ACKNOWLEDGEMENTS
1
Table of Contents
Introduction
Chapter 1
MALARIa
Chapter 2
DRugs – Out of reach
Chapter 3
The lifeblood of economics
Chapter 4
The tomorrow of today
Conclusion
3
4
4
6
6
17
17
23
23
26
2
Introduction
Malaria and Africa is without doubt a very broad topic and there are many
aspects in which to view it. The sheer depth and complexity of this raging
epidemic is impossible to comprehend much report in a balanced fashion.
This dissertation is a whirlwind tour of the science and economic of drugs
implemented to aid the crisis of Malaria in the Sub- Sahara Africa.
I chose Sub- Sahara Africa to focus on
mainly because it is in this poor country
that a child is killed every 30 seconds;
3000 die everyday; a staggering 1.5 to 2.7 million African deaths a year,
according to the World Health Organization (WHO)’s estimates. 1Most of
those dying are children and pregnant women, with 300 to 500 million infected
every year. This colossal burden appears to be growing heavier and we will
identify the major players and take a quick glance into their inner workings in, I
hope, an evenhanded way.
We will highlight the development of drugs and incessant search for a vaccine
through trials and more trials. The stumbling block in creating a successful
cure is discussed as well as the fraught with political, economical and scientific implications which have to be
overcome to bring the drugs to where it will be in years to come. From that we will observe the victories through the
discovery of effective drugs as well as failures, through inadequacies, incompetence and selfishness.
There is no right and wrong, and as this is crisis is on a human level, mistakes are inevitably made. There are
however a great many things that we can do. The current situation in sub-sahara Africa emphasizes the need for a
more pro-active response by all parties involved to broaden the approach to help the development of the country.
Lastly, it is my hope that you will enjoy reading this dissertation as I have writing it. 1
Rachel Mak
1
Due to the nature of some of the contents discussed in this report, I would like to express my
sincerest apologies should any material in this dissertation insult or offend you, the reader, in
any way and it is by no means my intention and regrettable.
3
Chapter 1
MALARIA
1.1 What is Malaria?
M
alaria is a life-threatening parasitic disease of the blood
which is transmitted to human beings by the female
Anopheles mosquito. It is caused by any one of four species of
one-celled (protozoan) parasites, called Plasmodium. The four
types of plasmodium are P. falciparum (which is the most deadly),
P. vivax, P. ovale and P. malariae. The typical symptom of malaria
is a violent fever lasting 6 to 8 hours, recurring every two or three
days. Plasmodium falciparum malaria presents an irregular tertian
fever which leads to a coma and eventually death.2 This is most
common in Africa, south of the Sahara, accounting for the extremely high mortality in this region.
The three stages of an
attack of malaria
1.2 The Vicious Cycle
The female Anopheline mosquito transmits malaria parasites from one person
to another - male mosquitos do not as they feed only on plant juices. It uses its
proboscis to penetrate the victim's skin and the saliva which flows into the
victim's skin to ease the pain is where the Protozoan is located. 3The malaria
parasite enters the human host when an infected Anopheles mosquito has a
blood meal. Inside the human host, the parasite undergoes a series of changes
as part of its complex life-cycle. It is these multiple stages that allow plasmodia
Figure 1- Man and mosquito play
complementary roles in Malaria
cycle
to evade the immune system, infect the liver and red blood cells and finally
develop into a form that is able to infect another mosquito as feeds on an
infected person. Inside the mosquito, the parasite matures until it reaches the sexual stage where it can again infect
a human host when the mosquito takes her next blood meal, 10 to 14 or more days later.
4
Inside the human blood, the parasites
travel to the liver cells to grow and
multiply. At this point, the infected person
shows no symptoms. About 8 days to
several months later, the parasite leaves
the liver cells and enters the red blood
cells where they grow and multiply again.
Upon maturing, the ruptured red blood
cells free the parasites (gametocytes)
which go on to attack and enter other red
blood cells. Toxins released when the red
cells
burst
is
what
causes
fever,
headache, vomiting and other flu-like
symptoms. 4
Figure 3 – The Life Cycle of Malaria
1.3 How it kills?
5Malaria
kills by infecting and destroying red blood cells (anaemia) as well as
clogging capillaries that carry blood to the brain (cerebral malaria) or other vital
organs affecting the central nervous system. In the less common blackwater fever it
is the haemoglobin from the burst red blood cells that damage the kidney and
excreted in the urine causing its dark colour. Without immediate treatment or
should the parasites be resistant to them the infection is life-threatening.
Figure 2 - The effect of
Malaria on blood cells
providing anaemia in time.
1.4 Transmission
The cycle of transmission carries on only if the female Anopheles mosquito bites an infected person and ingests the
‘gametocytes’. Since the malaria parasite is found in red blood cells, blood transfusion, organ transplant, shared use
of blood-contaminated syringes will transmit malaria. A mother can also transmit malaria to her fetus before or
during delivery, a condition known as ‘Congenital Malaria’.6
1.5 Why the plague goes on…
The epidemic outbreak of malaria is closely linked to the weather, surrounding
temperatures, humidity and rainfall. Mosquitoes breed in areas of stagnant water
such as swamps which become more pronounced in Africa during the rainy
seasons.7 Mosquitoes that transmit the disease are becoming increasingly
resistant to insecticides and the parasites themselves are evolving with high resistance to drugs used to treat the
disease. Humans are left vulnerable to the disease since there is yet to be a vaccine to build antibodies. Lack of
resources and political instability prevents the building of solid malaria control programs in Africa. Lack of funding is
key as to why this disease still ravages Africa which is closer examined in the later sections.
5
chapter 2
DRUGS – OUT OF REACH
2.1 VACCINE
So near yet so far…
A malaria vaccine could help; vaccines are seen as the backbone of public health
interventions, especially in poor countries, where they help contain or even eradicate
leading killer diseases such as polio, measles and tetanus. A vaccine could
significantly improve malaria control, particularly in Africa where the ecological habitat
is such that effective mosquito control has proved difficult or impossible to maintain.
Intensive research is currently conducted into the vaccine development against both
falciparum and vivax malaria. The development criteria require that the antigen serves
a function critical to the parasite, is associated with naturally acquired immunity, or is
protective in animal models.8
RTS,S/AS02A or Mosquirix is the most advanced pre-erythrocytic vaccine
intended to prevent invasion of hepatocytes by sporozoites or to destroy infected
hepatocytes. It is a hybrid molecule in which circumsporozoite protein of
P.falciparum is expressed with Hepatitis-B surface antigens (HBsAg) in yeast. 9 The
vaccine provides short-lived protection in volunteers, exposed experimentally to bites
by infected mosquito.10 A trial of RTS,S/AS02A in Mozambican children,11 gave 30%
protection against the first clinical episode of malaria and 58% protection against
severe malaria.
MSP-1 (merozoite surface protein-1) and AMA (apical
merozoite antigen)-1 blood-stage vaccines are designed at
eliminating or reducing the number of blood-stage parasites.12
A combination vaccine of three blood-stage antigens
contributing to erythrocyte invasion reduced parasite density
in a strain-specific manner. Unfortunately, it had no
pronounced effect on the overall number of clinical malaria
episodes.13 These vaccines are currently undergoing trials.
Figure 2 - AMA-1
molecular structure
segment
Transmission blocking vaccines are designed to reduce transmission by preventing mosquitoes from becoming
infected from feeding on vaccinated individuals.14 Transmission-blocking vaccines against P falciparum and P
vivax are in phase I trials.
6
Vaccines to trigger and boost T cells aims to elicit cytotoxic T cells that can kill malaria parasites in infected
liver cells. Unlike red blood cells, liver cells can alert the immune system to the parasite invasion and thereby
render themselves targets for killing.
This ‘'prime-boost' vaccines involve a two-step procedure in which volunteers are first given a DNA-based vaccine
to instruct body cells to produce malaria proteins as if they were infected with the parasite. This first step provides
the initial stimulus to T cells that can detect these liver-stage antigen targets. The second step, booster
vaccination contains attenuated viruses that carry synthetic portions of various pre-erythrocytic, liver-stage
antigens, including CSP (circumsporozoite protein) and also another sporozoite protein known as TRAP
(thrombospondin-related adhesion protein). It is capable of recognizing and killing malaria-infected cells. Phase I
trials have shown safety and some immunogenicity, Phase IIb trials on adult male Gambian volunteers have not
shown significant protective efficacy of such vaccines. Further clinical trials of alternative prime-boost vaccines
designed to produce stronger responses are underway.15
Approximately 40 malaria vaccines are now in clinical trials, according to WHO. Some 45 are in preclinical
development and about 20 are at the research stage. It has progressed rapidly by the availability of more funds
and by improved organisation mediated through organisations such as the Malaria Vaccine Initiative.140
However, it is likely to be at least a decade before an effective vaccine is available for widespread use in malariaendemic countries.
Fever, represented as a frenzied beast,
and ague, depicted as a blue monster.
1788
2. 2 DRUGS
Evolution- from witchcraft to…..
For centuries, fever has haunted mankind and in turn mankind came up
with ingenious remedies to combat them. In ancient times, vomiting,
amputation, limb blood-letting, even skull operations, were tried to treat
malarial fever. It finished off sufferers in a fairly short time.
In England, they tried opium laced beer with opium grown from local poppies. The help of astrology was also sought
as the periodicity of the malarial fever suggested a connection with astronomical phenomena. Believe it or not, many
turned to witchcraft. One suggestion by the Dominican scholar Albertus Magnus, was to have insects devour 77
small cakes made from dough prepared by mixing flour with the patient’s urine. For the patient, the remedy was to
drink brandy with a concoction of pepper and three drops of cat’s blood from its cut ear. Ironically, the poor who
could not afford the help of the medical profession managed to survive! 16
Discoveries
It was in the remarkable year of 1820, that a feasible antimalarial drug was isolated by Pelletier and Caventou from the
yellow cinchona bark in the form of a sticky, pale yellow gum,
which
Figure 3 - Cinchona
Ledgeriana
is
non Figure 4 – Cinchona
Ledgeriana bark
7
crystallizable. The gum was soluble in acid, alcohol and ether and highly effective against malaria. The four chief
alkaloids (a basic compound from amino acid metabolism which usually contains at least one nitrogen atom in a
heterocyclic ring) extracted from this Cinchona ledgerian bark are two pairs of diastereoisomers, quinine and
quinidine and cinchonidine and cinchonine, the latter pair lacking the 6-methoxy group.17
What’s so great about Quinine or NOT?
Quinine (C20H24N2O2) is one of the 36 alkaloids with a structure containing ‘asymmetric’ carbon atoms, which are
connected to four different chemical groups and allows the overall structure to be arranged in different ways. Hence,
16 stereoisomers are possible but only one corresponds to the active drug form.
Haemoglobin is the main protein inside a red blood cell. The malaria parasite creates a vacuole in the cell where it
breaks the hemoglobin down for its own use in building up its own protein for growth. This causes the release of the
iron-containing haemo part of the molecule, which could build up and become toxic, so the parasite detoxifies it by
converting it into an insoluble form. Quinine interferes with this conversion and the parasite is killed by the buildup of
iron compounds.
18It
is thought that because the quinine structure resembles DNA bases, it can interfere with DNA replication within
the malarial parasite by forming complexes using its flat aromatic rings. Though quinine kills malarial parasites in red
blood cells, alleviates fever and is analgesic (pain-relieving), it does not kill the parasites living outside the red blood
cells allowing relapses to occur if quinine therapy is halted.
19Resistance
to the drug has been reported sporadically
in 1844 and 1910; hence, research was initiated to find a quinine substitute. Nonetheless, it still remains an
important and effective treatment especially for severe falciparum malaria in most parts of the world.
20The
total synthesis of quinine shows how the formation of quinine by oxidation of deoxyquinine with oxygen in tert-
butyl alcohol-DMSO, in the presence of potassium tert-butoxide, proceeded selectively, as had been found by the
Hoffmann-La Roche group.
21
It was this group that illustrated a number of syntheses of quinine in which the
quinuclidine ring was created by forming the bond between N-1 and C-8. That strategy, which may be called the
Rabe connection, was endorsed by the workers who followed Rabe, starting with Woodward and Doering, 22
presumably because of the attractive structural simplification it seemed to offer.
8
Current biotechnology has developed a method to produce quinine by culturing plant cells. Grown in test tubes on a
special medium containing absorbent resins, the cells can be manipulated to release quinine which is absorbed by
the resin and then extracted. This method has high yields but is extremely expensive and fragile. 23
With the advent of World War II, many more drugs were developed to counter the shortage in quinine when Japan
invaded Java in 1941 and took most of the supplies. Two main derivatives of quinine are Chloroquine and
Mefloquine.
CHLOROQUINE: ARALEN™
AN D
Chloroquine
MEFLOQUINE: L AR I AM ™
Mefloquine
These two compounds have similar molecular structure to quinine, composing of two flat aromatic rings, with an
offset section. They both have a mechanism of action similar to Quinine, but with their own special ‘something’. In
1934, the introduction of Chloroquine (a 4-aminoquinoline derivative of quinine) by Hans Andersag24 was seen as a
breakthrough and this is now regarded as ‘the’ prototype anti malarial drug, most widely used to treat ALL types of
malaria infection. It was also the cheapest, time tested and safe anti malaria agent.
9
Technology and the drug’s pathway
With improving technology, an electron microscope was used to study the effect of quinolinecontaining drugs on Plasmodium Falciparum. It appeared that the first physical changes
were the swelling of the food vacuole and accumulation of undigested hemoglobin. As
mentioned above, this vacuole is the site of hemoglobin degradation to provide amino acids
for growth, and the drug operates by blocking action of the food vacuole. Chloroquine is a
diprotic weak base and is attracted to the acidic pH of the parasite’s food vacuole raising the
pH. Once in the vacuole it deprotonates and become membrane impenetrable, accumulating toxic haem in the
vacuole-within the parasite.25
THE TARGET
The latest research reference 26suggests that the target for drugs to act on is Ferriprotoporphyrin IX (FP), a self-toxic
protein involved in the parasite enzyme heme polymerase that converts toxic heme into non-toxic hemazoin (malaria
pigment). Chloroquine is effective because it binds to FP and the complex acts as a catalytic poison to the
polymerization process and stops the conversion. It operates against asexual forms of pathogenic malaria
parasites (called the "haemo-schizontocidal effect"). However, it is inefficient against gametocytes or exoerythrocytic liver forms and induces many side effects. The most serious reaction is pigmentary retenitis with an
irreversible loss of visual field; however, this only occurs after an accumulative dose of 1000 mg or more.
Nevertheless in Chloroquine sensitive malaria, it reduces the fever and clears blood of parasites within 24 hours.
This is a radical cure for P. falciparum infection, but not for P. ovale or P. vivax as there is always an exo-erythrocytic
phase in which the hypnozoites may lead to a clinical relapse attack.
THE ANTAGONISTIC EFFECT
27
Mefloquine inhibits the uptake of chloroquine in infected cells by blocking ingestion of hemoglobin which in turn
disrupts the generation of FP to which chloroquine binds to. This is the antagonistic effect of chloroquine and
mefloquine on parasite growth – increased resistance of parasites to chloroquine makes it more sensitive to
mefloquine.
Mefloquine works well because it interferes with the transport of hemoglobin and other substances from
erythrocytes to the food vacuoles of the malaria parasite. Like Chloroquine,
28Mefloquine
affects only the asexual
form of the parasite with no effect on exo-erthrocytic liver forms or on gametocytes. Resistance has been
reported, but if combined with Chloroquine or quinine it is overcome. Mefloquine is a blood schizonticidal of the
erythrocytic malaria and will kill hypnozoites if given as a combination treatment with primaquine. Side effects
include: vertigo, nausea, vomiting, abdominal pain and diarrhoea. On very rare occasions neuropsychiatric
sympto€ms may occur.
10
Yet another to battle Chloroquine resistant-Pyrimethamine/Sulfadoxine
Pyrimethamine
Sulfadoxine
Pyrimethamine and sulphadoxine are adjuncts which are useful for treatment of uncomplicated, chloroquine
resistant, P. falciparum malaria. They cause the failure of nuclear division during schizont formation in
erythrocytes and liver.
29Pyrimethamine
inhibits the dihydrofolate reductase of plasmodia and blocks the
biosynthesis or purines and pyrimidines, which are essential for DNA synthesis and cell multiplication.
Sulofadoxine inhibits the utilisation of para-aminobenzoic acid in the synthesis of dihydropteroic acid. The
combination of pyrimethamine and sulfa thus offers two step synergistic barrier of plasmodial division. However,
the side effects of Pyrimethamine are occasional skin rashes and depression of hematopoiesis. Excessive doses
can produce megaloblastic anemia.
30Sulfonamides
on the other hand, can cause numerous adverse effects such as Agranulocytosis; a plastic
anemia; hypersensitivity reactions like rashes, fixed drug eruptions, erythema multiforme of the Steven Johnson
type, exfoliative dermatitis, serum sickness; liver dysfunction; anorexia, vomiting and acute hemolytic anemia can
also occur.
So far, all the drugs discussed all under the category of Blood schizonticidal drugs whereby they act on the
blood forms of the parasite and thereby terminate clinical attacks of malaria. These are the most important drugs
in anti malarial chemotherapy.
The Gametocytocidal Drug
These drugs destroy the sexual forms of the parasite in the blood and prevent transmission of the infection to the
mosquito. Chloroquine and quinine have gametocytocidal activity against P. vivax and P. malariae, but not
against P. falciparum. The main drug is Primaquine.
Primaquine (8-aminoquinolines)
It is the essential co-drug with chloroquine because it is both gametocytocidal drug
as well as a prototype for the tissue schizonticides to prevent relapses. It is highly
effective against the gametocytes of all plasmodia and thereby prevents spread of
the disease to the mosquito from the patient.
31It
is also effective in treating the
dormant tissue forms (hypnozoites) of P. Vivax or Ovale malaria in the liver. Once
the parasite has been eliminated from the bloodstream, the remaining schizonts
must be removed from the liver and this is done by administering a 14 day course of
11
Primaquine. It has insignificant activity against the asexual blood forms of the parasite and only affects the
parasite in tissue therefore it is always used in conjunction with a blood schizonticide and never as a single agent.
If Primaquine is not administered there is a very high likelihood of a P. Vivax relapse within weeks or months,
sometimes even years. The mechanism of action is not well understood, but it may be acting by generating
reactive oxygen species or by interfering with the election transport in the parasite.
Atovaquone/Proguanil: Malarone™
NH
HN
CH3
C
CH
HN
C
CH3
N
H
NH
HCl
Cl
Atovaquone
Proguanil Hydrochloride
This is a prophylactic antimalarial drug; its purpose is to prevent, rather than treat or cure, disease. The
difference between this and a vaccine which is also prophylactic is the drug measures are divided between
primary prophylaxis (to prevent the development of a disease) and secondary prophylaxis (whereby the disease
has already developed and the patient is protected against worsening of this process). A vaccine is used before
an illness has developed.
32Proguanil
Hydrochloride with atovaquone prevents malaria caused by Plasmodium falciparum.
Proguanil
Hydrochloride prevents malaria by stopping the parasite from reproducing once it is in the red blood cells. It does
this by blocking the action of an enzyme that is found in the Plasmodium parasite. Then, the enzyme dihydrofolate
reductase is involved in the reproduction of the parasite by converting folic acid into folinic acid in the parasite,
which is a step essential for the parasite to produce new genetic material (DNA). New DNA is necessary for the
parasite to reproduce. By blocking its production, proguanil prevents any malarial parasites that have entered the
red blood cells from reproducing and increasing in number.
Atovaquone also works by interfering with the production of substances needed for malarial parasites
reproduction. It works in a slightly different way, but when combined with Proguanil Hydrochloride, it is an
effective drug. Proguanil with atovaquone may be particularly useful for preventing malaria in areas where this
parasite is known to be resistant to other antimalarial medicines, such as Chloroquine.
Some of the
33side
effects of this drug include nausea, vomiting, diarrhoea or abdominal pain; fever (pyrexia);
headache; inflammation of the lining of the mouth (stomatitis); mouth ulcers; loss of appetite and dizziness. This
drug is also unsuitable during pregnancy or breastfeeding as safety has yet to have been established.
12
2.3 THE REMARKABLE CHINESE DRUG
ARTEMISININ- The sweet wormwood
34The
Chinese call it Qinghao; western botanists dub it Artemisia annua or sweet wormwood. The Chinese have
used this to treat fevers for thousands of years but little did they realize that Artemisia held the key to beating
malaria. In the 1970s, without the sophisticated knowledge of organic chemistry, Tu Youyou managed to extract a
chemical called Artemisinin.
In 1979, chemists successfully determined the structure of artemisinin using X-ray crystallographic analysis. They
discovered that artemisinin was a sesquiterpene (consisting of three isoprene units and have the molecular
formula C15H24) with five oxygen atoms, two of them in a peroxide bridge system over a seven-membered ring
and two others in a lactone ring structure. As Artemisinin is highly insoluble in oil and water, it can only be
administered orally.
Artemisinin’s reaction to malaria was ground breaking. Its mechanism worked with such
pace and effectiveness that when the drug encountered the parasite, it immediately
acted as a deadly toxin eradicating the parasite from the bloodstream.
35Artemisinin
derivatives such as the water soluble ester called artesunate and two oil soluble
preparations called artemether and arteether have now been developed.
Artemisinin
Mode of Action
The commonality between Artemisinin and its derivatives is a trioxane
pharmacophore containing a peroxide bridge. The peroxide bridge present
undergoes reductive scission by low-valency transition metals to generate
oxygen-centred radicals. These radicals, due to affinity for hydrogen, might
generate carbon-centred radicals and produce an FP=O, leading to an epoxidea highly active alkylating agent. The carbon-centred radicals may alkylate either
haemo or other proteins, such as Translationally Controlled Tumor Protein
13
(TCTP) – it still remains unknown. It is also unclear whether haem-bound artemisinin can react with proteins
which do not bind to haem.36 In fact, there are loopholes with the carbon-centered radical theory. It is common in
reductive cleavage of endoperoxides but not linked with antimalarial activity. Radical proteins are short lived –
they do not survive to even reach the target molecules.
With that, comes yet another proposal.
37The
trioxane pharmacophore acts as a source of hydroperoxide by
generation of an oxo-stabilised cation upon heterolyisis of the C3-O2 bond. By reduction, an electrophilic
oxygenating species or hydroxyl and alkoxyl radicals would be capable of hydroxylating biomolecules or
abstracting hydrogen atoms. Nonetheless, the true mode of action is still being investigated. As for now, a simple
explanation would be the two oxygen atoms forming the epoxide bridge reacts with the detoxified iron compound
and releases free radicals which damage proteins produced by the malarial parasites. It also disrupts the normal
function of the electron transport chain within mitochondria. This exploits the difference between the human red
blood cell - which does not need to produce proteins and also does not contain mitochondria - and the malarial
parasite - which needs both.
38The
WHO accorded high priority to the development of fast acting, effective artemisinin derivatives drugs for the
treatment of cerebral malaria as well as for the control of multi-drug resistant P. falciparum malaria. WHO lists in its
2005 malaria control guide the following advantages of artemisinin derivatives: Rapid reduction of parasite
densities; rapid resolution of clinical symptoms; effective action against multi-drug resistant P. falciparum; no
documented parasite resistance to artemisinin and its derivatives; few clinical adverse reactions; and reduction of
gametocyte carrier rate, which may reduce transmission (i.e., fewer of the parasite’s gametocytes within an
infected person lowers the probability of a biting mosquito becoming a carrier).
They highly recommend combination therapy that includes artemisinin drugs as the standard treatment in
countries where malaria is resistant to the older individual drugs such as Quinine and Chloroquine.
ACT
A combination of artemisinin derivatives with another effective antimalarial medicine is called artemisinin-based
combination therapy (ACT) and is currently the most effective medicine available to treat malaria. The total effect
of artemisinin combinations (which can be simultaneous or sequential) is to reduce the chance of parasite
recurrence, improve cure rates, and prevent transmission.
39Studies
have revealed high levels of resistance to
chloroquine and sulfadoxine-pyrimethamine of up to 78%. In the few areas where amodiaquine and sulfadoxinepyrimethamine remain effective, they can be partnered with artemesinins as artesunate-amodiaquine and
artesunate/sulfadoxine-pyrimethamine combinations. Where parasite resistance to these partner drugs has built
up, artemether-lumefantrine or artesunate-mefloquine is more successful.
Artemisinin based combinations
 Artesunate + Chloroquine
 Artesunate + Amodiaquine
 Artesunate + Mefloquine
 Artesunate + Sulfadoxine/Pyrimethamine (SP)
14
 Artemether + Lumefantrine (Coartem,TM RiametTM)
To optimize cure rates, four particularly challenging requirements must be fulfilled: the entire course of treatment
must be completed by patient; the drugs need to be good-quality; they also need to be appropriately selected; and
the vast majority of malaria infections need to be treated with ACTs.
Uganda- doing it THEIR way!
For centuries, Ugandans have used herbs to treat the symptoms of malaria.
Effective as it has been, it has not gone through any safety tests. These traditional
anti-malaria ‘drugs’ are derived from three plants:
⊱
Aristolochia elegans, known locally as kapapula or 'little paper'
⊱
Vernonia amygdalina, commonly known as mululuza
⊱
Artemisia annua, introduced to Africa from its native Asia
Jar of seeds and tree bark used in African Traditional
Medicine
40Along
with HIV/AIDS, malaria is widespread in
Uganda — so common it is accepted as ordinary to
be infected by either. Nambatya, director of research
at the state-run Natural Chemotherapeutic and
Research Laboratory (NCRL) says the remedies "clearly treat malaria", and
explains that tests on people who have used them have shown that they do rid the
parasite. The aim is to scale up extraction of key components from herbs that prove
to be safe and effective and to mass-produce remedies based on them, so that they
may be sold cheaply while retaining their quality. Eventually, they might even be
exported to other needy countries.
“To be inflicted with malaria is considered normal and to go to a burial as a result is thought
normal too, but we have to reject this situation because we do not have to be so sick or die so
”
prematurely in such large numbers.
-Jim MuhzewiUganda Minister of Health
15
2.4 DRUG RESISTANCE – greatest threat to malaria control!
Drug resistance has been confirmed in 2 out of 4 of the human malaria parasites, Plasmodium falciparum and P.
vivax.
Drug-resistant Plasmodium falciparum
41In
the late 1950’s and early 1960’s, Chloroquine was resistant to the P.falciparum and since then, it has only gotten
worse with the resistance spreading to nearly all areas of the world where P.falciparum malaria is transmitted. As
other drugs were developed to overcome chloroquine’s resistance, P. Falciparum eventually developed resistance to
them as well. They are sulfadoxine/ pyrimethamine, mefloquine, halofantrine, and quinine. In Africa, chloroquine
resistance was first documented in Tanzania in 1979 and has spread and intensified in the last 20 years. In most
countries of East Africa and in Ethiopia more than 50% of patients currently experience a recurrence of parasitaemia
with symptoms by day 14 after treatment. In some areas of the world, this would cause an extensive impact on the
multi-drug resistant malaria.
Drug-resistant Plasmodium vivax
In 1989, Chloroquine resistant P. vivax malaria was identified among Australians living in or traveling to Papua New
Guinea. Now, all over Southeast Asia, on the Indian subcontinent, and South America have all been affected. Nearly
50% of strains from these areas currently show evidence of reduced susceptibility in 28-day in vivo tests. Particularly
in Oceania, Vivax malaria exhibits decreased susceptibility to Primaquine.
Tests for Drug Resistance
The four basic methods are:
i.
42
In vivo tests: Patients with clinical malaria are given a dose of an antimalarial drug and are observed
and monitored over time for any signs of reappearance of parasites or failure to clear parasites.
ii.
43
In vitro tests: Blood samples are taken from malaria
patients and the malaria parasites are exposed to
different concentrations of antimalarial drugs in the
laboratory. One method is by adaptation of parasites to
culture first, and the other, the blood from patients is
directly put into the test system.
iii.
Molecular characterization: Molecular markers of P. falciparum that confer resistance have been
identified for some drugs like chloroquine, SP, atovaquone and cycloguanil), whilst for others, they are yet
to be determined. Molecular techniques such as polymerase chain reaction (PCR) or gene sequencing
can identify these markers in blood taken from malaria patients.
iv.
Animal model studies: These tests allow for the testing of parasites which cannot be adapted to in vitro
enviroments (provided a suitable animal host is available) and the testing of drugs not yet approved for
use in humans. [This is not routinely done compared to the other 3 tests] 44
16
Chapter 3
THE LIFEBLOOD OF ECONOMICS
Some say Malaria is like the ‘silent tsunami’. Ironically, the distressing statistical death toll rises every year and
millions of cases are audible enough to many- as are the economic costs,
by WHO. Malaria and poverty are intimately connected.
46T.H.
45estimated
at US$12 billion per annum
Weller, a Nobel laureate in medicine, once said, ‘It
has long been recognized that a malarious community is an impoverished community.’ The risk of malaria has
always been geographically specific as is poverty. Almost all rich countries are outside the bounds of the killer
Sending a clear signal to the world community: No money-no drugs.
The Players
Malaria
sufferers
Pharmaceuticals
The players all play a part in
the
fight
against
malaria.
Some may be complacent,
Scientists
Non-profit
organizations
Malaria
but others try their best. The
economic
implications
all
draw the players together and
in some way or another they
are all linked.
Countries
Philanthropists
3.1 The ARTEMISININ DRUG
Drawbacks, drawbacks, drawbacks
Artemisinin is isolated from Artemisia annua- a plant that takes up to 18 months to get from seed to pill. This lengthy
period makes it very difficult to secure the drug, resulting not only in delays and shortages but in making scale-up
production a highly costly venture. The World Health Organisation (WHO) estimates the world will need 132million
courses of ACT treatment (which cost up to $2.40 each) in 2005 – a four-fold increase over 2004 – and almost eightfold in 200647. In fact, at $2.40, it is at least 10 times more expensive than other anti-malarial drugs. As effective as
ACTs are where extensive tests have proven effectiveness of more than 90%, they do have a number of drawbacks.
Since 2001, the WHO has recommended that countries where drug resistance occurs to switch to ACT.
Unfortunately, international efforts were sluggish until early 2004, when a stinging paper published in the Lancet
accused the WHO and the Global Fund to Fight AIDS, Tuberculosis and Malaria of “ medical malpractice” for
17
continuing to approve and fund proposals from poor countries to treat malaria using older, cheaper drugs even
though it may be less effective than of ACT.
Getting countries to switch to ACT is merely a question of securing drugs. Doctors
need proper training on how to use and administer them and surveillance systems
have to be set up to monitor resistance.
One project aimed at addressing these problems attempts to engineer an artificial
artemisinin. OneWorld Heath, a California-based nonprofit pharmaceutical
company, is using technology developed at the University of California, Berkeley
(which granted royalty-free licenses to the company) to create the drug.
48With
a $42 million grant from the Bill and
Melinda Gates Foundation, OneWorld Health over the next five years will use synthetic biology technology to try to
lower the price from $2.40 to $0.24 per treatment.
In fact, Chinese firms such as Guilin Pharmaceuticals are also trying to cultivate the plant – both on their own
plantations and through contracts with local farmers, rather than relying on wild leaves.
The cost of Artemisinin treatment threatens to undermine not only the OneWorld Health effort, but the very
effectiveness of artemisinin itself. This has proliferated the counterfeiting trade of ACT in Southeast Asia where
fraudulent treatments contain minute amounts of artemisinin. This negligible amount fools simple dye authenticity
tests. Paul Newton of Oxford University emphasizes that a diluted treatment is by no means a cure.
"This would be a disaster for malaria control globally,” Newton has said in a number of publications. "We may have
malaria that could not be treated in any affordable way." Medicines for Malaria Venture (MMV) has set the goal of
registering at least one new effective and affordable drug before 2010 as a means of avoiding such a disaster. An
optimistic J Carl Craft, MMV’s chief scientific officer, has said that he expects to have one or two new combination
drugs by 2007 and as many as three or four by 2010 to meet any change in resistance patterns.49
3.2 THE VACCINE
Scientists are optimistic as prospects for a malaria vaccine have been boosted by “tantalising” results from trials on
children in Mozambique in 2000 which investigators reported in an article in the Lancet, a British medical journal.50
The big question though, is how these new vaccines will be introduced in low income countries and how long it will
take regulatory authorities to approve them? These two other hurdles need to be overcome in order for these
vaccines to get to the people who need them most as quickly as possible.
The discovery of a successful and effective vaccine is the best chance of sending the disease into retreat, however
hopes for that fall as quickly as they rise. Therefore, as a result of this, research into malaria receives only some
$60million a year, compared with $140million for asthma, $300million for Alzheimer’s disease and $950million for
AIDS. 51
Malaria Vaccine Initiative (MVI), a non-profit organization, coordinated and funded the trials conducted by
researchers from GlaxoSmithKline (GSK) – the world’s second largest drug company, the University of Barcelona
18
and Mozambique’s health ministry. GSK which own the Mosquirix (RTS,S/AS02A) vaccine has said it will make it for
the public sector but since it is so costly, and as the vaccine is not suitable for the more lucrative travelers’ market,
the company will need assurances that rich countries will buy it for poor ones.
The Bill and Melinda Gates
Foundation gave a $108 million grant in November 2005 to support clinical development of the vaccine but at 1/10 th
of the research money of AIDS, much more is required 52
3.3 POVERTY – the driving force of parasitic infection
A WHO report pointed out that various economic analyses show that malaria is not only the
product of poverty; they also create poverty.
53"You
don't need to sustain it (donations from
wealthy countries) indefinitely...Healthy people can get themselves out of poverty," said David L.
Heymann, head of communicable disease programs at WHO.
The scale of carnage wrought by malaria in Africa afflicts a hundred times more people than it kills - the cost of
treatment impoverishes those who could initially afford it, and those who are already impoverished are left to knock
on death’s door.
African’s health budget is minuscule- they do not have enough money to fight this disease.
The anti-malarial drugs are inaccessible and unaffordable leading to a limited access of
drugs and a very small percentage of children who need treatment actually get it. There is
also the problem of a dis-
regulated
with counterfeit drugs on offer,
so
environment is very poor and
very often the drug
taken is not what they think it is. The country itself does
not have sufficient
income to bring in the effective drugs that have proved
useful against multi
the
system
regulatory
drug resistant strains.
In fact, it would be some time before such drugs or
vaccines
will
be
widely available in Africa due to low production,
comparatively
costs, dosing complexity and the lack of clinical
experience - all of
high
which is due to poverty one way or another.
Africa does not have money set aside for research development, and hence, it is up to the developed nations for aid
and research funding to help find a cure and save millions of lives. The lack of research capacities leads to severe
constraints in Africa. Time and time again, we come across the issue of poverty, since many of the interventions
required are simply unaffordable. There are many constraints to ideal control measures of a severe disease such as
malaria – this in the form of strong infrastructures in place for immediate treatment, referral to more detailed medical
care and ultimately, hospital-based management. Underdeveloped health care services and severe shortages of
trained staff to administer treatments continue to be one of the key underlying failures of the African healthcare
system. Health and wealth are inextricably linked. A malaria sufferer would not only be spending accumulated
wealth on treatments but loss in productivity would also cause the economy to suffer.
Its mind boggling how so little has been done to curb it.
19
3.4 Lacking Investment
The global burden of malaria is unevenly distributed with malaria-endemic countries like Africa absorbing large
economic and social penalties. Studies have shown that the growth rate of per capita gross domestic product (GDP)
in countries with malaria is markedly lower than those countries that are malaria free. The difference appears
modest – malaria-endemic countries have a rate of between 0.25% to 1.3% lower than non-malarial countries but
when extrapolated over a 25 year period, this difference adds up to almost half the per capita GDP of poor
countries.54
Richard Feachem, executive director of the Global Fund to Fight AIDS, Tuberculosis and Malaria, has said that he is
convinced that the Millennium Development Goals (MDG) target of halting and reversing the incidence of malaria
may only actually be achievable by 2015. Experts beg to differ, saying that malaria research and development
receiving inadequate funding to ensure the MDG will be met. It somehow seems that donations by The Gates
Foundation are the only factor making a difference.
The New York Times, published on the 25th of April 2006, reported that the World Bank has failed to follow
through on its pledges to spend up to $500 million to combat malaria. Public health
experts writing inThe Lancet claims that they have allowed the staff working on the
disease to shrink to zero, used false statistical data to claim success and wasted
money on ineffective medicines whilst recommending that the bank should relinquish
the money it has to fight malaria and reduce mortality and it be put to more effective
uses.55
Even diabetes’s burden to society which is about one-third of that of malaria
Problem of money which is
given to charities ends up in
the hands of the government
gets nearly six times more money for R&D.
3.5 Pharmaceutical Companies
Lives should come before profit shouldn’t they?
Malaria is neglected by the pharmaceutical industry because there is more money to
be made from other more ‘lucrative’ disease. Without commitment to strengthening
malaria vaccine research capacity, an effective malaria vaccine may never be
produced and tested, or, if it is, may even benefit the Africans who need it most. For example, pharmaceutical
companies target tourists and provide them with more lucrative malaria vaccines rather than the inhabitants of
developing countries who cannot afford them. Profit driven pharmaceuticals therefore,have very little incentive to
research a vaccine or drug for a disease that affects mainly the poor resulting in them missing out on breakthroughs.
“Although the technology is there it is not affordable by majority of our people," says a paediatrician in a research
institute in Nairobi.
20
Evidence: A highly effective drug – Coartem –recommended by the Ministry of Health as a drug of choice and
currently in the market, but not accessible at public hospitals. Where it is available though, the poor are definitely
locked out.
Dr Wellington Muiruri of Novartis Pharmaceuticals – manufacturers of Coartem – made an agreement with WHO
to supply the drugs to the government, on one condition. The drugs have to be offered free of charge to the
public. Those who can afford the drugs could obtain it from the private sector. So, the question is why has the
state not stocked them in government hospitals? The answer to that is the government, without donor assistance
cannot buy the drugs for free distribution. , hence, Africans can say goodbye to effective drugs.
Without organizations like the Bill and Melinda Gates Foundation who have generously sponsored some
encouraging research, Africa’s population would deplete and no one would care!
3.6 TAXATION- making things worse
There are several proven, cost effective techniques for curbing malaria, none of which
is as widely used as it should. One example is the Insecticide-treated bed net. In
2002, the government of Malawi launched one of the largest insecticide-treated bed
net (ITN) distribution programmes in Africa. ITNs were subsidised to the highest levels
possible and distributed through child health clinics, community networks and the
private sector. The programme proved to be successful to a significant degree and
reduced the number of people infected with malaria. So why is it that those who live in
some of the most isolated and malaria-infested areas are still unable to buy ITNs,
despite the reduced prices? That is because these ‘reduced’ prices are still too
expensive!
Although nets have grown cheaper in the recent years, they still cost about $5 each –
equivalent to as much as a typical African country spends on health care, per person
per annum! Malaria prone countries need to abolish taxation on bed nets because as
it is, they might not even be able to pay for them even if it were tax free. In fact, they
should give it out for free! African governments should realise that making life-saving
devices more costly is hardly a rational health policy. Their argument against
subsidising ITNs has been that subsidies could not be sustained unless rich nations
were prepared to provide funding indefinitely.56
21
3.7 MONOPOLY– developed countries
It cannot be denied that developed countries have the upper hand in terms of
research, pre-clinical research and early phases of clinical trials. This headstart
allows for them to gain academic accolades with their research published and
products patented quickly. African institutions lack the necessary facilities and
expertise with African researchers and study participants finding themselves out in
the cold. Researchers in Africa may be forced to take on the later stages of research
which are highly demanding but less rewarding academically. Along with study
participants, they may be excluded from patent negotiations. At the end of the day,
products may never become available to people on whom it was tested. 57
3.8 African Scientists
What is holding Africa back?
Research has two driving forces: the quest for basic knowledge, and the need to use
scientific understanding to improve our lives. Are African researchers trained to ask the
right questions?
Before there even is research there has to be researchers. Being faced with rising debt,
struggling healthcare systems and food shortages, many African governments rank
scientific research — even for a disease of such magnitude as malaria — the lowest on
their list of priorities. This lack of support means that researchers often battle with basic
infrastructure problems such as frequent power cuts and poor access to water and electricity. Without these
improvements, many observers fear the competent researchers would leave the continent, taking vital knowledge
and experience with them. “As we see more and more drugs and vaccines that need to be tested in African
populations, the presence of well-trained African scientists could become the critical factor in their success or
failure,” said Ogobara Doumbo, director of the Malaria Research and Training Centre at the University of Bamako
in Mali.
Apart from that, experts are also concerned about the deaths of malaria researchers in Africa.
58In
1999, there
were only 752 trained malaria researchers in sub-Saharan Africa, according to the Multilateral Initiative on Malaria
(MIM). Unfortunately however, very few of them are experienced at preparing research proposals and protocols,
mobilising money, acting as consultants, networking with the scientific, health and donor communities, or liaising
with policy and decision makers. Malaria researchers in Africa must not simply sit back and wait for a malaria
vaccine to appear. They must become fully familiar with the scientific advances, and establish early collaborative
links with malaria vaccine developers.
22
Chapter 4
THE TOMORROW OF TODAY
59In
“The simplicity of the theory of malaria
this final chapter, we examine the prospects for malaria
eradication and how much, or how little it has changed in the three or
more decades since Hackett’s cry of exasperation.
control is surpassed only by the difficulties
”
involved in its application.
In terms of antimalarial drugs and the development of resistant strains
of malaria parasites, a number of single drugs and drug combinations
-L.W.Hackett (1937)An Ecological Study
are available to treat and prevent infections with such strains.
Unfortunately, the ‘ideal drug’ which is a good and safe anti-relapse
agent with complete curative action, sporontocidal activity, low toxicity, prolonged action, little liability to produce
resistance, palatability and low cost is unlikely to be forthcoming. The rapid expansion in parasite biochemistry may
well allow the development of a rationale or the design of new drugs with the involvement of universities.
Dr. Oliver Bilker from the Divison of Cell and Molecular Biology at Imperial College and the biological science team
are investigating the key life cycle in the malaria parasite and studying a number
of parasite gene family which are involved in regulating the calcium- dependent
protein kinase 4 (CDPK4) - a molecule found in plants. By doing so, they will be
one step closer in identifying the drug targets.
“There is a high potential
that the drugs needed may be
found in the environment
”
itself.
As for now, drug combinations will probably continue to stem the tide for the next
decade until new drugs become available.
-Dr. Oliver Billker-
4.1 The Role of Vector Control
Drugs can only do so much, but when they fail, other options become a possibility.
The major weapon in the fight to reduce transmission to
the anopheline vectors is spraying with residual
insecticides. New insecticides of all types continue to
be developed to cope with the DDT-resistant strains.
Carbamate
Figure ? : DDT
and
organophosphate
insecticides
were
introduced and thought to be comparatively free from the
resistance liability associated with DDT. Indoor residual spraying (IRS) does not directly
prevent people from being bitten by mosquitoes. Rather, it usually kills mosquitoes after
they have fed, if they come to rest on the sprayed surface, thus preventing transmission
23
60DDT
of infection to other people. However,
was banned in the United States in 1973 due to its high toxicity
especially to fishes, although it is still in use in some other parts of the world.
Another major intervention in malaria control is the Insecticide treated bed
nets which provide protection by killing mosquitoes and other insects. They
have repellent properties that reduce the number of mosquitoes that enter
the house and attempt to feed on humans.
61The
government is trying to
achieve high community coverage so as to reduce the numbers and
longevity
of
mosquitoes.
When
this
happens, all members of the community will
be
protected,
regardless
of
bed
net
ownership.
In Chapter 1, we discussed on why the plague goes on. We saw that it was because
there were habitats for mosquitoes to breed and now, a method of source reduction
or larval control is aimed at destroying the larval habitats by filling depressions that
collect water, by draining swamps or by ditching muddy areas to remove standing
water. Container-breeding mosquitoes are particularly susceptible to source
reduction as Mosquitoes that breed in irrigation water can be controlled through
careful water management. People can be educated to ensure standing water in cans or rain barrels are covered.
4.2 Reaching out to lend a helping hand
“We do not have the money, the
62Those
manpower or the health facilities to protect
people as we would like to do.
”
-Dr. Samuel MabundaMozambique’s Health Ministry
Official
words of Dr. Samuel Mabunda can all change with the
help of developed countries; one of it being Britain. British
Chancellor of the Exchequer, Gordon Brown, was very much
aware that there were insufficient funds to make sure the vaccine
goes into commercial production and was affordable to the world’s
poorest countries like Africa.
63He
then made the statement “I can
announce that the British government, working with other
governments, is ready to enter into agreements to purchase these
vaccines in advance to ensure a secure market and that the vaccines are available more cheaply."
With scientists confident that the new vaccine may be able to protect a significant proportion of children against
the mosquito-borne disease, Africa can be hopeful of malaria free future. GSK says its vaccine could reach the
market in 2010, if it is successful in a final round of large-scale clinical testing.
64On
June 30, 2005, President Bush announced the President’s Malaria
Initiative (PMI), a U.S. government program designed to cut malaria deaths in
half in target countries in sub-Saharan Africa. To make this a reality, the
President pledged to increase U.S. funding of malaria prevention and treatment
in sub-Saharan Africa by more than $1.2 billion over 5 years. Other donors;,
24
foundations; and private, public, and voluntary organizations were called on to complement the U.S. commitment
by providing additional funding. They work together with Roll Back Malaria among many others with their goal
being partnership and raising awareness.
65RBM
was launched in 1998 by the World Health Organization (WHO),
the United Nations Children’s Fund (UNICEF), the United Nations Development Programme (UNDP) and the
World Bank. The RBM Partnership’s goal is to halve the burden of malaria by 2010.
25th of April is a very special day for Africans. It is the Africa Malaria Day and this event is commemorated every
year offering an annual opportunity to raise the world’s awareness of Africa’s fight against malaria. It is also an
occasion to take stock of the situation, midway toward the goal of 2010.
25
Conclusion
My perceptions and views when I embarked on this dissertation are no different from what it is now, following
more in-depth research and analysis into this topic. There is no one enemy to point your guns at, but a host of
contributory factors, some easily corrected, and others, a more daunting challenge. I still believe that not nearly
enough has been done by the different parties involved, when there is still much more room for improvement.
There are still hard truths that have to be faced.
The wily Plasmodium remains extraordinarily adept at evading the effects of toxic chemicals and will continue to
present the chemotherapist with one of his greatest challenges. A malaria vaccine may ultimately be the greatest
promise as it would break the cycle of transmission and possibly achieve a global state of anophelism without
malaria that exists only in certain parts of the world.
Nonetheless, Africa has to realize that they need to take responsibility and play its part before seeking any
assistance, which at the moment has to expect. Incompetence and complacency has to be eradicated. Education
and pro-active involvement by the government should be priority. It is clearly essential to balance the probable
benefits of eradication of malaria, in terms of improvement in health and economic advancement, against the cost
in human resources and money.
The events of the last two decades have served to teach that neither the parasite nor the vector keeps to the
status quo; they remain flexible, and the successful drugs of today are invariably the failures of tomorrow. Malaria
remains a formidable global problem. Nevertheless, success has been achieved in some African nations; there is
no reason why others cannot achieve the same.
Millions are suffering and dying, the plague raging on.
ф
Don’t let the innocent and helpless be a victim of this apocalypse.
ф
Don’t let 2 people die every minute, leaving 3000 African lives perished by the end of the day.
ф
26
We
can
make
a
difference
-
27
we
have
to
act
now
!
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32