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Email: anthonymusso@gmail.

com Tel: + 1 561 5064032 USA Anthony Musso Malaria Training Manual By: Anthony Musso 2012 Copyright
Section 1 Malaria 1. Introduction--------------------------------------------------------------------------------------3 2. History of Malaria------------------------------------------------------------------------------3 3. Points to Remember--------------------------------------------------------------------------3-4 4. The Parasite------------------------------------------------------------------------------------4-5 5. Morphologic Characteristics of the Plasmodia--------------------------------------------5-6 6. Life Cycle----------------------------------------------------------------------------------------6 7. Plasmodium Life Cycle-----------------------------------------------------------------------6-7 8. Human Part-------------------------------------------------------------------------------------7-8 9. Mosquito Part----------------------------------------------------------------------------------8-9 10. The Malaria Vector----------------------------------------------------------------------------9-11 11. Malaria: the disease----------------------------------------------------------------------------11 12. The Attack & Fever----------------------------------------------------------------------------11 13. The Classical Fever Stages------------------------------------------------------------------11-12 14. Other symptoms--------------------------------------------------------------------------------12 15. Falciparum Malaria---------------------------------------------------------------------------12-13 16. Untreated Malaria Attack----------------------------------------------------------------------13 17. Some Characteristics of Four Species of Human Malaria-------------------------------14-15 18. Malaria in Pregnancy-------------------------------------------------------------------------15-16 19. Malaria in Children-----------------------------------------------------------------------------16 20. Diagnoses of Malaria and Its Problems----------------------------------------------------16-17 21. Eradications of Malaria-----------------------------------------------------------------------17-18 22. Control of Malaria Section 2 Anti-malarial 1. First Anti-malarias------------------------------------------------------------------------------19 2. Synthetic Anti-malarias----------------------------------------------------------------------19-20 3. Resistance to Anti-malarias--------------------------------------------------------------------20 4. Extent of Resistance----------------------------------------------------------------------------20 5. Resistance Drugs------------------------------------------------------------------------------20-21 6. Spread of Resistance----------------------------------------------------------------------------21 7. The Anti-malarial Drugs----------------------------------------------------------------------21-23 8. Spectrum Activity of Anti-malaria-----------------------------------------------------------24-26 9. Drugs Used for Malaria Treatment----------------------------------------------------------27-32 10. Clinical Use of Anti-malaria-------------------------------------------------------------------32 11. Principles of Malaria Treatment---------------------------------------------------------------32 12. A Treatment of non-resistant Malaria-------------------------------------------------------32-33 13. B Treatment of drug resistant Malaria--------------------------------------------------------33

14. 15. 16. 17. 18. 19. 20.

C Malaria Prevention--------------------------------------------------------------------------33-34 Malaria Treatment and Prevention-------------------------------------------------------------34 Immunity to Malaria and Treatment---------------------------------------------------------34-35 Acquired Immunity------------------------------------------------------------------------------35 Passive Immunity-------------------------------------------------------------------------------35 Malaria Treatment during Pregnancy-------------------------------------------------------35-36 Treatment in Children--------------------------------------------------------------------------36

Section 3 ActRx Cure for Malaria 1. Introduction of Artemisinin-------------------------------------------------------------------37 2. Mechanism of Action--------------------------------------------------------------------------37 3. Pharmacokinetics-------------------------------------------------------------------------------37 4. Clinical Use------------------------------------------------------------------------------------37-38 5. Toxicity-------------------------------------------------------------------------------------------38 6. Combination Therapy---------------------------------------------------------------------------38 7. Artemisinin Derivatives----------------------------------------------------------------------38-39 8. About Dihydroartemisinin---------------------------------------------------------------------39 9. Clinical Success Rate of Dihydroartemisinin-----------------------------------------------39 10. Benefits of Dihydroartemisinin-------------------------------------------------------------39-40 11. Combination Product Criteria-----------------------------------------------------------------40 12. The Rationale----------------------------------------------------------------------------------40-41 13. The Evidence------------------------------------------------------------------------------------41 14. WHO Recommendations on Malaria Treatment-------------------------------------------41 15. ActRx Cure for Malaria-----------------------------------------------------------------------41-45

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 many developed 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, acting on 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 Plasmodium falciparum Plasmodium vivax Plasmodium ovale Plasmodium malariae Infections Falciparum malaria Vivax malaria Ovale malaria Quartan malaria Common, obsolete names Malignant tertian Benign tertian, simple Ovale tertian Benign quartan

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.

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 mosquitoes transmit 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 Cycle


SCHIZOGONY

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.

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 eythrocytic schizogony. 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 schizonts burst 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 and b- 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 and the 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 blood transfusion 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 Duration of Liver Cycle 1/2-7 days Duration of Blood Cycle 1 day Parasitaemia *% infected 0.4%-10% red blood cells Duration of Mosquito 9 days or more Phase ..Also can be expressed as 0% infected red cells Number of infected red cells/mm Number of red cells/100 white blood cells

P. malariae, P. vivax, P. ovale 6-16 days 2-3 days 0.12-14% 12 days or more(8-10 in P.V)

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. Habitat We 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 plant juices. 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, she injects 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 an adult 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 population and 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& Fever The 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 fever starts 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 Symptoms Malaria 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 Gastro-intestinal tract Vomiting, Diarrhea, Brain Delirium, Coma, Kidneys Convulsion Liver Renal failure Lungs Jaundice, Fever Pulmonary oedema

Typical mis-diagnosed Gastric flu, cholera, infectious diarrhea encephalitis, 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 the natural 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 patient s 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 other severe 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 Pregnancy Women 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 pregnancy The 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 Children Malaria 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 problems The only certain way to diagnose malaria is the finding of the malarial parasites in the blood. (see ActRx Malaria Test Kit) 21. Eradiation of malaria Since 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 mosquito ii. Controlling the mosquito breeding sites
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iii. iv.

Controlling the biting of man by mosquito 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 to the 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: Operational Not 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 malaria Global 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 mosquitoes Spraying new insecticides B- Control of the mosquito breeding sites By drainage of pooled water, larvae killed by Larvicides. C- Control the biting of man by mosquito By covering exposed skin in the evening, using insect repellents, covering beds with nets. D- Control of disease in man By 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 spread of 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-malarial The 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 two centuries 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-malarial During 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 to solve 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-malarial The 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 resistance Although 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 Drugs Resistance 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 resistance Resistance 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 Drugs The 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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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 phase with 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 the release 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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1):

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 Treatment Chloroquine Brand Names: Aralen, Avlochlor, Nivaquine(sulphate), Resochin (phosphate) and many others. Chemical Class: 4-aminoquinoline Actions: 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 may cause 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 against some 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: Fansidar Chemical 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 followed by 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 with artesunate 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. Pyronaridine 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 so resistance 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 falciparum malaria 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-malarial The 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 Treatment The 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 Malaria Treating 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 that recurrences 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 radical cure 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 Malaria The 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 Prevention People 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 (casual prophylaxis). 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 Treatment Repeated 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 parasitaemia 2- 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 immunity The 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 lost their 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 Immunity This 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 Pregnancy Treatment 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 Children In 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 the frequency 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 and Chloroquine 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) 1 1-5 6-12 12 Body weight 5 5-20 21-40 40 (kg) 1/8-1/4 1/2 3/4 1 Proportion of Adult Dose 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), a sesquiterpene 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 action Artemisinin 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. Pharmacokinetics Clinical 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 for children, 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 Use Warrell, 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 of parasites 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 Artemisinin Well-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 than the 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 Derivatives Artesunate Brand 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-drug resistant 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 management on 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 occur than 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 treat severe as well as uncomplicated malaria. It inhibits the production of gametocytes and therefore has a potential to reduce transmission and finally, so far, there has been evidence of stable resistance either in therapeutic use or in experimental systems.

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The regimen of Artemisinin is shorter than any other anti-malarials. 13. Evidence There is an increasing body of field evidence supporting the theoretical basis for Acts, principally from the Thailand-Myanmar border and more recently from South Africa. In an area on the Thailand-M border, the widespread deployment of ACT was associated with a decreased incidence in Malaria, sustained effectiveness of the combination for more than 10 years, and an increase in mefloquine sensitivity in vitro. These results were obtained despite artesunate being added to mefloquine when resistance to the latter was already widespread, a less than ideal scenario in terms of delaying anti-malarial resistance. In Kwa-Zulu-Natal in South Africa, the combined effect of switching from SP to the fixed combination of artemether-lumefantrine and residual spraying with DDT was associated with a decrease in cases of 78% and an increase in cure rate of 87%. 14. WHO Recommendations on Malaria Treatment As a response to increasing levels of resistance to anti-malarial medicines, WHO recommends that all countries experiencing resistance to conventional monotherapies, such as chlorquine, amodiaquine or sulfadoxine-pyrimethamine, should use combination therapies, preferably those containing artemisinin derivatives (ACTs artemisinin-based combination therapies) for P. falciparum. As yet another step towards combating drug resistance in Africa, WHO has lowered the resistance-threshold recommended for treatment policy change from 25% to 10% as assessed by standard WHO protocols in children under 5 years, meaning that a more effective treatment should be adopted when the proportion of treatment failures to the old treatment reaches 10%. 15. ActRx Cures for Malaria No.1: ActRx Malaria Injection Ingredient: Artesunate Molecular Formula: C19H25O8 Pharmacology: This product is a derivative of Artemisinin, have strong and rapid malariacidal action to the erythrocytic stage of plasmodium asexual form, can quickly control clinical episode and symptoms. The mechanism of action of Artemisinin is not clear. It has been observed that Artesunate mainly act on membranous structure of plasmodium by optical and electro microscope etc. method in the early days. In recent years, further research on molecular level discover that haemtochrome content peroxide group with bivalenferrum which has catalytic decomposition action on medicine, can produce oxdicing free radical and the free radical combined certain acceptor of plasmodium to cause biochemical reaction which results in the death of plasmodium. Pharmacokinetics:
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After iv injecting, the drug serum concentration declines quickly, T1/2 is about 30 minutes. The distribution of the product is very wide and the level is intestine, liver and kidney are relatively high. The drug mainly metabolite and transform in vivo, only a little unchanged is excreted from urine and faeces.. Indications: Used in the treatment of cerebral malaria and the emergency treatment of various critical cases. Administration and Dosage: The product can be administered in im or iv. 60mg once by daily for 5-7 days successively, doubled in the first day, total dose is 360-480mg. For children, 1.2mg/kg of body weight dose Before using, inject the added 1ml 5% sodium bicarbonate injection solution into the Artesunate vial for injection, repeat shaking 2-3 minutes, and wait till it completely dissolve. For iv, add 5% glucose injection or 5ml (im 2ml) physiological saline to make each 1ml solution content Artesunate 10mg (im 20mg), inhale needed amount of drug solution and injection slowly. Speed of iv: 3-4 minutes Patients with high falciparum density (erythrocyte injection rate10%), the initial dose on the first day is 120mg, 4-6hours. After that, inject again 60mg. Precaution: 1. Inject in time after its dissolving, it must not be used if it occurs opacity, the product should not be used by intravenous drip. 2. Use 5 days course of treatment to deal with falciparum malaria in chloroquine-resistant areas, the recurrence rate is below 10%. It is available to adopt 7 days course of treatment to deal with the patients without immunity or severe symptom. When patients come to or can be orally administered, transform injecting into oral giving. Pregnancy and Lactation Women: Early (within 3 months) pregnant women should use the drug carefully. Over-dosage: . Transient reticulcytopenia may occur when over-dose. (3.75mg/kg) Comments: It is the developed in China, which effects on asexual forms of plasmodium at erythrocytic stage and is It is used in the emergency treatment of various kinds of malaria, especially multi-drug resistance P. falciparum malaria and it also is the first-line treatment for complicated malaria. It has a remarkable inhibitory and gametocidal effect on falciparum gametocyte which may contribute to the reduction of malaria transmission. Its rapid effect proves great significance in clinical therapy. Patients with high protoza density in blood will lose consciousness, when parasites mature from large ring form to trophzoites, and the immediately be administered, the ActRx injection will arrive in a few minutes to prevent the mature of parasite to trophzoites and to avoid coma and the damage of vital organs, which greatly reduce the incidence and mortality of complicated malaria. So far, there is no other anti-malarial can achieve
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