malaria training manual for malaria updated 6 2013 by: anthony musso

7/30/2019 Malaria Training Manual for Malaria Updated 6 2013 By: Anthony Musso

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Email:[email protected] Tel: + 1 561 5064032 USA

Anthony Musso

Malaria Training Manual By: Anthony Musso 2012 Copyright

Section 1 Malaria

1. Introduction--------------------------------------------------------------------------------------32. History of Malaria------------------------------------------------------------------------------33. Points to Remember--------------------------------------------------------------------------3-44. The Parasite------------------------------------------------------------------------------------4-55. Morphologic Characteristics of the Plasmodia--------------------------------------------5-66. Life Cycle----------------------------------------------------------------------------------------67. Plasmodium Life Cycle-----------------------------------------------------------------------6-78. Human Part-------------------------------------------------------------------------------------7-89. Mosquito Part----------------------------------------------------------------------------------8-910. The Malaria Vector----------------------------------------------------------------------------9-1111. Malaria: the disease----------------------------------------------------------------------------1112. The Attack & Fever----------------------------------------------------------------------------1113. The Classical Fever Stages------------------------------------------------------------------11-1214. Other symptoms--------------------------------------------------------------------------------1215. Falciparum Malaria---------------------------------------------------------------------------12-1316. Untreated Malaria Attack----------------------------------------------------------------------1317. Some Characteristics of Four Species of Human Malaria-------------------------------14-1518. Malaria in Pregnancy-------------------------------------------------------------------------15-1619. Malaria in Children-----------------------------------------------------------------------------1620. Diagnoses of Malaria and Its Problems----------------------------------------------------16-1721. Eradications of Malaria-----------------------------------------------------------------------17-1822. Control of MalariaSection 2 Anti-malarial

1. First Anti-malarias------------------------------------------------------------------------------192. Synthetic Anti-malarias----------------------------------------------------------------------19-203. Resistance to Anti-malarias--------------------------------------------------------------------204. Extent of Resistance----------------------------------------------------------------------------205. Resistance Drugs------------------------------------------------------------------------------20-216. Spread of Resistance----------------------------------------------------------------------------217. The Anti-malarial Drugs----------------------------------------------------------------------21-238. Spectrum Activity of Anti-malaria-----------------------------------------------------------24-269. Drugs Used for Malaria Treatment----------------------------------------------------------27-3210. Clinical Use of Anti-malaria-------------------------------------------------------------------3211. Principles of Malaria Treatment---------------------------------------------------------------3212. A Treatment of non-resistant Malaria-------------------------------------------------------32-3313. B Treatment of drug resistant Malaria--------------------------------------------------------33
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14. C Malaria Prevention--------------------------------------------------------------------------33-3415. Malaria Treatment and Prevention-------------------------------------------------------------3416. Immunity to Malaria and Treatment---------------------------------------------------------34-3517. Acquired Immunity------------------------------------------------------------------------------3518. Passive Immunity-------------------------------------------------------------------------------3519. Malaria Treatment during Pregnancy-------------------------------------------------------35-3620. Treatment in Children--------------------------------------------------------------------------36Section 3 ActRx Cure for Malaria

1. Introduction of Artemisinin-------------------------------------------------------------------372. Mechanism of Action--------------------------------------------------------------------------373. Pharmacokinetics-------------------------------------------------------------------------------374. Clinical Use------------------------------------------------------------------------------------37-385. Toxicity-------------------------------------------------------------------------------------------386. Combination Therapy---------------------------------------------------------------------------387. Artemisinin Derivatives----------------------------------------------------------------------38-398. About Dihydroartemisinin---------------------------------------------------------------------399. Clinical Success Rate of Dihydroartemisinin-----------------------------------------------3910. Benefits of Dihydroartemisinin-------------------------------------------------------------39-4011. Combination Product Criteria-----------------------------------------------------------------4012. The Rationale----------------------------------------------------------------------------------40-4113. The Evidence------------------------------------------------------------------------------------4114. WHO Recommendations on Malaria Treatment-------------------------------------------4115. ActRx Cure for Malaria-----------------------------------------------------------------------41-45


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Section 1 Malaria

1. Introduction

Malaria is one of the most important infections in terms of human suffering and

death. It is estimated that over 300 million people suffer globally from acute malaria

and almost one million die each year and the majority of the victims are children. In

spite of the fact for 50 years huge efforts have been made to ride the world of this

affliction, the depressing fact is that half of the worlds population is still at risk of

having the disease.

Malaria eradication programs have been partially successful only l. Although manydeveloped countries have either been freed of malaria or have their number of cases

drastically reduced, most tropical areas where the disease is endemic, seeing renewed

resurgence. The first reason is renewed spread of mosquito, the carrier of the disease

and development of resistance to the parasite, the cause of the disease, to drugs used

to treat disease. The other reason is in the USA and Europe, where the mosquito-borne

infections have been eradicated, malaria is again presenting a health problem due to

the enormous increase in travel to the endemic regions.

2. History of Malaria

Malaria is a very old disease and prehistoric man is thought to have suffered from

malaria. It probably originated in Africa and accompanied human migration to the

Mediterranean shores, India and South East Asia. In the past it used to be common in

the marshy areas around Rome and the name is derived from the Italian (mal-aria) or

bad air; it was known as Roman fever. The important events in our understanding of

the cause of malaria took place towards the end of 19th century via the science of

pathology and parasitology. In 1880 Laveran, a French army surgeon in Algeria, first

saw described malarial parasite in the red blood cells in man. However, the way in

which the spread was still uncertain until Patrick Manson, a Scottish doctor put

forward the theory that mosquitoes transmitted malaria from man to man. Ross, actingon this suggestion, returned India with a microscope to do the detective work, and in

1897 provided the final link in the malarial parasites life cycle, the evidence was

finding of malaria parasite in the body of a mosquito that had previously bitten a

malaria patient.

3. Points to Remember

The mysteries of malaria were unraveled over many centuries and today we know

how all the stages are linked. They are as follows:

Malaria is caused by a parasite infection in man.

The parasite circulates in the blood stream in man.


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When a mosquito bites an infected person, it sucks up the blood, which contains

parasite.

The parasite do not cause disease in the mosquito but undergo a development

process. When this mosquito bites another person, it injects infectious parasite into

blood stream and thus transmits from one person to another.Man is the host to the malaria parasite and contracts the disease.

The mosquito is the vector; it transmits the disease but doesnt suffer from

infection.

Malaria is one of the most serious of all the tropical diseases, causing much

morbidity and mortality. It is widely distributed in the tropical and subtropical zones

being endemic throughout South and South East Asia, Africa, Middle East, South and

Central America.

Sex and age are not important factors with regard to the malarial infections.

However, pregnant women and children are more susceptible to the effects of the

disease.The pattern of disease distribution around the world reflects that of different

parasite species, with the most dangerous now recognized as drug resistant forms of

Plasmodium falciparum.

In addition to the risk of malaria to the inhabitant of endemic regions, the risk to

travelers to these regions must be mentioned. During the past decade, the greatly

increased speed and volume of tourist and business traveler has resulted in large

number of imported cases of malaria into countries where the disease has already

been eradicated.

4. Parasite

The parasites, which cause malaria, are microscopic, unicellular organisms called


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protozoa. They are larger than bacteria and capable of free movement (motile). The

specific malaria parasite all belong to one genus namely, plasmodium. There are four

species that infect man and each cause a different form of malaria. The four species

and the type of malaria they cause are given below. Sometimes the common but

obsolete names are used.

Species Infections Common, obsolete names

Plasmodium falciparum

Plasmodium vivax

Plasmodium ovale

Plasmodium malariae

Falciparum malaria

Vivax malaria

Ovale malaria

Quartan malaria

Malignant tertian

Benign tertian, simple

Ovale tertian

Benign quartan


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Plasmodium falciparum is the most dangerous parasite of all because:

-It causes the worst illness (highest morbidity)

-Unless treated quickly it frequently causes death (highest mortality)

-It is highly infective

-It is widely distributed in tropical and sub-tropical areas.

-It is the major infection in the areas of endemic malaria.


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6. Life Cycle

To understand malarial disease it is necessary to have a detailed knowledge of the

life cycle of the infective parasite. For the four types of malarial parasite the lifecycle

is essentially same.

The natural carrier of the malarial parasite is man. Female Anopheles mosquitoestransmit them from man to man. The parasite has two phases in the life cycle, one in

man and the other in mosquito.

In man, the vertebrate host, parasites multiply dividing Asexually-Schizogony.

In mosquito, in invertebrate host, parasites multiply by sexual process-Sprogony.

The two phases in the parasite life cycle:

7. Plasmodium Life CycleSCHIZOGONY

Female Anopheles mosquito (definitive host-our Vetoria) bites human (intermediate

host) injecting SPOROZOITES in mosquito saliva into human bloodstream.

Sporozoites travel to liver where they mature and undergo asexual reproduction

(exoerythrocytic schizogony) through cell division producing merozoites.

The resulting merozoites invade red blood cells where they grow into trophozoites

and feed upon the cell hemoglobin.


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The nuclei begin to divide in asexual reproduction (erythrocytic schizogony) forming

schizonts which are made up of individual merozoites.

The cell containing the schizont eventually bursts releasing the merozoites into

bloodstream where they invade new red cells and repeat the process of eythrocyticschizogony.

After several generation of erythrocytic schizogony, some of the merozoites develop

into male and female gametocytes which are ingested by a mosquito when she takes a

blood meal.

SPOROGONY

Gametocytes travel to the mosquito gut where they mature into gametes.

Fertilization occurs forming a zygote which matures into oocyst.

The occyst produces hundreds of motile sporozoites which travel to the mosquito

salivary glands to be injected into a human host when the mosquito takes a blood

meal.

8 Human Part

The schizogony phase in humans consists of two development stages:

Liver-stage- in the hepatocytes called the pre-erythrocytic or exothrocytic stage

Blood-stage- The erythrocytic stage, in the red blood cell.

Liver stage

Pre-erythrocyte schizogony

When mosquito bites a man it injects thin, spindle-shaped protozoa called

sporozoites, into the blood. These are cleared from the blood in about an hour, a

proportion entering into the cells of the liver. In this liver, the sporozoites grow and by

multiple division of their nuclei produce large, multinucleate, cyst-like structures

Schizonts. They are in fact called pre-erythocytic schizonts to distinguish them

from their cousins which are produced later. These schizonts develop; each nucleus

forms into a new small, elongated cell merozite. When mature, the liver schizontsburst and release thousands of merozoites into blood stream.

With P.falciparum, schizogony can produce up to 40,000 merozoites per schizont

while vivaz may produce 10,000. This is the further reason why P.falciparum us much

more serious than others.

For P.faliciparum and P.malariae, the liver stage stop here, i.e. They undergo only

primary of pre-erythrocytic schizogony . However, for P.vivax and P.ovale, further

liver stages can occur latent forms Hypnozoites remain in the liver and delayed cell

division(exo-erythrocytic schizogony) leads to relapses of malaria.

Red Blood cell Stage


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Erythrocytic schizogony

The merozoites released by the liver attach themselves to, and either the red blood

cells. This begins the red blood cell stage (erythrocytic stage or cycle), in which the

merozoites develop in two ways:

a-

into more merozoites andb- into sexual gametocytes.a- The merozoites feed on the red cell haemoglobin, grow and progressively

change into various forms, ring form, early and late trophozoites. Then the

fully-grown trophozoites divide into schizonts (erythcytic schizogony). These

related to the liver schizonts, the mature schizonts contain only 6-24

merozoites, depending on the species, which are released into the blood

stream when the red cells burst. These merozoites can infect new red cells and

the cycle is repeated with more and more parasites being produced until they

kill the patient or are controlled by anti-malarial drugs or the immune

response.It is the release of merozoites into the blood stream which causes the fever of

the malarial attack, with each new cycle repeating the fever.

The followings are the commonly used terms.

The pre-patent period, is the interval between infection and the time when the

malarial parasite are detectable in the blood but cause no symptoms

The time between first infection and first appearance of the symptoms of the

disease is called incubation period.

The length of the incubation period depends on the infecting parasite:

P.falciparum: 12 days

P.ovale: 13-17 days

P.malariae: 28-30 days

P.vivax: 13-19 days, up to 9 months.

b- After several generations of merozoites have been produced in the red cells,

some of the merozoites instead of developing into schizonts, undergo sexual

differentiation to become male or female cells (Gametocytes).

9. Mosquito Part

When the mosquito sucks the blood of an infected person, the parasites are

released into its stomach. The asexual merozoites and red blood cells are digested andthe gametocytes undergo further developments.

The sexual phase of the life cycle (sporogony) starts when the gametocytes into

male and female gametes and these are united to produce a single cell (zygote). The

zygote changes into a motile cell (ookinete), which penetrates the stomach, and forms

a small sphere on the stomach wall (oocyst). The oocyst grows and by multiple fission

of its nucleus produces sporozoites. These burst through the oocyst wall and invade

the mosquitos body vavity with a proportion reaching the salivary glands. At this

stage the mosquito may contain up to half of a million sporozoites.

The next time this mosquito feeds on man it injects the sporozoites in the salivary

glands into the blood stream, and the parasite life cycle starts afresh in a new victim.


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The time taken for the development of the malarial parasite in the mosquito is called

the extrinsic incubation period. It varies with the different parasite and mosquito

species and the environmental factors especially temperature but it is never shorter

than 9 days.

It should be pointed out that passed on via blood, for example, by bloodtransfusion or from mother to her baby though placenta. Neither of these two ways

requires the mosquito. However, once the parasite has entered the erythrocytic stage,

they cannot invade the tissue, so there is no liver stage when infection is induced by

this method of transmission.

Characteristics of Malarial Parasites

Characteristics P. falciparum P. malariae, P. vivax, P.

ovale

Duration of Liver Cycle

Duration of Blood CycleParasitaemia *% infected

red blood cells

Duration of Mosquito

Phase

1/2-7 days

1 day0.4%-10%

9 days or more

6-16 days

2-3 days0.12-14%

12 days or more(8-10 in

P.V)

..Also can be expressed as

0% infected red cells

Number of infected red cells/mm

Number of red cells/100 white blood cells

10. The Malaria Vector

Only mosquitoes of the genus anopheles can transmit human malaria. It is the

malaria vector. There are about 400 species of Anopheles in the world, but only 60 of

them are vectors of malaria under natural conditions,

Distribution

Since mosquitoes see warmth to survive, they live mainly in tropical and

subtropical regions, but in summer are also found in temperature areas.

HabitatWe have seen the age-old association of malaria with swamps, marches and mist

etc. common to all this is water, the natural habitat of mosquitoes. The mosquito

needs to lay its eggs in water.

For this reason attempts to control the spread of malaria have included steps to

reduce or eliminate the accumulation of still water from any source such as leaking

taps, sewerage, improper drainage, irrigation water and swamps.

10.1 Feeding and Behavior

Only the female mosquito feeds on blood, the male feeds on nectar and plantjuices. The male is only need once for mating because the female for all the future egg


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batches stores the supply of sperms. The female need the food in blood for egg

development. She needs on the warm-blooded animals. Different types of mosquito

prefer different types of species, such as birds, monkeys and of particular significance

humans. She is very good at finding her prey, because she is able to sense temperature,

light, smell, moisture, etc. after piercing the skin and capillary blood vessel, sheinjects the contents of her salivary glands into the wound to irritate it and increase the

blood flow. This incidentally, is what causes the itch and the small wheal experienced

after the mosquito bite.

Feeding takes place in the dark, either at night, between dusk and dawn, or in the

daytime in dense shade of in dark dwellings.

After feeding the mosquito rests in dark, humid places-notably in houses on walls

and ceilings.

10.2 Reproduction

Lets follow the female mosquito through her life span. When she becomes anadult and after mating with a male she has two blood meals and 4-5 days later her first

batch of eggs develops. Following egg batches are produced more quickly, every 2-3

days and only need one blood meal. The eggs, 100-200 in each batch, are laid singly I,

or near, water to incubate for 2-3 days, or up to 16 days or more if conditions are

unfavorable. They must have water to survive. Dried eggs cannot survive. Larvae

develop and float horizontally just below the water surface. They are easily to be

recognized by their shape and their jerky movements. The larvae develop into

comma-shaped pupae, still living in water, and after 2-4 days the skin of the pupa

splits and adult mosquito emerges.

The development from eggs to adult takes place between 1-3 weeks, depending on

temperature. The adult male lives for few days only but the adult female lives for 3-4

weeks at least. Thus, under optimum conditions she can lay about 12 batches of eggs

and potentially, if most hatch they can produce 2,000 adult mosquitoes.

The length of time the adult female survives is very important to the spread of

malaria. We saw that the mosquito phase of the life cycle of P. falciparum is at least

10 days depending on temperature. This means that if infected with parasite in first

meal, she does not transmit the disease until 10 days later at least.

Since breeding depends on temperature, rainfall and humidity, seasonal variations

will affect breeding. This explains the seasonal changes in the mosquito populationand hence the incidence of malaria. For example, in 1968 Ethiopia had high rainfall

and high temperatures, which cause an unusually severe epidemic with over 3 million

cases of malaria.

The parasites are not transmitted from the mosquito to its egg.

11. Malaria: the disease

Infections with the four different malaria species have many clinical features and

therefore will be dealt with together. The clinical features of falciparum malaria will

be covered in great detail, as this species causes the most severe infection presents

the greater therapeutic problems.


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The clinical differences between each form of malaria are due to the differences

in their rate of multiplication in erythrocyte and pre-erythrocytes stages. Their

selectivity for a particular state of maturity may also be important.

P. vivax and P. ovale enter young red blood cells and P. malariae enter older cells.

P. falciparum parasites invades the red cells at any state of maturity.The clinical features of malaria are associated with the erythrocyte stage of the

infection. In fact, all the symptoms of malaria are due to the invasion and consequent

destruction, occurring at 48-72 hours, of the infected red cells.

The characteristic signs of malaria are the recurring bouts of fever.

The fever occurs each time the parasite infected red cells burst and release

merozoites, and toxin of parasite metabolism, into the blood stream.

12. The Attack& FeverThe initial symptoms of malaria, at the end of incubation period, are rather

diffuse, consisting of lethargy, headache, nausea, vomiting, diarrhea and muscular

pain. During this prodromal phase the release of parasites and the destruction of red

cells are irregular. Once the erythrocyte cycles become synchronized, large number

of parasite is released from the red cells and the bouts of paroxysms of fever begins.

The malarial attach lasts for 8-12 hours, except for falciparum malaria which

lasts for 16-36 hours or longer and as accompanied by an increase in the intensity of

the initial symptoms. The timing of the following paroxysm is related to the time it

takes for the development of a sufficient number of mature schizonts and their

subsequent rupture.

13. The Classical Fever Stage

1-Cold stage (1-4hours): The patient shivers and feels very cold. The teeth chatter

and the patient covers himself to keep warm.

2-Hot stage(2-6hours): The patient is flushed and has a high fever.

3-Sweating stage (2-4hours): The patient sweats freely, commonly drenching

clothes and bedding. The temperature begins to come down, and the patient

usually falls into a deep sleep.

In vivax and ovale malaria, the phase of maturation takes 48 hours, and feverstarts on the third day (tetian); in quartan malaria, due to P. malariae it occurs at

72-hour intervals i.e. on the fourth day.

This strong periodicity does not seem to apply to falciparum malaria, where the

fever has a more irregular 48-hour cycle.

14. Other Symptoms

A variety of additional symptoms, common to all the malarias, persist after the

fever attack. They are also as follows:

Anaemia- Due to the destruction of the red cells by the parasites; and increased


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Phagocytosis by the spleen.

Spleen enlargement- Early in the acute attack and in chronic malaria the spleen

can become grossly enlarged. This is related both to reed cell destruction and to the

increased activity of immune system. Indeed, spleen size is used as an indicator of

the prevalence and intensity of malaria in population surveys.Gastro-intestinal symptoms- Frequent stools containing blood, mucus and pus,

watery diarrhea and muscle cramps. These symptoms are some what like dysentery

or cholera Jaundice-Yellow skin due to haemolysis and liver damage.

Renal insufficient-Kidney complications such as albuminuria, granular casts,

heamaturia, and nephritis are due to disturbed micro circulation in the kidneys.

Other systemic manifestations-Involve the liver and lungs, the later resembling

pneumonia.

15. Falciparum malaria

SymptomsMalaria can cause other more severe symptoms, which can have potentially fatal

complications but they are seen only with falciparum malaria, including:

Cerebral malaria- Headache and drowsiness is followed by a comatose stage with

contracted pupils, exaggerated reflexes and many neurological symptoms. It is

thought to be due to the blocking of the brain blood vessels by the damaged red cells,

and onset can be sudden.

Algid malaria-Much is rare but usually fatal, in a shock like state. The skin is pale,

cold and clammy, the breathing shallow, the pulse weak and rapid and the blood

pressure is low. It is thought to be due to adrenal insufficiency.

Black water fever-A condition in which there is a large degree of haemolysis

within the blood vessels giving rise to haemoblobin in the urine which is often

followed by renal failure.

Falciparum malaria presents with a large number of symptoms, which maybe

sudden and severe and difficult to distinguish from other disease.

Typical misdiagnosed malarial symptoms

Organs most affected Main symptoms of signs Typical mis-diagnosed

Gastro-intestinal tract

BrainKidneys

Liver

Lungs

Vomiting, Diarrhea,

Delirium, Coma,Convulsion

Renal failure

Jaundice, Fever

Pulmonary oedema

Gastric flu, cholera,

infectious diarrheaencephalitis, meningitis,

status epilepticus,

hypoglycemic coma,

nephritis, bacterial and

viral hepatitis pneumonia,

heart failure.

16. Untreated Malarial Attack

After the primary malarial attack, further attacks can follow for years, but thenatural history of malaria is different with the different species. If the patient is not


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treated the clinical course will depend on the malaria type, the patients age and state

of immunity.

Course of primary attack, relapses and recrudesce.

Recrudescence is early relapses resulting from survival of parasite in the red blood

cells, typically due to treatment failure. All four species can recrudesce.Recurrences are relapses due to re-infection of red cells from the latent forms of

parasites in the liver. These occur in P. vivax and P. ovale.

Falciparum malaria is the most serious type of malaria

The largest number of parasites which are formed in the blood probably account

for the severe morbidity and mortality of the infection. In common with the other

malarias, headache, malaise and muscle pains are the prodromal symptoms, however

the paroxysms of fever are irregular and convulsions cause Nausea. Vomiting and

diarrhea increase, followed by anaemia, spleen enlargement and jaundice. The othersevere symptoms, specific to falciparum malaria are cerebral, algid malaria and

blackwater fever.

A patient, not previously exposed to malaria, may die following a single

exposure to falciparum malaria, unless the disease is recognized and immediately

treated with effective treatment.

If a patient survives an attack he will develop some immunity and recrudescence

may occur over the course of the next year due to the persistence of small numbers

of blood forms in between attacks. In the absence of re-infection, the disease will

finally die out spontaneously. Resistance is soon lost unless there is frequent

re-infection. In that event, after approximately 5 years of repeated challenge, a high

degree of immunity to clinical illness develops. Vivax, ovale and quartan malaria

progress differently and cause diseases which are more chronic, but rarely fatal.

In quartan malaria, following a single exposure, the patient develops a recurrent

fever which occurs at decreasing frequencies. If no treatment is given to clear the

blood forms of the parasite, recrudescence may occur from time to time for as long

as 50 years. Attacks tend to diminish in severity as time passes, until bouts of fever

last a few days.


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Vivax and ovale malaria are very similar illnesses, with bouts of fever which

relapse periodically but irregularly over a period of up to 5 years. These are true

recurrence and not simple recrudescence, because they may occur despite the

treatment with drugs that entirely eliminate that parasite from the blood. Re-invasion

of the blood occurs when the liver hypnozoites awake from dormancy.

To prevent recurrence, it is necessary to use drugs aimed at liver hypnozoites.

18.Malaria in PregnancyWomen are more vulnerable to malaria during pregnancy. This is because during

the second half of the pregnancy, steroid production and hormonal chemistry change

so much that the immune system becomes impaired. Thus, even if a woman had

developed some immunity before pregnancy, she temporarily loses this protection and

therefore can easily be infected particularly by the parasites already has in her body.

This can lead to recrudescence or recurrence of malaria in the absence of a mosquito


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bite.

It is breakdown of the red cells and the resultant damage which cause most of the

ill effects on the mother and her baby.

The risk of malaria is highest in--

The first pregnancyThe second half of pregnancy

The dilemma arises:

Should a pregnant woman be treated with potent drugs to prevent the malaria and

possibly risk adverse effects on her baby? In high prevalence areas there is no doubt

that such fears must not prevent drug therapy.

Women should receive adequate anti-malarial drugs in pregnancy.

19.Malaria in ChildrenMalaria can be a serious disease in children under 5 years of age and often leads to

death.

As it was discussed earlier that malaria can be passed from mother to fetus, but

this happens more commonly if the mother has not been previously exposed to

malaria before becoming pregnant. The reason for this is that the mothers who have

acquired some immune protection by previous exposure to malaria, pass this

protection to their babies. The protection lasts for a few months and is called passive

immunity. Thus these babies are free of malaria after birth, and only show signs of

infection when they lost this passive immunity.

Malaria in children presents the following difficulties:

-the classical signs which occur in adult are not as obvious in small children

-the disease may be mistaken for other disorders

-the course of disease is variable

-malaria predisposes children to other infections and disease.

It is estimated that rural African populations about one million children under 5

years old die each year from malaria.

20.Diagnoses of Malaria and Its problemsThe only certain way to diagnose malaria is the finding of the malarial parasites in

the blood. (see ActRx Malaria Test Kit)

21.Eradiation of malariaSince the 1950s, global malaria eradiation was the aim of the WHO and was

believed to be possible because of the development of powerful insecticides such as

DDT. If the life span of the female anopheles mosquito could be reduced to less than

the minimum parasite development period of 10 days, then even if a mosquito fed on

a human carrier, she should die before she had time to be infective.

Eradication requires simultaneous programs of:

i. Controlling the mosquitoii. Controlling the mosquito breeding sites


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iii. Controlling the biting of man by mosquitoiv. Controlling the disease in man

Eradication is assumed that:

All dwelling in the endemic areas could be sprayed periodically.

Mosquitoes would rest on the sprayed surfaces and so be exposed tothe insecticides.

The mosquitoes would remain sensitive to the lethal effects of

insecticides.

People in the endemic regions would cooperate.

Nations would collaborate in both spraying and rug treatment.

The dream of eradicating the world of malaria has not been fulfilled.

Eradications have succeeded only in temperature regions and only in

some regions of tropics, mostly islands. The main reasons for failure are:

OperationalNot all houses were sprayed

Technical

Mosquitoes become resistant to insecticides. Parasites become

resistant to drugs.

Political

Lack of cooperation, resources and expertise

Conviction

Eradication programs not are considered necessary.

Financial

Lack of money for the issue

22.Control of malariaGlobal eradication of malaria is now considered unrealistic and has abandoned.

Instead, many parts of the world are concentrating on control measures in isolated

program.

A- Control of mosquitoesSpraying new insecticides

B- Control of the mosquito breeding sitesBy drainage of pooled water, larvae killed by Larvicides.

C- Control the biting of man by mosquitoBy covering exposed skin in the evening, using insect repellents, covering

beds with nets.

D- Control of disease in manBy offering effective drugs

These measures require a coordinated approach from the highest national levels of

government support, though the countrys health program, and via primary health care

activities, to community education and participation.

The major problem is that the parasite have found ways to survive in the presence


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of anti-malarial drugs i.e. They have become drug resistant of the plasmodium species

that infect man, acquired drug resistance poses a serious clinical problem only with P.

falciparum. However, this species account for the majority of symptomatic cases and

much of the mortality of human malaria. In fact, the deterioration in the malaria

situation and resurgence of malaria during the last decade is mainly due to the spreadof chloroquine resistant P. falciparum of great concerns is the fact that resistance has

also developed to mall the alternative anti-malarial, including the first discovered

quinine, and newer drugs such as mefloquine.

As more and more currently available drugs lost their efficacy, the task of treating

malaria becomes extremely difficult. Discovering more effective drugs is the current

key to improve healthcare and reduce the suffering and death from malaria.

Section 2 Anti-malarial


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1. First Anti-malarialThe first malaria remedy dates from the beginning of the 17th century when

Peruvian bark was found to be of value in reducing the fevers. This remedy, brought

back by the Spanish who conquered Peru, was soon widely used in Europe. The

fever tree was given the names cinchona by Linnaeus in 1749. For almost twocenturies the bark was used for medicines as a powder extract, or infusion before its

major active constituent, quinine was extracted and used as pure alkaloid. However,

the native forest of Peru could not supply the large demand for the drug, especially

during the civil war in America. Plantations were therefore developed in such places

as Java, Ceylon and India. By the 1930s the Dutch plantations of Java were producing

97% of the worlds supply of quinine about 10 million kilos of bark of a year.

Although quinine was eventually synthesized, the procedure was too complex and

expensive to provide and economic source of the drug and it is still obtained entirely

from natural source.

2. Synthetic Anti-malarialDuring the First World War, the Germans began looking at the possibilities of

producing alternative substances. Their chemists succeeded, using the quinine

structure as a model, and first synthetic anti-malarial, primaquine was developed in

1928. It had too many draw backs to be used generally and in 1932 the highly

successful mepacrine (quinacrine in US) was synthesized.

It is true to say that the history of anti-malarial is closely intertwined with the

major wars. During the Second World War, the Allies were cut off their main source

of quinine in Indonesia. Since they were fighting in the highly malarious areas, their

needs were desperate and as a result research received a very high priority.

During this time, mepacrine became established drug for routine treatment and

prevention and it probably changed the course of history.

The period also saw the development of derivatives of 4-aminoquinolines by

German, French and American scientists, leading to the introduction of chloroqunie

and amodiaquine, both remained the most widely used anti-malarial for over 25 years.

British scientists worked on the pyrimidine derivatives, resulting in the introduction of

proguanil which proved the most effective for malaria prevention. In the 1950s, with

the introduction of primaquine for the radical cure of vivax malaria, the range of

anti-malarial seemed complete, most of the problems of malaria therapy appeared tosolve and research efforts dropped. However, in the late 1950s, a new and menacing

event occurred which has dominated malaria ever since. Resistance P. falciparum to

chloroquine was suspected in South America and reported in Thailand in 1959. It did

not remain isolated, but began to spread into other countries in the South East Asia

and was also confirmed in South America. This presented a very serious threat to the

eradication program which was beginning to show results.

The problem of chloroquine resistance revived interest in the anti-bacterial,

sulphonamides and sulphones, and they entered anti-malarial therapy in the 1960s.

The threat of resistance led the WHO to sponsor the research for the new compounds.


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3. Resistance to Anti-malarialThe biggest obstacle to successful drug therapy of malaria is the development

resistance to the available drugs. Before the appearance of resistance in 1960s the

malaria could be controlled quite well. The situation has deteriorated and now is very

worrying. Indeed it is the reason why new drugs are being developed.So what exactly is drug resistance, why and how does it arise?

Resistance in malaria is defined by the WHO as the:

Ability of a parasite strain to survive and to multiply despite the administration

and absorption of a drug given in does equal to, or higher than those usually

recommended, but within the limits of tolerance of the subject.

This means that parasite, which had previously been susceptible to a drug, have

found ways of resisting its lethal or controlling actions.

Resistance is not confined to malaria parasite, but is a general principle common

to infecting organisms, particularly bacteria. It occurs because of excessive exposure

to and often also incorrect or inappropriate use of, chemotherapeutic agents.Resistance occurs because micro-organisms reproduce very rapidly and thus can,

in a short span of time, spontaneously mutate into slightly different strains. In the

presence of low levels of the drug for long period, parasites are selected which can

withstand the drug. Chloroquine encourages the development of resistant strains

because it has long half-life and thus persists in the body in sub-therapeutic

concentrations for a long time. Resistant mutants have an altered genetic and survive,

either by using alternative metabolic pathways to those blocked by the drug or by

preventing the entry of drug into the cell.

4. Extent of resistanceAlthough all four malaria parasites can become resistant to drugs, the term is not

commonly applied to the resistance of P. falciparum to the blood schizontocides, in

particular the 4-aminoquinoline, chloroquine. None of the other species of malaria

parasites has yet become resistant to chloroquine.

In practice, drug resistance should be suspected when acute cases of malaria (P.

falciparum) do not fully and rapidly respond to proper drug treatment, or when

symptoms and parasites in blood reappear quickly. There is a graded responsiveness

of P. falciparum to chloroquine, between complete sensitivity and complete resistance.

It ranges from a small loss of effect to a complete loss of effect.

5. Resistance DrugsResistance to Antifolate, such as pyrimethamine was noted soon after their

introduction after the Second World War. However, other effective drugs were still

available. Drug resistance became a major problem when P. falciparum resistancec to

chloroquine was observed. The reason for the concerns is two fold. Chloroquine was

and is still the most widely used anti-malarial drug, and falciparum malaria is the

most dangerous and prevalent form of malaria.

In efforts to overcome resistance, combination therapies of two different drugs

were used. The first combination, introduced in the late 1960s was pyrimethamine and


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sulphadoxine (SP, Fasidar). It was marketed as an answer to chloroquine resistance,

and while it was very effective at first, resistance to this combination has since

developed. In some areas R resistance has been reported requiring the use of

alternative drugs. Similarly resistance has been reported with other

pyrimethamine/sulphones or sulphonamides combinations,Quinine is an alternative, but some strains of P. falciparum resistant to chloroquine

are shoeing cross-resistance to quinine. Cross resistance refers to resistance to drugs

with similar structure. Thus resistance to chloroquine generally implies resistance to

amodiaquine, another 4-aminoquineoline.

The worrying problem of chloroquine resistance has now been further

complicated by the increasing resistance to combination therapies. The term

multi-drug resistance is increasingly used, denoting the multiplicity of drugs to which

P. falciparum has developed resistance. Mefloquine is one of the latest anti-malarial to

be introduced, and cases of resistance to it have been observed in areas where it has

not been used.

6. Spread of resistanceResistance to chloroquine was first documented in Thailand in 1959 and

Columbia in 1960. From these local areas, resistant organisms have been spread by

migration of carriers from village to village, acting as reservoirs of resistant parasites

to local mosquitoes along the way. The spread over longer distances has been

facilitated by increasing travel by air, road and ship. If one were to map the progress

of resistance one would see high grade resistance in the central zone of resistance with

progressive spread into sensitive areas, Like pressure zones on a weather map.

In the years since chloroquine resistant P.falciparum first emerged, it has spread in

all directions to affect large regions of South-east Asia, Central and South-east India,

Central and South America, the Western Pacific, East and West Africa. Although east

Africa became affected only as recently as 1978, starting with Kenya and Tanzania,

resistance has now spread westward to many neighboring countries. The development

of multi-drug resistant falciparum malaria poses a threat to the lives of millions of

people. Although drug resistance poses a serious clinical problem only P. falciparum,

this species accounts for the majority (85%) of cases and much of the mortality of

human beings.

7. The Anti-malarial DrugsThe ideal drug to treat malaria would:

--be effective against all stages of the life cycle of all malaria parasites

--act selectively on the parasite

--have no detrimental effects in man

--be effective in inhibiting the transmission

Thus, treatment of malaria requires knowledge and understanding of the precise

actions, advantage and disadvantage of each of the anti-malarial drugs.

Please Remember:


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1): Malaria is caused by one or several of four plasmodium species,

namely P. falciparum, P. vivax, P. ovale, P. malariae.

2): The parasites are transmitted to man in the form of sporozoites

introduced be the bite of a female anopheline mosquito.

3): The life cycle of all parasites is the same. It comprises a sexual phasewith multiplication in mosquito and an asexual phase with

multiplication in human body.

4): The human phase has several components:

--Invasion of liver cells by sporozoites

--Multiplication in liver (pre-erythrocytic schizogony)

--Red cell development cycle (erythrocytic schizogony)

--Dormant forms in liver (hypnozoites) multiply to cause relapse

(exo-erythrocytic schizogony) only with P. vivax & P. ovale.

The clinical symptoms are caused by the rupture of red blood cells and therelease of merozoites and toxins of parasite metabolism.

The various stages in the life cycle of the malaria parasites show different

susceptibility to anti-malarial drugs. The drugs can therefore be classified into five

groups according to their actions:

1): Primary tissue schizontocides:

Inhibit the growth of the pre-erythrocytic stage of the parasite in the liver

cell. This stops the schizonts from reaching the blood. Examples are

praguanil abd pyrimethamine (tetracycline also shows activity at this

stage).

Function: They are called casual prophylactics because they prevent

both the disease and its further transmission.

2): Secondary tissue schizontocides

Or hypozoitocides act in liver but on the exo-erythrocytic stage, i.e. on

the latent hypbozoite forms of P. vivax & P. ovale. The hypnozoites are

killed so that preventing the further development of disease, e.g.

primaquine.

Function: Also called anti-relapse drugs, they prevent relapse of vivax

and ovale malaria and may thus achieve a radical cure.3): Blood schizontocides

Act on the asexual erythrocytic stage of the parasites in the red blood

cells to stop the production of schizont and merozoites. This reduces or

completely abolishes the parasites. Chloroquine is an example of this

group, but drugs like pyrimethamine, proguanil, sulphonamides,

sulphones and antibiotics also have blood schizontocidal effects.

4): Gametocytocides

Destroy the sexual erythrocytic forms of the parasites thereby preventing

infection of the mosquito, primaquine is an example

Function: They prevent the transmission of malaria


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5): Sporontocide

Inhabits the formation of sporozoites in infected mosquitoes thus

interrupt the parasite life cycle in mosquito. Example are

pyrimethamine, proguanil and primaquine.

Function: They prevent the transmission of malaria.

There are no drugs available which can destroy the sporozoites introduced

when mosquito bites a person.


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9. Drugs Commonly Used for Malarial TreatmentChloroquine

Brand Names: Aralen, Avlochlor, Nivaquine(sulphate), Resochin (phosphate) and

many others.

Chemical Class: 4-aminoquinolineActions: Powerful, rapidly acting blood schizontocide, effective against P. vivax,

P. ovale, P. malariae and susceptible strains of P. falciparum. Also has

gametocytocidal activity against P. vivax and P. malariae.

Indications: Treatment of acute malarial attacks. Used prophylactically during

pregnancy and in persons at high risk (i.e. visitors with no

immunity to malarial areas, immunosuppressed patients and

infants.

Adverse Effect: headache, nausea, vomiting, diarrhea, pruritis, and blurred vision

occur infrequently. In susceptible individuals, attacks of

porphyroa can occur. If administered quickly I.V injections maycause an abrupt fall in blood pressure which can be fatal. In long

term use at higher doses, keratopathy and retinopathy may occur.

To use over dosage with doses as low as 50mg/kg can be fatal.

Serious adverse reactions are rare at anti-malarial dosages but

have included blood dyscrasias.

Contraindications: Psoriasis, porphyria, hypersensitivity.

Pharmacokinetics: Long half-life ( three weeks or more), concentrates in tissues.

Forms and administrations:

Tablet (150mg base), syrup (120mg/5ml, or 50mg/5ml), Injections (50mg/ml in

1,3 or 5ml vials or 40mg/ml in 2 or 5 ml vials).

IM Chloroquine can also be given intramuscularly in a reduced dose 2.5mg/kg. 3

times a day.

Dosage (as base)

Treatment:

Adults: 1500mg total over 3 days. (1st day:900mg ( 600mg then 300mg 6-8 hours

later; 2nd and 3rd : 300mg single dose)).

Children: 1st day: 10mg/kg; 5mg/kg after 6-8 hours.

2nd and 3rd day: 5mg/kg

Prevention:Adults: 300mg weekly

Children: 5mg/kg weekly

Dose and duration of treatment often increases in areas of drug resistance.

Comments:

It is a very effective and well tolerated drug but now of very limited use in many

areas because of the high levels of resistance. Bitter taste can be a problem with

administration to children. Chloroquine and its derivatives are also used in the

treatment of rheumatoid arthritis.


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Amodiaquine:

Brand name: Basoquine

Chemical class: 4-aminoquinoline

Actions: similar blood schizontocidal action to chloroquine. Its effective againstsome chloroquine resistant strains of P. falciparum. It also has

gametocytocidal activity against P. vivax and P. malariae.

Indications: Treatment of acute malaria attacks.

Adverse effect: Nausea, vomiting, insomnia, vertigo and lethargy occur occasionally.

On ong term use, corneal deposits, pigmentation of skin and nails may

occur. Rare reports of hepatitis, peripheral neuropathy,

agranulolocytosis and other blood dyscrasia have been reported.

Contraindications: Retinopathy, hypersensitivity, history of drug induced

agranulocytosis.

Pharmacokinetics: Long half-life (at least 1 week)Forms and administration: Tablets (200mg), suspension (150mg/5ml)

Dosage: (as base)

Treatment:

Adults: 1,400-1800mg total over 3 days.

Children: 25mg/kg total over 3 days.

Not recommended for prevention, but sometimes 400mg per week used.

Comments:

No longer used for prevention because of the unacceptably high risk of

agranulocytosis occurring. The majority of cases have occurred during concurrent

administration of proguanil for prevention but agranulocytosis has been reported with

amodiaquine alone.

Quinine:

Brand Name: Hydroquine

Chemical class: Aryl amino alcohol, purified from cinchona bark.

Actions: Powerful, rapidly acting blood schizontocide, effective against

gametocyctes of P. vivax and P. malariae. Variety of other actions on

heart, muscles etc.

Indications: Treatment of acute malarial attacks by drug resistant. P. falciparum.Adverse Reaction: Mild to moderate cinchonism occurs commonly at therapeutic

doses. Tinnitus, headache, blurred vision, altered hearting,

nausea and diarrhea. Hypoglycaemia (due to increase in insulin

release) also occurs. Idiosyncratic reactions are less common, e.g.

pruritis, skin rashes, thrombocytopenia. Rare reports of auditory

and visual impairment, hypotension and cardiac dysfunction,

vomiting, abdominal pains and hepatitis have been reported.

Contraindications: Pregnancy, quinine hypersensitivity, G-6-PD deficiency, history

of thromobocytopenic, purpura, tinnitus, optic neuritis or black water fever.

Forms and Administration:


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IV injections (300mg/ml)

Dosage:

Adults: 600mg every 8 hours for 3-7 days

Children: 10mg/kg every 8 hours for 3-7 days.

It should not be administered as bolus injection when given i.v.Comments:

Adverse events are more common than with other anti-malarial, particularly

useful for emergency treatment of severe malaria. It is often used in combination with

tetracylines to treat chloroquine resistant P. falciparum. It must be administered

slowly when given i.v. injection to avoid sudden falls in blood pressure. Infusion is

usually given in preference. Some formulas have bitter taste.

Pyrimethamine/ Sulphadoxine

Brand Name: FansidarChemical Class: Diaminopyrimidine and sulphonamides, respectively.

Actions: pyrimethamine and sulphadocxine both have some blood schizontocidal

activity against P. falciparum, and to a lessere extent P. vivax

Pyrimethamine also acts on the primary tissue phase of P. falciparum, has

some action against the secondary tissue phase of P. vivax and is

sporontocidal.

Indications: Treatment of acute malarial attacks by chloroquine resistant P.

falciparum and also for patients who refuse to take chloroquine. It is no

longer recommended for prevention.

Adverse Reactions: Reactions to pyrimethamine are dose related and reversible, i.e.

anorexia, abdominal cramps, vomiting, ataxia, tremors, seizure and

megaloblastic anaemia. Sulphonamide induced hypersensitivity

reactions are uncommon but can be severe and life threatening, e.g.

erythma multiforme, Stevens-Johnson syndrome and toxic epidermal

necrolysis. Infrequently blood dyscrasias occur and occasionally

haemolysis in G-6-PD deficiency. Jaundice, hepatitis and vasculitis.

Contraindications: Pregnancy, neonates, severe renal or hepatic insufficiency.

Pharmacokinetics: Long half-life time (about 100hours)

Precaution: Haematological monitoring required when other folate inhibitors (e.g.trimethroprim, methotrexate, anti-convulsants) are given concurrently.

Forms and administration:

Tablets: pyrimethamine 25mg+ sulphadoxine 500mg

Dosage: Adults: 3 tablets as single dose

Children: Not used below age 5 weeks

2 tablets for 12-15 years old

1 tablet for 4-11 years old

1/2 tablet for 1-3 years old

1/4 tablet for 6 months to 1 year old

1/8 tablet for 6 weeks to 6 months year old


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Comments:

No long to used for prevention because of the risk of serious skin reactions.

Fansidar resistance spreads in a similar way with chloroquine.

Primaquine:Chemical class: 8-aminoquinoline

Actions: Highly active secondary tissue schizontocidal, effective against primary and

where appropriate latent liver forms f P.vivax, P. ovale, P. malariae and P.

falciparum. Weak blood schizontocide

Pharmacokinetics: short half-life (4-6hours)

Adverse reactions: Dose-related gastrointestinal symptoms including anorexia,

nausea & abdominal pain may occur. Acute haemolytic anaemia

may occur in G-6-PD deficientcy.

Comments:

the only drug to provide a radical cure in vivax amd ovale malaria. It tastes bitter.Its too slow acting as a blood schizontocide to be used in acute treatment, therefore

commonly given with a schizontocide to produce radical cure in vivax or ovale

malaria.

Melfloquine+Pyrimethamine+Sulphadoxine

Brand Name: Fansimef

Chemical class: aryl amino clcohol, diaminopyridine and sulphones, respectively.

Actions: Blood schizontocide active against all species of malaria parasite, also has

gametocytocidal action against P. vivax, P.ovale and P. malariae, but not P.

falciparum.

Comments:

Not recommended for use in pregnancy because of the risk of adverse effect of

sulphonamide. It should be reserved for treatment of multiple drug resistance. The

combination was originally developed to prevent the emergence of mefloquine

resistance. However it is currently only use in areas where SP resistance is common

and with the increased toxicological potential, it is now considered to be illogical.

Tetracyline:Brand Names: Terramycin, Vibramycin

Chemical class: Tetracyline

Comments:

It has to be administrated with a rapidly-acting blood schizontocide as

schizontocidal effects only observed after 3-4 days. It cant be used in children up to

12 years, who form a large part of the population suffering from malaria.

Halofantrine


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Brand Names: Halfan

Chemical class: Phenanthrene methanol

Comments:

Precise action is not known. The relative bioavailability increased approximately 6

folds when taken with fatty meals. In the threat of P. vivax malaria should be followedby an 8-aminoquinoline derivative to eliminate hepatic forms. The WHO recommends

that it should be placed under strict government control due to the adverse reactions.

Mefloquine:

Chemical names: Lariam, Mephaquine.

Comments:

Due to its severe side effects and long term effect on mental activities, mefloquine

needs further investigation and evaluation. And as a long half life product, which arise

the resistance in South East Asia and part of African countries, the combination withartesunate therapy has been developed by Mepha from Belgium.

Pyronaridine

Brand Name: malaridine

Molecular Formula: C29H32C1N5O2

Pyronaridine Story:

It was first developed in China. In studies, ED50 (mg/kg) was found to be 6.8

1.4 compared to chloroquine, 45.66.3 after oral administration. Its therapeutic index,

201.3 was also found to be far greater than Chloroquines, 14.5. Py ronaridine was

concluded to be very effective in P.vivax and P. falciparum malaria and well tolerated.

In another randomized, unblind study, the safety, the tolerance, and the clinical

efficacy of pyronaridine in Cameroonian children with acute uncomplicated

falciparum malaria was established. It is highly efficacious in Africa, where

chloroquine resistance is well established. Pyronaridine is also found to treat P. ovale

and P. malariae in 4 days. Limitations here is the lack of established pharmacokinetic

and problem with recrudescence. Pyronaridine adopts the quinine moiety and soresistance to it will become inevitable. The biggest issue was that the pharmaceutical

giants were not interested and it is too expensive.

The mutagenic activity of a new anti-malarial drug, pyronaridine, was studied on

5 histidine-requiring strains of Salmonella typhimurium (TA100, TA98, TA1535,

TA1537 and TA 1538) with and without S-9, using the plate test. After the rats had

been induced by PCB, S-9 were isolated from the licers. Two anti-parasitic drugs with

known mutagenicity, hycanthone and furapromide, were used as positive controls. In

strain TA1537, pyronaridine induced mutations without S-9 at the doses of 100-1000

/plate. The scientific data of pyronaridine is still lack of A pharmaceutical company

from Korea is undergoing its combination with artesunate under the support of MMV.


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Halofantrine

(Phenathrene-Methanol) is a blood schizonticidal against the erythrocytic P.

falciparum resistant to Chloroquine as well as P. vivax erythrocytic but not the

hypnozoites. It used to treat acute form of uncomplicated, multi-resistant falciparummalaria and as a stand by drug if chemoprophylaxis fails and there is no medical aid

available. If taken orally, it is slowly and irregularly absorbed (aided by a fatty meal),

with a peak plasma concentration at 4-6 hours later. Half-life is 1-2 days and

elimination through faces. Toxicity includes abdominal pain, gastrointestinal

disturbances headache, a transient rise in hepatic enzymes, cough (pruritus), and slight

dysrhythmias, and a report of sudden cardiac deaths, haemolytic anaemia and

convulsions.

10.Clinical use of Anti-malarialThe clinical attacks of malaria occur each time the erythrocytes rupture to release

the merozoites.

The attack of malaria begins with a prodromal phase consisting of non-specific

symptoms such as lethargy, headache, nausea, vomiting, diarrhea and muscle pains.

These are followed by paroxysms of fever, classically consisting of three stages:

--cold stage, hot stage and sweating stage

The bouts of fever occur at intervals which are characteristic to each parasite

species.A variety of additional symptoms may occur with the bouts of fever i.e.

anaemia, splenomegaly, gastrointestinal symptoms, jaundice and renal insufficiency

etc.

Falciparum malaria can cause more severe symptoms which maybe fatal i.e.

cerebral malaria, algid malaria and black water fever.

Recurrent attacks may occur for a number of years, the clinical course depend on

malaria type, the parasite and state of immunity.

All four species can recrudesce, mainly due to the treatment failure. Only vivax

and ovale malaria occur, due to re-infection from liver hypnozoites.

11.Principles of Malaria TreatmentThe treatment of and prevention of falciparum malaria has become more complex

and less satisfactory for the increasing resistance to the anti-malarial drugs.

Accordingly treatment of malaria depends mainly on the infecting organism and on

resistance patterns within a particular country or region.

12.A treatment of non-resistant MalariaTreating acute attacks is same for all four species.

There are a few important exceptions, notably relating to immune status, children

and pregnancy.

As clinical illness results from the parasitaemia of the asexual erythrocytic cycle,


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the most useful drugs are rapid and potent blood schizontocides. The drug of choice is

chloroquine, but the other 4-aminioquinoline, amodiaquine can also be effective, it is

less well tolerated and treatment is more prolonged.

Eradicating the infection is a more difficult task. In order to cure malaria

permanently, a radical cure, all traces of parasite must be eradicated so thatrecurrences and recrudescences do not occur.

In eradicating infection, treatment does not depend on the nature of the infecting

species.

For P. falciparum and P. malariae, eradicate the source of infection, i.e. the

parasites in the erythrocytes, resulting in a complex cure. This can be achieved by the

treatment of the acute attack, with chloroquine or other blood schizontocides, until the

supply of parasites in the liver and peripheral blood is exhausted.

For P. vivax and P. ovale, blood schizontocides will eliminate the circulating

forms of parasites, but not the latent liver forms. It is these which are responsible for

recurrences, weeks, months or years after an apparent cure. In these infections radicalcure requires an additional course of treatment with a secondary tissue schizontocide,

i.e. one of the 8-aminoquinolines. Primaquine is the best known, most active and least

toxic drug.

13.B Treatment of Drug Resistant MalariaThe treatment of an attack of Chloroquine resistant malaria depends on the grade

of resistance. Chloroquine is still frequently used in areas with RI resistance. With RII

resistance other drugs are administered or Chloroquine is used in combination with

another anti-malarial.

Drugs used in combination are either the antifolates (pyrimethamine,

sulphonamides and sulphones), or other blood schizontocides, tetracycline or

mefloquine. The dose and duration of Chloroquine treatment is often increased in

areas where RI and RII resistance occurs.

When resistance is of grade of RIII Chloroquine must be replaced with another

blood schizontocide. The current drug of choice is quinine. It is administered either

singly or in various combinations with other drugs (e.g. tetracyclines), depending on

the severity of infection.

Note that tetracyclines are contraindicated in pregnancy, lactation and for children.

14.C Malaria PreventionPeople can be protected from malaria by the regular administration of drugs

before clinical symptoms occur. As yet, no drug destroys the parasites as they are

injected by the mosquitoes.

Prevention can be achieved by two ways.

1- By destroying liver forms with primary tissue schizontocides (casualprophylaxis). Pyrimethamine is the drug of choice, generally used in

combination sulphadoxine or dapsone to prevent the emergence of resistance

organisms.

2- By destroying the parasites as they enter blood cells with blood schizontocides,


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such as chloroquine.

In areas where Chloroquine-resistant P. falciparum infections are prevalent, the

WHO has recommended that the prevention of malaria should be based as far as

practicable, on protection against mosquito contact drugs such as melfoquine or SP

could be used in the first sign of a febrile reaction (presumptive treatment).

15.Malaria Treatment and Prevention

16.Immunity to Malaria and TreatmentRepeated attacks of malaria in endemic areas confer partial immunity only, and

total immunity such as seen with bacteria and viruses does not develop. Partial

immunity does not preclude the development of disease and morbidity and mortality

still occur, especially in children, who have generally lower levels of immunity, and in

pregnant women, whose immune response is modified by the pregnancy.

Immunity has two components:

1- An ability to limit the parasitaemia2- Physiological tolerance, so that low parasitaemia produces no fever or illness.

The state of immunity is important to the use of drug, since patients who have


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been exposed can be cured or protected more easily with drugs than not

previously exposed.

17.Acquired immunityThe process involved in acquiring immunity is complex.On the first contact with the specific malaria parasite (antigen), the defense

mechanism is activated and antibodies are produced. On the next encounter with the

parasite the response is faster because the body remembers the foreign antigen and

antibodies are rapidly produced to neutralize the parasite by the antigen-antibody

interaction. Another process called cell-mediated immunity, helps to dispose of the

parasite and is considered one of the main mechanism of defense in malaria.

However, in order to maintain an acquired immunity to malaria, frequent

re-exposure to infection is necessary. If this does not occur, the immunity declines

over a period of months to a few years. So, when immune individuals leave their

malarious area to reside for several years in a non-malarious area, they gradually losttheir protective antibodies. Although they rapidly regain immunity to infection, the

price may well be several attacks of malaria on first returning to the infected area.

Naturally acquired immunity may be suppressed by pregnancy, major surgery,

sever illness of any type and immunosuppressive drugs.

18.Passive ImmunityThis is another type of acquired immunity. This does not involve any infection,

but is brought about by passing the protective antibodies themselves for instance from

mother to child through placenta. This is only effective in the short term, and soon is

lost.

Natural Immunity

It is possible for inherent factors to provide some protection against malaria. Such

natural resistance is genetically determined, and interferes with the development of

the parasite in the red cells.

It applies to the people with haemoglobin S, sickle cell disorder, and those with

glucose-6 phosphate dehydrogenase (G-6-PD) deficiency.

19.Malaria Treatment during PregnancyTreatment of malaria in pregnant women deserves special attention because:1): Previously exposed women lose their partial protection during the second half

of pregnancy

2): Malaria, especially falciparum, tends to be severe

3): An attack can cause miscarriage, premature labor, reduce birth weight or

infect baby

4): Adverse drug effects may be more detrimental to the mother

5): There is potential danger of toxicity to the foetus.

Prophylactic drug treatment should be given during pregnancy and particularly

during the latter part.

The drug of choice for prophylaxis during pregnancy is Cholroquine.


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Should a malaria attack occur during pregnancy it must be considered serious and

treated immediately?

The drug of choice for treating an attack is Chlroquine, or quinine in Chloroquine

resistance cases.

Tetracylines, primaquine and amodiaquine should avoided in pregnancy .The reasons being that tetracylines are desposited in teeth and bones, primaquine is

potentially toxic and amodiaquine can cause blood cell toxicity.

Quinine is teratogenic and contraindicated in early pregnancy, except in sever

infection where the maternal life is endangered.

20.Treatment on ChildrenIn endemic areas babies born to previously exposed mothers are protected,

through passive immunity, for about the first 6 months. Thereafter, if they are infected,

they will be at great danger and must be treated in time. Continuous exposure to the

parasites gradually confers immunity, but this takes up to 5 years depending on thefrequency of infected bites. It is estimated that 40-60 bites from malaria infected

mosquitoes are required to develop partial immunity, although not all bites develop

acute malaria. This enplanes why malaria causes such high rate mortality in young

children.

The proper treatment of malaria in children is crucial since malaria infections,

particularly with P. falciparum tent to be especially severe.

With appropriate dosage adjustments, the treatment of children is generally the same

as adults that:

1): Quinine is better tolerated

2): Antifolates as single drug i.e. Pyrimethamine, sulphonamides, sulphones

should not be prescribed to infants, the combinations however are relatively

safe.

3): The 8-aminoquinolines e.g. primaqunine are fairly toxic

4): Tetracycline is contraindicated because of effects on permanent dentition and

bone.

Oral treatment is safest. It is however limited by palatability and availability of

liquid forms. Many drugs e.g. quinine is rather bitter and cause children to vomit.

Coma and sever vomiting may make oral therapy impossible in which case drugs

must be injected. This must be done with great caution, especially with quinine andChloroquine which can cause severe tissue reactions and even convulsions and death.

Relapsing and drug-resistant malaria in children is treated the same as in adults.

Age (years)

Body weight

(kg)

Proportion of

Adult Dose

1

5

1/8-1/4

1-5

5-20

1/2

6-12

21-40

3/4

12

40

1

Relative doses of anti-malarial in children.Fansidar and maloprim should not be used in infants under 5 weeks of age, due to

the immaturity of several enzyme systems.


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Section 3 ActRx Anti-malarials

1. Introduction of Aretemisin

Aretemisinin was originally developed in 1972 in China (Chinese Institute of

material medicine) from the plant Artemisia annual (sweet wormwood), asesquiterpene lactone (empirical formula C12H22O5). Artemisinin is the active

ingredient in qinghao, a Chinese herbal tea that have been used for 150 years to treat

malaria and hemorrhoids. It grows in the wild in China and now has been found to

grow in other parts of the world too, though the species are different. Locally, it is

prepared as an infusion of the dried leaves.

Derivatives of Artemisinin as follows:

artemether, artesunate, arteether and artelinate. Artemisinin, thereinto, artemether

and arteether are water-insoluble, artsunate and artelinate are water-soluble.

2. Mechanism of actionArtemisinin is a rapid parasiticidal of the asexual stages; it is anti-gametocyte and

blocks sporogony (Heppner and Ballou 1998). It produces ultra-structural changes to

the growing trophozoite parasite. A whorl is produced in the food vacuole and the

parasites mitochondria proliferated. This reduces parasites survival (Hien and White

1993). Endoperoxide bridge is essential for its anti-malarial activity. The compound is

activated by the intra-parasitic haem to irreversibly decompose, generating free

radicals that alkylate and oxidizes proteins and lipids. The membrane of the parasite is

damaged by lipid peroxidation and channel proteins inactivation. (Ridley&Hudson

1998). Parasites clearance times are shorter than with chloroquine and symptomatic

response.

3. PharmacokineticsClinical evaluation of therapeutic regimens is required to validate clinical efficacy

of this promising herbal (Oduola et al 1998) Artemisinin has a quick action with

stopping the parasites growing while cytoadherence is not reached too. Drug

disposition of Artemisinin after oral administration has been determined, using a one

compartment model with separate pharmacokinetic estimates for children and adults.

The population estimates for Artemisinin clearance and distribution volume,

repectively, were 432 Lh-1 and 1600ml for adults and 14.4 Lh-1kg-1 and 37.9Lkg-1 forchildren, with an inter-subject variability (collectively for both age groups) of 45%

and 104%, respectively. The oral bioavailability was estimated to decrease from Day

1 to Day 5 by a factor of 6.9, a value found to be similar for children and adults

(Sidhu et al.1998). Half-lives of Artemisinin is 4 hours, artesunate, 45mins and

artemether, 4-11hrs (Batty et al 1998). Findings like this have advocated the dosing of

Artemisinin to children according to bodyweight and to adults according to a standard

dose.

4. Clinical UseWarrell, D.A (1997) predicted that Artemisinin and derivatives will become the


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treatment of choice in the coming decade. Artemisinin, aremether. Artesunate,

arteether are widly used in South East Asia, some parts of Africa, while artelinate is a

research agent in the Walter Reed Army Institute of Research, Washington D.C

Artemisinin derivatives have become the treatment of choice in the coastal parts of

Malaya, Sarawak, Singapore and Asian Pacific region. Clinical efficacy, in terms ofparasites clearance and fever subsidence times, was comparable between children and

adults. Within 48hrs, 70% of the cases do become afebrile and the peripheral smears

usually negative in 100% of the cases. They are well tolerated.

5. Toxicity of ArtemisininWell-documented clinical uses of Artemisinin and derivatives have shown few

insignificant side effects, but findings in rat studies are controversial. Intra-muscular

artemether at 25mg/kg/day resulted in rats brainstem pathology with damage to the

auditory nuclei. Parenteral artemether in the treatment of cerebral malaria in Gambien

children shows a prolonged recovery from coma and post-treatment convulsions thanthe same treatment with quinine. Also in Vietnamese adults, a prolonged recovery was

noted, but no increasing in mortality or neurological behavior afterwards (Heppner

and Ballou 1998). Others are transient heart block, and transient decrease in blood

neutrophills and brief episodes of fever.

6. Combination Therapy.Short course artemisinin derivatives as monotherapy have been shown to be

limited by secondary malaria episodes. Therefore, combinations have being tried for a

long time. In rodent studies, Artemisinins potentiate the effects of mefloquine,

primaquine and tetracycline. Thailands multi-drug resistant P. falciparum malaria

(uncomplicated acute) is now treated with artemether-mefloquine as a short course

treatment, which has good patients compliance, clinical effectiveness, efficacy, and

tolerability. Low dose intravenous artesunate followed by mefloquine was found to be

well tolerated and rapidly effective in treating severe falciparum malaria contracted in

Indonesia and India. There was no relapse of clinical disease in all four cases after 28

days.

7. Artemisinin DerivativesArtesunateBrand Name: arsumax, plasmotrim, arinate

Artemether:

Brand Name: paluther, artesiane, artenam, artemedine.

Dihydroartemisinin

Brand Name: cotecxin, alaxin, malaxin.


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8. about Dihydroartemisinin

Dihydroartemisinin is the active and potent derivative of Artemisinin popularly

called Qinghaosu in Chinese. The use of Artemisinin dates back to over 2000 years

ago, when it was used in the crude form as anti-pyretic. Very little was then known

about malaria as a disease and also of anti-malarial function of Qinghaosu.

9. Clinical Success Rate of Dihydroartemisin

In a study by Li et al; 1994, (N=349) to establish clinical success rate on treatment

of uncomplicated falciparum malaria with artemisinin and its derivatives, the use of

dihydroartemisin resulted in the highest treatment success rate of over 98%. Clinical

studies by Molta N.B et al and Mosanya M.F showed 100% success rates with

dihydroartemisin in Nigeria..

10. Benefits of Dihydroartemisin

A: Because of its activity against all forms of plasmodia parasites, it can be used

in all cases malaria including simple malaria, severe Malaria, multi-drugresistant malaria, chloroquine resistant malaria and cerebral malaria.

B: Dihydroartemisinin instantly reduces over 80% cases of infant and adult

mortality from malaria related death nationwide due to its excellent safety

profile.

C: Because of its rapid plasmodicidal effect, it gives a fast relief from symptoms

of malaria and patients will get better quickly.

D: Rapidly clear malaria protozoa and symptoms in very severe infections

particularly in cerebral malaria. Thus hospital admission time will be reduced

for more bed spaces to other patients. This is particularly significant in cases

where there are limited hospital beds e.g. Primary Health Care Centers and


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general hospitals.

E: It reduces the transmission of parasites from an infected person (if a patient is

on dihydroartemisinin) to another via mosquito bite due to its marked

gametocidal action. This will in turn reduce the number of people that will get

infected with malaria and thus markedly reduce the cost of malaria managementon the long run.

F: Dihydroartemisinin will reduce malaria treatment cost by eliminating cost of

hospitalization because of it rapid anti-malaria action. Thus patients will not

need to stay in hospital.

G: Dihydroartemisinin being of herbal derivative completely gives the comfort of

total clinical cure. Of several side effect associated with most therapies that

presently exist, this factor makes the product unique in the sense that most

patients abandon their drug due to side effects and since this is an herbal

derivative, its has an excellent safety profile.

11.Combination Product Criteria--contain 2 active ingredients (API) which are synergistic or additive.

--contain at least 1 API which is relatively fast acting and at least one which is

present for a third/fourth intraerythrocytic cycle after a 3 days dose regimen.

--be gametocytocidal and preferably have P. vivax activity.

--have no negative pharmacological interactions, be well-tolerated and show

acceptable toxicity.

--be suitable for use in children and pregnant women.

12. The rationale

The rationale for using drugs in combination is well established in the treatment of

tuberculosis, infection with human immunodeficiency virus, and cancer. The

possibility of a parasite arising that is resistant simultaneously to two drugs with

unrelated modes of action is the product of the per parasite mutation frequencies

multiplied by the total number of parasites exposed to drugs. Therefore, if the

probability of a parasite being resistant to a drug A is 109 and to drug B is 109 then the

probability that a parasite will be simultaneously resistant to both is one in 1018,

representing a billion-fold reduction in probability. Mutations conferring resistance to

artemisinins have never been documented and are therefore much less likely to occurthan mutations to some other drugs such as SP.

Artemisinin is a particularly effective partner drug because its more active than

any other anti-malarials., reducing the number of parasites by approximately 104 per

asexual cycle and therefore reducing the number of parasites that are exposed to the

partner drug alone. In addition, artemisinin has broad stage specificity and can be

used to trea

malaria training manual for malaria updated 6 2013 by: anthony musso

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