Information For The Patient).
Hematological Changes
Agranulocytosis, aplastic anemia, megaloblastic anemia, thrombocytopenia, leukopenia,
hemolytic anemia, purpura, hypoprothrombinemia, methemoglobinemia, and
eosinophilia.
50
Respiratory Reactions
Pulmonary infiltrates resembling eosinophilic or allergic alveolitis.
Genitourinary
Renal failure, interstitial nephritis, BUN and serum creatinine elevation, toxic nephrosis
with oliguria and anuria, and crystalluria.
Pregnancy
Teratogenic Effects: Pregnancy Category C
Fansidar has been shown to be teratogenic in rats when given in weekly doses
approximately 12 times the weekly human prophylactic dose. Teratology studies with
pyrimethamine plus sulfadoxine (1:20) in rats showed the minimum oral teratogenic dose
to be approximately 0.9 mg/kg pyrimethamine plus 18 mg/kg sulfadoxine. In rabbits, no
teratogenic effects were noted at oral doses as high as 20 mg/kg pyrimethamine plus 400
mg/kg sulfadoxine.
There are no adequate and well-controlled studies in pregnant women. However, due to
the teratogenic effect shown in animals and because pyrimethamine plus sulfadoxine may
interfere with folic acid metabolism, Fansidar therapy should be used during pregnancy
only if the potential benefit justifies the potential risk to the fetus.
WARNING
FATALITIES ASSOCIATED WITH THE ADMINISTRATION OF FANSIDAR HAVE OCCURRED DUE TO SEVERE
REACTIONS, INCLUDING STEVENS-JOHNSON SYNDROME AND TOXIC EPIDERMAL NECROLYSIS. FANSIDAR
PROPHYLAXIS MUST BE DISCONTINUED AT THE FIRST APPEARANCE OF SKIN RASH, IF A SIGNIFICANT
REDUCTION IN THE COUNT OF ANY FORMED BLOOD ELEMENTS IS NOTED, OR UPON THE OCCURRENCE OF
ACTIVE BACTERIAL OR FUNGAL INFECTIONS.
DRUG DESCRIPTION
51
OVERDOSE
Acute intoxication may be manifested by headache, nausea, anorexia, vomiting and
central nervous system stimulation (including convulsions), followed by megaloblastic
anemia, leukopenia, thrombocytopenia, glossitis and crystalluria. In acute intoxication,
emesis and gastric lavage followed by purges may be of benefit. The patient should be
adequately hydrated to prevent renal damage. The renal, hepatic, and hematopoietic
systems should be monitored for at least 1 month after an overdosage. If the patient is
having convulsions, the use of parenteral diazepam or a barbiturate is indicated. For
depressed platelet or white blood cell counts, folinic acid (leucovorin) should be
administered in a dosage of 5 mg to 15 mg intramuscularly daily for 3 days or longer.
CONTRAINDICATIONS
Mechanism of Action
Sulfadoxine and pyrimethamine, the constituents of Fansidar, are folic acid antagonists.
Sulfadoxine inhibits the activity of dihydropteroate synthase whereas pyrimethamine
inhibits dihydrofolate reductase.
52
Pharmacokinetics
Absorption
After administration of 1 tablet, peak plasma levels for pyrimethamine (approximately
0.2 mg/L) and for sulfadoxine (approximately 60 mg/L) are reached after about 4 hours.
Distribution
The volume of distribution for sulfadoxine and pyrimethamine is 0.14 L/kg and 2.3 L/kg,
respectively.
Patients taking 1 tablet a week (recommended adult dose for malaria prophylaxis) can be
expected to have mean steady state plasma concentrations of about 0.15 mg/L for
pyrimethamine after about four weeks and about 98 mg/L for sulfadoxine after about
seven weeks. Plasma protein binding is about 90% for both pyrimethamine and
sulfadoxine. Both pyrimethamine and sulfadoxine cross the placental barrier and pass
into breast milk.
Metabolism
About 5% of sulfadoxine appears in the plasma as acetylated metabolite, about 2 to 3% as
the glucuronide. Pyrimethamine is transformed to several unidentified metabolites.
Elimination
A relatively long elimination half-life is characteristic of both components. The mean
values are about 100 hours for pyrimethamine and about 200 hours for sulfadoxine. Both
pyrimethamine and sulfadoxine are eliminated mainly via the kidneys.
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Formulations
Efficacy
The antimalarial activity of artemisinin and its derivatives is extremely rapid and most
patients show clinical improvement within 1-3 days after treatment. However, the
recrudescence rate is high when the drugs are used in monotherapy, depending on the
drug dose administered, the duration of treatment and the severity of disease, but not at
present on parasite resistance . Treatment for < 7 days gave unacceptably high
recrudescence rates . So far there is no confirmed in vivo evidence of resistance of P.
falciparum to artemisinin and its derivatives. The susceptibility of P. falciparum strains
from the China-Lao People’s Democratic Republic and China-Myanmar border areas to
various antimalarial drugs have been tested in vitro. The results have indicated declining
susceptibility of P. falciparum to artemisinin derivatives .
These compounds are not recommended for use in the treatment of malaria due to P.
vivax, P. malariae or P. ovale since other effective antimalarial drugs are available for
this purpose. However, they may be used in the absence of micro-scopic diagnosis if they
are the recommended first-line treatment.
Use in pregnancy
Preclinical studies have consistently shown that artemisinin and its derivatives do not
exhibit mutagenic or teratogenic activity, but all of these drugs caused fetal resorption in
rodents at relatively low doses of 1/200-1/400 of the LD50,
i.e. > 10 mg/kg, when given after the sixth day of gestation . Reports on the use of these
drugs during pregnancy are limited . However, malaria can be particularly hazardous
during pregnancy. Artemisinin and its derivatives are therefore the drugs of choice for
severe malaria and can be used for treatment of uncomplicated malaria during the second
and third trimester of pregnancy in areas of multiple drug resistance . Owing to lack of
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Drug disposition
Oral bioavailability varies with the derivative and is influenced by disease status. All
derivatives, but not artemisinin itself are metabolized to a common bioactive metabolite,
dihydroartemisinin, at variable rates .
Adverse effects
Extensive clinical trials in China, Myanmar, Thailand and Viet Nam demonstrated no
acute cardiovascular or other vital organ toxicity. However, animal studies have
demonstrated severe neurotoxicity following parenteral administration of very high doses
of artemether or arteether. Both drugs produced a unique pattern of selective neuropathy
with chromatolysis and necrosis of scattered neurons in vestibular, motor and auditory
brain stem nuclei in rats, dogs and rhesus monkeys . Such effects have not been observed
with oral administration of any artemisinin derivative or with intravenous artesunate. This
has led to the suggestion that the effect is related to specific molecules and their route of
administration. The cause, however, appears to be due to sustainable high levels of the
drugs and their metabolites, which may occur following intramuscular injection, rather
than to the route of administration itself (T.G. Brewer, personal communication, 1996).
There is no clinical evidence to date of serious neurotoxicity resulting from the use of any
artemisinin drug in humans in prospective studies of more than 10 000 patients or in the
more than 2 million persons who have received these drugs . In Thailand, full
neurological examinations in more than 1 100 patients who had received an artemisinin
drug showed no specific pattern of neurological abnormalities. Studies in Thailand and
Viet Nam provided no evidence of any brain stem toxicity attributable to artemisinin and
artesunate . There is some concern about cerebellar dysfunction and prolonged or
repetitive treatment with artemisinin and its derivatives, which may occur in areas of high
transmission, must be viewed with caution. Additional studies to monitor subtle
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A. ARTEMISININ
Formulations
Efficacy
Artemisinin is poorly soluble in oils or water. Preclinical and clinical studies show that
artemisinin is effective against parasites resistant to all other operationally used
antimalarial drugs . It is not hypnozoiticidal. It reduces gametocyte carriage
Use
To reduce the recrudesence rate and the risk of development of resistance, as well as to
improve compliance, artemisinin should preferably be administered in combination with
another effective blood schizonticide. The use of artemisinin as monotherapy should be
limited to specific indications, such as in patients with a history of adverse reactions to
the combination drug. When mono-therapy is used, a 7-day course of therapy is
recommended and adherence to the treatment should be ensured.
When given as monotherapy to patients with uncomplicated falciparum malaria who have
some degree of immunity, a 5-day oral regimen of artemisinin has generally proven to be
curative.
Recommended treatment
Although oral artemisinin has been widely employed in the treatment of uncomplicated
multidrug-resistant falciparum infections , very few well-designed dose-finding studies of
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Monotherapy 20 mg/kg in a divided loading dose on the first day, followed by 10 mg/kg
once a day for 6 days.
Combination therapy
20 mg/kg in a divided loading dose on the first day, followed by 10 mg/kg once a day for
two more days plus mefloquine (15-25 mg of base per kg) as a single or split dose on the
second and/or third day.
Rectal administration
In emergency pre-referral treatment of severe malaria or for patients who cannot take oral
medication, artemisinin can be given by rectal administration before referral to hospital
or before medication becomes possible . This is intended as emergency management of
malaria in life-treatening circumstances and may be provided on a presumptive diagnosis
of malaria.
A single dose of 40 mg/kg should be given intarectally, then 20 mg/kg 24, 48 and 72
hours later, followed by oral treatment with an effective antimalarial drug.
Chemoprophylaxis
Use in pregnancy
Artemisinin can be used for treatment of uncomplicated malaria during the second and
third trimester of pregnancy in areas of multidrug resistance . Owing to lack of data, use
in the first trimester of pregnancy is not recommended (see above).
Drug disposition
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Adverse effects
Adverse effects may include headache, nausea, vomiting, abdominal pain, itching, drug
fever abnormal bleeding and dark urine. Minor cardiac changes (mainly non-specific ST
changes and first degree atrioventricular block) have been noted during clinical trials.
These returned to normal after improvement of malaria symptoms. Experience indicates
that artemisinin and its derivatives are less toxic than the quinoline antimalarial drugs,
few adverse effects being associated with their use.
Prolonged or repetitive treatment with artemisinin and its derivatives must be treated with
caution. Additional studies, which monitor subtle neurological changes and hearing loss,
are required especially in patients undergoing repetitive treatment. Post-marketing
surveillance is recommended in countries where these drugs are marketed and used.
Contraindications
Overdosage
B. ARTEMETHER
Formulations
Efficacy
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Use
Artemether is not recommended for the treatment of malaria caused by P. vivax, P. ovale
and P. malariae since other effective antimalarial drugs are available for this purpose.
However, it may be used in the absence of microscopic diagnosis if the compound is the
recommended first-line treatment.
Recommended treatment
ARTEMETHER INJECTION:
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• This drug is given IMI as a daily dose. You can change over to tablet once the
patient is able to take oral medication.
• Like the tablet, the first dose of injection is also double.
Uncomplicated malaria
Monotherapy: 4 mg/kg loading dose on the first day, followed by 2 mg/kg once a day for
6 days.
Combination therapy
4 mg/kg once a day for 3 days, plus mefloquine (15 mg or 25 mg of base per kg) as a
single dose or split dose on the second and/or third day.
Severe malaria
3.2 mg/kg by the intramuscular route as a loading dose on the first day, followed by 1.6
mg/kg daily for a minimum of 3 days or until the patient can take oral therapy to
complete a 7-day course. The daily dose can be given as a single injection. In children,
the use of a tuberculin syringe is advisable since the injection volume will be small.
Use in pregnancy
Similar to artemisinin.
Drug disposition
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Toxicity studies in dogs and rats indicate that dose-dependent and potentially fatal
neurotoxic effects may occur after intramuscular injection of artemether at doses higher
than those used for malaria treatment . These changes can be widespread but mainly
affect areas associated with vestibular, motor and auditory functions . No similar findings
have been reported in humans treated with normal therapeutic doses of artemether.
Contraindications
Similar to artemisinin.
Overdosage
Similar to artemisinin.
C. ARTESUNATE
Formulations
Efficacy
Use
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Recommended treatment
Giving a dose twice daily offered no advantage over once daily dosing . While 7-day
regimens have a therapeutic advantage over 5-day regimens, this might be offset by
decreased patient adherence to the treatment; recrudescence rates of 50% are reported
following 3-day regimens regardless of the dosage used . The shorter courses provided
higher cure rates when a double dose was given on the first day of treatment or if the
drugs were combined with a longer-acting single-dose antimalarial such as mefloquine .
A regimen of 3-5 days of artesunate in combination with mefloquine given either
concomitantly or sequentially provides cure rates of nearly 100% .
ARTESUNATE TABLET
Dosage
4 – 5.7 ½ ¼
6 – 8.9 ¾ ½
9 – 12.5 1 ½
12.6 – 18.5 1½ ¾
18.6 – 24.9 2 1
25 – 31.9 2½ 1½
32 – 37.5 3 1½
Over 37.5 4 2
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Monotherapy: 4 mg/kg loading dose on the first day, followed by 2 mg/kg once a day for
6 days.
Combination therapy
4 mg/kg once a day for 3 days, plus mefloquine (15 mg or 25 mg of base per kg) as a
single dose or split dose on the second and/or third day .
Severe malaria
2.4 mg/kg by the intramuscular route followed by 1.2 mg/kg at 12 and 24 h, then 1.2
mg/kg daily for 6 days. If the patient can swallow, the daily dose can be given orally.
2.4 mg/kg intravenously on the first day followed by 1.2 mg/kg daily until the patient can
take orally artesunate or another effective antimalarial drug.
Drug disposition
Adverse effects
Prospective clinical studies of more than 10 000 patients, and post-marketing surveillance
of over 4 600 patients in Thailand has not shown any serious drug-related adverse
reactions.
Rectal administration
In emergency pre-referral treatment of severe malaria or for patients who cannot take oral
medication, artesunate can be given by rectal administration before referral to hospital or
before oral medication becomes possible . This is intended as emergency pre-referral
management of malaria in life-threatening circumstances and may be provided to patients
on a presumptive diagnosis of malaria.
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There is no information on efficacy in patients with severe and complicated malaria who
have organ and systems failure, including renal failure and liver disease. No studies have
been undertaken with this formulation in pregnant or lactating women or in patients with
diarrhoea.
D. DIHYDROARTEMISININ
Formulations
Efficacy
These derivatives have more potent blood schizonticidal activity than the parent
compound. Dihydroartemisinin is the most potent antimalarial of this group of
compounds but it is also the least stable.
Use
Recommended treatment
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Data on dihydroartemisinin are very limited, but the currently recommended dosage is as
shown above. Dihydroartemisinin has been used in combination with mefloquine . Short
courses of treatment of less than 5 days have higher recrudescence rates .
Drug disposition
Oral dihydroartemisinin is rapidly absorbed and has a short elimination half-life although
little is known of its metabolism. Peak plasma concentrations are achieved in 1-2 h and
the drug disappears from the circulation within 8-10 h.
E. ARTEETHER
Formulations
Efficacy
Use
Arteether is not recommended for the treatment of malaria caused by P. vivax, P. ovale
and P. malariae since other effective antimalarial drugs are available for this purpose.
Recommended treatment
For adults, 150 mg/day administrated once daily by the intramuscular route for 3 days.
For children, 3 mg/kg per day by the intramuscular route for 3 days.
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Intramuscular arteether has the lowest bioavailability (34%) of all the artemisinin
derivatives tested in the rat, with approximately 14% converted to dihydroartemisinin. It
has a long elimination half-life (> 20 h) and is more stable and more lipophilic than the
other artemisinin compounds.
Adverse effects
F. ARTELINIC ACID
Efficacy
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