malaria drugs 210

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Malaria

Plasmodium falciparum ring-forms and gametocytes in human blood.

Malaria is a mosquito-borne infectious disease caused by a eukaryotic protist of the genus Plasmodium. It is widespread in tropical and subtropical regions, including parts of the Americas, Asia, and Africa. Each year, there are approximately 350–500 million cases of malaria, killing between one and three million people, the majority of whom are young children in Sub-Saharan Africa. Ninety percent of malaria-related deaths occur in Sub-Saharan Africa. Malaria is commonly associated with poverty, but is also a cause of poverty and a major hindrance to economic development.

Five species of the plasmodium parasite can infect humans; the most serious forms of the disease are caused by Plasmodium falciparum. Malaria caused by Plasmodium vivax, Plasmodium ovale and Plasmodium malariae causes milder disease in humans that is not generally fatal. A fifth species, Plasmodium knowlesi, is a zoonosis that causes malaria in macaques but can also infect humans.

Malaria is naturally transmitted by the bite of a female Anopheles mosquito. When a mosquito bites an infected person, a small amount of blood is taken, which contains malaria parasites. These develop within the mosquito and about one week later, when the mosquito takes its next blood meal, the parasites are injected into the person being bitten

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with the mosquito's saliva. After a period of between 2 weeks and several months (occasionally years) spent in the liver, the malaria parasites start to multiply within, causing symptoms that include fever and headache. In severe cases the disease worsens leading to coma, and death.

A wide variety of antimalarial drugs are available to treat malaria. In the last 5 years treatment of P. falciparum infections in endemic countries has been transformed by the use of combinations of drugs containing an artemisinin derivative. Severe malaria is treated with intravenous or intramuscular quinine or, increasingly, the artemisinin derivative artesunate. Several drugs are also available to prevent malaria in travellers to malaria-endemic countries (prophylaxis). Resistance has developed to several antimalarial drugs, most notably chloroquine.

Malaria transmission can be reduced by preventing mosquito bites with mosquito nets and insect repellents, or by mosquito control measures such as spraying insecticides inside houses and draining standing water where mosquitoes lay their eggs.

Although many are under development, the challenge of producing a widely available vaccine that provides a high level of protection for a sustained period is still to be met

Signs and symptoms

Main symptoms of malaria.

Symptoms of malaria include fever, shivering, arthralgia (joint pain), vomiting, anemia (caused by hemolysis), hemoglobinuria, retinal damage, and convulsions. The classic symptom of malaria is cyclical occurrence of sudden coldness followed by rigor and then fever and sweating lasting four to six hours, occurring every two days in P. vivax and P. ovale infections, while every three for P. malariae. P. falciparum can have recurrent fever every 36–48 hours or a less pronounced and almost continuous fever. For



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reasons that are poorly understood, but that may be related to high intracranial pressure, children with malaria frequently exhibit abnormal posturing, a sign indicating severe brain damage. Malaria has been found to cause cognitive impairments, especially in children. It causes widespread anemia during a period of rapid brain development and also direct brain damage. This neurologic damage results from cerebral malaria to which children are more vulnerable. Cerebral malaria is associated with retinal whitening, which may be a useful clinical sign in distinguishing malaria from other causes of fever.

Species Appearance Periodicity Persistent in liver?

Plasmodium vivax

tertian yes

Plasmodium ovale

tertian yes

Plasmodium falciparum

tertian no



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Plasmodium malariae

quartan no

Severe malaria is almost exclusively caused by P. falciparum infection and usually arises 6–14 days after infection. Consequences of severe malaria include coma and death if untreated—young children and pregnant women are especially vulnerable. Splenomegaly (enlarged spleen), severe headache, cerebral ischemia, hepatomegaly (enlarged liver), hypoglycemia, and hemoglobinuria with renal failure may occur. Renal failure may cause blackwater fever, where hemoglobin from lysed red blood cells leaks into the urine. Severe malaria can progress extremely rapidly and cause death within hours or days. In the most severe cases of the disease fatality rates can exceed 20%, even with intensive care and treatment. In endemic areas, treatment is often less satisfactory and the overall fatality rate for all cases of malaria can be as high as one in ten. Over the longer term, developmental impairments have been documented in children who have suffered episodes of severe malaria.

Chronic malaria is seen in both P. vivax and P. ovale, but not in P. falciparum. Here, the disease can relapse months or years after exposure, due to the presence of latent parasites in the liver. Describing a case of malaria as cured by observing the disappearance of parasites from the bloodstream can, therefore, be deceptive. The longest incubation period reported for a P. vivax infection is 30 years. Approximately one in five of P. vivax malaria cases in temperate areas involve overwintering by hypnozoites (i.e., relapses begin the year after the mosquito bite).

Causes



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A Plasmodium sporozoite traverses the cytoplasm of a mosquito midgut epithelial cell in this false-color electron micrograph.

Malaria parasites

Malaria parasites are members of the genus Plasmodium (phylum Apicomplexa). In humans malaria is caused by P. falciparum, P. malariae, P. ovale, P. vivax and P. knowlesi. P. falciparum is the most common cause of infection and is responsible for about 80% of all malaria cases, and is also responsible for about 90% of the deaths from malaria. Parasitic Plasmodium species also infect birds, reptiles, monkeys, chimpanzees and rodents. There have been documented human infections with several simian species of malaria, namely P. knowlesi, P. inui, P. cynomolgi, P. simiovale, P. brazilianum, P. schwetzi and P. simium; however, with the exception of P. knowlesi, these are mostly of limited public health importance.

Mosquito vectors and the Plasmodium life cycle

The parasite's primary (definitive) hosts and transmission vectors are female mosquitoes of the Anopheles genus, while humans and other vertebrates are secondary hosts. Young mosquitoes first ingest the malaria parasite by feeding on an infected human carrier and the infected Anopheles mosquitoes carry Plasmodium sporozoites in their salivary glands. A mosquito becomes infected when it takes a blood meal from an infected human. Once ingested, the parasite gametocytes taken up in the blood will further differentiate into male or female gametes and then fuse in the mosquito gut. This produces an ookinete that penetrates the gut lining and produces an oocyst in the gut wall. When the oocyst ruptures, it releases sporozoites that migrate through the mosquito's body to the salivary glands, where they are then ready to infect a new human host. This type of transmission is occasionally referred to as anterior station transfer. The sporozoites are injected into the skin, alongside saliva, when the mosquito takes a subsequent blood meal.

Only female mosquitoes feed on blood, thus males do not transmit the disease. The females of the Anopheles genus of mosquito prefer to feed at night. They usually start searching for a meal at dusk, and will continue throughout the night until taking a meal. Malaria parasites can also be transmitted by blood transfusions, although this is rare



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Pathogenesis

The life cycle of malaria parasites in the human body. A mosquito infects a person by taking a blood meal. First, sporozoites enter the bloodstream, and migrate to the liver. They infect liver cells (hepatocytes), where they multiply into merozoites, rupture the liver cells, and escape back into the bloodstream. Then, the merozoites infect red blood cells, where they develop into ring forms, then trophozoites (a feeding stage), then schizonts (a reproduction stage), then back into merozoites. Sexual forms called gametocytes are also produced, which, if taken up by a mosquito, will infect the insect and continue the life cycle.

Malaria in humans develops via two phases: an exoerythrocytic and an erythrocytic phase. The exoerythrocytic phase involves infection of the hepatic system, or liver, whereas the erythrocytic phase involves infection of the erythrocytes, or red blood cells. When an infected mosquito pierces a person's skin to take a blood meal, sporozoites in the mosquito's saliva enter the bloodstream and migrate to the liver. Within 30 minutes of being introduced into the human host, the sporozoites infect hepatocytes, multiplying asexually and asymptomatically for a period of 6–15 days. Once in the liver, these organisms differentiate to yield thousands of merozoites, which, following rupture of their host cells, escape into the blood and infect red blood cells, thus beginning the



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erythrocytic stage of the life cycle. The parasite escapes from the liver undetected by wrapping itself in the cell membrane of the infected host liver cell.

Within the red blood cells, the parasites multiply further, again asexually, periodically breaking out of their hosts to invade fresh red blood cells. Several such amplification cycles occur. Thus, classical descriptions of waves of fever arise from simultaneous waves of merozoites escaping and infecting red blood cells.

Some P. vivax and P. ovale sporozoites do not immediately develop into exoerythrocytic-phase merozoites, but instead produce hypnozoites that remain dormant for periods ranging from several months (6–12 months is typical) to as long as three years. After a period of dormancy, they reactivate and produce merozoites. Hypnozoites are responsible for long incubation and late relapses in these two species of malaria.

The parasite is relatively protected from attack by the body's immune system because for most of its human life cycle it resides within the liver and blood cells and is relatively invisible to immune surveillance. However, circulating infected blood cells are destroyed in the spleen. To avoid this fate, the P. falciparum parasite displays adhesive proteins on the surface of the infected blood cells, causing the blood cells to stick to the walls of small blood vessels, thereby sequestering the parasite from passage through the general circulation and the spleen. This "stickiness" is the main factor giving rise to hemorrhagic complications of malaria. High endothelial venules (the smallest branches of the circulatory system) can be blocked by the attachment of masses of these infected red blood cells. The blockage of these vessels causes symptoms such as in placental and cerebral malaria. In cerebral malaria the sequestrated red blood cells can breach the blood brain barrier possibly leading to coma.

Although the red blood cell surface adhesive proteins (called PfEMP1, for Plasmodium falciparum erythrocyte membrane protein 1) are exposed to the immune system, they do not serve as good immune targets because of their extreme diversity; there are at least 60 variations of the protein within a single parasite and effectively limitless versions within parasite populations. The parasite switches between a broad repertoire of PfEMP1 surface proteins, thus staying one step ahead of the pursuing immune system.

Some merozoites turn into male and female gametocytes. If a mosquito pierces the skin of an infected person, it potentially picks up gametocytes within the blood. Fertilization and sexual recombination of the parasite occurs in the mosquito's gut, thereby defining the mosquito as the definitive host of the disease. New sporozoites develop and travel to the mosquito's salivary gland, completing the cycle. Pregnant women are especially attractive to the mosquitoes, and malaria in pregnant women is an important cause of stillbirths, infant mortality and low birth weight, particularly in P. falciparum infection, but also in other species infection, such as P. vivax.



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Diagnosis Blood film

Blood smear from a P. falciparum culture (K1 strain). Several red blood cells have ring stages inside them. Close to the center there is a schizont and on the left a trophozoite.

Since Charles Laveran first visualised the malaria parasite in blood in 1880, the mainstay of malaria diagnosis has been the microscopic examination of blood.

Fever and septic shock are commonly misdiagnosed as severe malaria in Africa, leading to a failure to treat other life-threatening illnesses. In malaria-endemic areas, parasitemia does not ensure a diagnosis of severe malaria because parasitemia can be incidental to other concurrent disease. Recent investigations suggest that malarial retinopathy is better (collective sensitivity of 95% and specificity of 90%) than any other clinical or laboratory feature in distinguishing malarial from non-malarial coma.

Although blood is the sample most frequently used to make a diagnosis, both saliva and urine have been investigated as alternative, less invasive specimens.

Symptomatic diagnosis

Areas that cannot afford even simple laboratory diagnostic tests often use only a history of subjective fever as the indication to treat for malaria. Using Giemsa-stained blood smears from children in Malawi, one study showed that when clinical predictors (rectal temperature, nailbed pallor, and splenomegaly) were used as treatment indications, rather than using only a history of subjective fevers, a correct diagnosis increased from 21% to 41% of cases and unnecessary treatment for malaria was significantly decreased.



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Microscopic examination of blood films

For more details on individual parasites, see P. falciparum, P. vivax, P. ovale, P. malariae.

The most economic, preferred, and reliable diagnosis of malaria is microscopic examination of blood films because each of the four major parasite species has distinguishing characteristics. Two sorts of blood film are traditionally used. Thin films are similar to usual blood films and allow species identification because the parasite's appearance is best preserved in this preparation. Thick films allow the microscopist to screen a larger volume of blood and are about eleven times more sensitive than the thin film, so picking up low levels of infection is easier on the thick film, but the appearance of the parasite is much more distorted and therefore distinguishing between the different species can be much more difficult. With the pros and cons of both thick and thin smears taken into consideration, it is imperative to utilize both smears while attempting to make a definitive diagnosis.

From the thick film, an experienced microscopist can detect parasite levels (or parasitemia) down to as low as 0.0000001% of red blood cells. Diagnosis of species can be difficult because the early trophozoites ("ring form") of all four species look identical and it is never possible to diagnose species on the basis of a single ring form; species identification is always based on several trophozoites.

Rapid antigen tests

OptiMAL-IT will reliably detect falciparum down to 0.01% parasitemia and non-falciparum down to 0.1%. Paracheck-Pf will detect parasitemias down to 0.002% but will not distinguish between falciparum and non-falciparum malaria. Parasite nucleic acids are detected using polymerase chain reaction. This technique is more accurate than microscopy. However, it is expensive, and requires a specialized laboratory. Moreover, levels of parasitemia are not necessarily correlative with the progression of disease, particularly when the parasite is able to adhere to blood vessel walls. Therefore more sensitive, low-tech diagnosis tools need to be developed in order to detect low levels of parasitaemia in the field.

Prevention



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Anopheles albimanus mosquito feeding on a human arm. This mosquito is a vector of malaria and mosquito control is a very effective way of reducing the incidence of malaria.

Methods used to prevent the spread of disease, or to protect individuals in areas where malaria is endemic, include prophylactic drugs, mosquito eradication, and the prevention of mosquito bites. The continued existence of malaria in an area requires a combination of high human population density, high mosquito population density, and high rates of transmission from humans to mosquitoes and from mosquitoes to humans. If any of these is lowered sufficiently, the parasite will sooner or later disappear from that area, as happened in North America, Europe and much of Middle East. However, unless the parasite is eliminated from the whole world, it could become re-established if conditions revert to a combination that favors the parasite's reproduction. Many countries are seeing an increasing number of imported malaria cases due to extensive travel and migration.

The distribution of funding varies among countries. Countries with large populations do not receive the same amount of support. The 34 countries that received a per capita annual support of less than $1 included some of the poorest countries in Africa.

Brazil, Eritrea, India, and Vietnam have, unlike many other developing nations, successfully reduced the malaria burden. Common success factors included conducive country conditions, a targeted technical approach using a package of effective tools, data-driven decision-making, active leadership at all levels of government, involvement of communities, decentralized implementation and control of finances, skilled technical and managerial capacity at national and sub-national levels, hands-on technical and programmatic support from partner agencies, and sufficient and flexible financing.

Prophylactic drugs

Several drugs, most of which are also used for treatment of malaria, can be taken preventively. Generally, these drugs are taken daily or weekly, at a lower dose than would be used for treatment of a person who had actually contracted the disease. Use of prophylactic drugs is seldom practical for full-time residents of malaria-endemic areas, and their use is usually restricted to short-term visitors and travelers to malarial regions. This is due to the cost of purchasing the drugs, negative side effects from long-term use, and because some effective anti-malarial drugs are difficult to obtain outside of wealthy nations.

Quinine was used starting in the 17th century as a prophylactic against malaria. The development of more effective alternatives such as quinacrine, chloroquine, and primaquine in the 20th century reduced the reliance on quinine. Today, quinine is still used to treat chloroquine resistant Plasmodium falciparum, as well as severe and cerebral stages of malaria, but is not generally used for prophylaxis.

Modern drugs used preventively include mefloquine (Lariam), doxycycline (available generically), and the combination of atovaquone and proguanil hydrochloride



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(Malarone). The choice of which drug to use depends on which drugs the parasites in the area are resistant to, as well as side-effects and other considerations. The prophylactic effect does not begin immediately upon starting taking the drugs, so people temporarily visiting malaria-endemic areas usually begin taking the drugs one to two weeks before arriving and must continue taking them for 4 weeks after leaving (with the exception of atovaquone proguanil that only needs be started 2 days prior and continued for 7 days afterwards).

The use of prophylactic drugs where malaria-bearing mosquitoes are present may encourage the development of partial immunity.

Treatment Active malaria infection with P. falciparum is a medical emergency requiring hospitalization. Infection with P. vivax, P. ovale or P. malariae can often be treated on an outpatient basis. Treatment of malaria involves supportive measures as well as specific antimalarial drugs. When properly treated, someone with malaria can expect a complete recovery.

Counterfeit drugs

Sophisticated counterfeits have been found in several Asian countries such as Cambodia, China, Indonesia, Laos, Thailand, Vietnam and are an important cause of avoidable death in those countries. WHO have said that studies indicate that up to 40% of artesunate based malaria medications are counterfeit, especially in the Greater Mekong region and have established a rapid alert system to enable information about counterfeit drugs to be rapidly reported to the relevant authorities in participating countries. There is no reliable way for doctors or lay people to detect counterfeit drugs without help from a laboratory. Companies are attempting to combat the persistence of counterfeit drugs by using new technology to provide security from source to distribution.

Epidemiology



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Countries which have regions where malaria is endemic as of 2003 (coloured yellow Countries in green are free of indigenous cases of malaria in all areas.

Disability-adjusted life year for malaria per 100,000 inhabitants in 2002. no data ≤10 10-50 50-100 100-250 250-500 500-1000 1000-1500 1500-2000 2000-2500 2500-3000 3000-3500 ≥3500

Malaria causes about 250 million cases of fever and approximately one million deaths annually. The vast majority of cases occur in children under 5 years old; pregnant women are also especially vulnerable. Despite efforts to reduce transmission and increase treatment, there has been little change in which areas are at risk of this disease since 1992. Indeed, if the prevalence of malaria stays on its present upwards course, the death rate could double in the next twenty years. Precise statistics are unknown because many cases occur in rural areas where people do not have access to hospitals or the means to afford health care. As a consequence, the majority of cases are undocumented.

Although co-infection with HIV and malaria does cause increased mortality, this is less of a problem than with HIV/tuberculosis co-infection, due to the two diseases usually attacking different age-ranges, with malaria being most common in the young and active tuberculosis most common in the old. Although HIV/malaria co-infection produces less severe symptoms than the interaction between HIV and TB, HIV and malaria do contribute to each other's spread. This effect comes from malaria increasing viral load and HIV infection increasing a person's susceptibility to malaria infection.

Malaria is presently endemic in a broad band around the equator, in areas of the Americas, many parts of Asia, and much of Africa; however, it is in sub-Saharan Africa where 85– 90% of malaria fatalities occur. The geographic distribution of malaria within large regions is complex, and malaria-afflicted and malaria-free areas are often found close to each other. In drier areas, outbreaks of malaria can be predicted with reasonable accuracy by mapping rainfall. Malaria is more common in rural areas than in cities; this is



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in contrast to dengue fever where urban areas present the greater risk. For example, the cities of Vietnam, Laos and Cambodia are essentially malaria-free, but the disease is present in many rural regions. By contrast, in Africa malaria is present in both rural and urban areas, though the risk is lower in the larger cities. The global endemic levels of malaria have not been mapped since the 1960s. However, the Wellcome Trust, UK, has funded the Malaria Atlas Project to rectify this, providing a more contemporary and robust means with which to assess current and future malaria disease burden.

History Malaria has infected humans for over 50,000 years, and Plasmodium may have been a human pathogen for the entire history of the species. Close relatives of the human malaria parasites remain common in chimpanzees. References to the unique periodic fevers of malaria are found throughout recorded history, beginning in 2700 BC in China. The term malaria originates from Medieval Italian: mala aria—"bad air"; and the disease was formerly called ague or marsh fever due to its association with swamps and marshland. Malaria was once common in most of Europe and North America, where it is no longer endemic, though imported cases do occur.

Scientific studies on malaria made their first significant advance in 1880, when a French army doctor working in the military hospital of Constantine in Algeria named Charles Louis Alphonse Laveran observed parasites for the first time, inside the red blood cells of people suffering from malaria. He, therefore, proposed that malaria is caused by this organism, the first time a protist was identified as causing disease. For this and later discoveries, he was awarded the 1907 Nobel Prize for Physiology or Medicine. The malarial parasite was called Plasmodium by the Italian scientists Ettore Marchiafava and Angelo Celli. A year later, Carlos Finlay, a Cuban doctor treating patients with yellow fever in Havana, provided strong evidence that mosquitoes were transmitting disease to and from humans. This work followed earlier suggestions by Josiah C. Nott, and work by Patrick Manson on the transmission of filariasis.

However, it was Britain's Sir Ronald Ross working in the Presidency General Hospital in Calcutta who finally proved in 1898 that malaria is transmitted by mosquitoes. He did this by showing that certain mosquito species transmit malaria to birds and isolating malaria parasites from the salivary glands of mosquitoes that had fed on infected birds. For this work Ross received the 1902 Nobel Prize in Medicine. After resigning from the Indian Medical Service, Ross worked at the newly-established Liverpool School of Tropical Medicine and directed malaria-control efforts in Egypt, Panama, Greece and Mauritius. The findings of Finlay and Ross were later confirmed by a medical board headed by Walter Reed in 1900, and its recommendations implemented by William C. Gorgas in the health measures undertaken during construction of the Panama Canal. This public-health work saved the lives of thousands of workers and helped develop the methods used in future public-health campaigns against this disease.

The first effective treatment for malaria came from the bark of cinchona tree, which contains quinine. This tree grows on the slopes of the Andes, mainly in Peru. A tincture



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made of this natural product was used by the inhabitants of Peru to control malaria, and the Jesuits introduced this practice to Europe during the 1640s, where it was rapidly accepted. However, it was not until 1820 that the active ingredient, quinine, was extracted from the bark, isolated and named by the French chemists Pierre Joseph Pelletier and Joseph Bienaimé Caventou.

In the early 20th century, before antibiotics became available, Julius Wagner-Jauregg discovered that patients with syphilis could be treated by intentionally infecting them with malaria; the resulting fever would kill the syphilis spirochetes, and quinine would then be administered to control the malaria. Although some patients died from malaria, this was considered preferable to the almost-certain death from syphilis.

Although the blood stage and mosquito stages of the malaria life cycle were identified in the 19th and early 20th centuries, it was not until the 1980s that the latent liver form of the parasite was observed. The discovery of this latent form of the parasite finally explained why people could appear to be cured of malaria but still relapse years after the parasite had disappeared from their bloodstreams.

ANTIMALARIAL DRUGS

A thin-film Giemsa stained micrograph of ring-forms, and gametocytes of Plasmodium falciparum. (CDC)

Antimalarial drugs are designed to prevent or cure malaria.

Uses of antimalarial drugs • Treatment of malaria in individuals with suspected or confirmed infection • Prevention of infection in individuals visiting a malaria-endemic region who have

no immunity (prophylaxis) • Routine Intermittent treatment of certain groups in endemic regions



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• Some antimalarial agents, particularly chloroquine and hydroxychloroquine, are also used in the treatment of rheumatoid arthritis and lupus associated arthritis.

Some agents are used for more than one application. It is therefore more practical to group antimalarials by chemical structure since this is associated with important properties of each drug, such as mechanism of action.

Quinine and related agents

Quinine has a long history stretching from Peru, and the discovery of the cinchona tree, and the potential uses of its bark, to the current day and a collection of derivatives that are still frequently used in the prevention and treatment of malaria. Quinine is an alkaloid that acts as a blood schizonticidal and weak gametocide against Plasmodium vivax and Plasmodium malariae. As an alkaloid, it is accumulated in the food vacuoles of Plasmodium species, especially Plasmodium falciparum. It acts by inhibiting the hemozoin biocrystallization, thus facilitating an aggregation of cytotoxic heme. Quinine is less effective and more toxic as a blood schizonticidal agent than chloroquine; however it is still very effective and widely used in the treatment of acute cases of severe P. falciparum. It is especially useful in areas where there is known to be a high level of resistance to chloroquine, mefloquine and sulfa drug combinations with pyrimethamine. Quinine is also used in post-exposure treatment of individuals returning from an area where malaria is endemic.

The treatment regimen of quinine is complex and is determined largely by the parasite's level of resistance and the reason for drug therapy (i.e. acute treatment or prophylaxis). The World Health Organization recommendation for quinine is 8 mg/kg three times daily for 3 days in areas where the level of adherence is questionable and for 7 days where parasites are sensitive to quinine. In areas where there is an increased level of resistance to quinine 8 mg/kg three times daily for 7 days is recommended, combined with doxycycline, tetracycline or clindamycin. Doses can be given by oral, intravenous or intramuscular routes. The recommended method depends on the urgency of treatment and the available resources (i.e. sterilised needles for IV or IM injections).

Use of quinine is characterised by a frequently experienced syndrome called cinchonism. Tinnitus (a hearing impairment), rashes, vertigo, nausea, vomiting and abdominal pain are the most common symptoms. Neurological effects are experienced in some cases due to the drug's neurotoxic properties. These actions are mediated through the interactions of Quinine causing a decrease in the excitability of the motor neuron end plates. This often results in functional impairment of the eight cranial nerve; resulting in confusion, delirium and coma. Quinine can cause hypoglycaemia through its action of stimulating insulin secretion, this occurs in therapeutic doses and therefore it is advised that glucose levels are monitored in all patients every 4–6 hours. This effect can be exaggerated in pregnancy and therefore additional care in administering and monitoring the dosage is essential. Repeated or over-dosage can result in renal failure and death through depression of the respiratory system.



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Quinimax and quinidine are the two most commonly used alkaloids related to quinine, in the treatment or prevention of malaria. Quinimax is a combination of four alkaloids (quinine, quinidine, cinchoine and cinchonidine). This combination has been shown in several studies to be more effective than quinine, supposedly due to a synergistic action between the four cinchona derivatives. Quinidine is a direct derivative of quinine. It is a distereoisomer, thus having similar anti-malarial properties to the parent compound. Quinidine is recommended only for the treatment of severe cases of malaria.

Chloroquine

Chloroquine was until recently the most widely used anti-malarial. It was the original prototype from which most other methods of treatment are derived. It is also the least expensive, best tested and safest of all available drugs. The emergence of drug resistant parasitic strains is rapidly decreasing its effectiveness; however it is still the first-line drug of choice in most sub-Saharan African countries. It is now suggested that it is used in combination with other antimalarial drugs to extend its effective usage.

Chloroquine is a 4-aminoquinolone compound with a complicated and still unclear mechanism of action. It is believed to reach high concentrations in the vacuoles of the parasite, which, due to its alkaline nature, raises the internal pH. It controls the conversion of toxic heme to hemozoin by inhibiting the biocrystallization of hemozoin thus poisoning the parasite through excess levels of toxicity. Other potential mechanisms through which it may act include interfering with the biosynthesis of parasitic nucleic acids, the formation of a chloroquine-haem or chloroquine-DNA complex. The most significant level of activity found is against all forms of the schizonts (with the obvious exception of chloroquine-resistant P. falciparum and P. vivax strains) and the gametocytes of P. vivax, P. malariae, P. ovale as well as the immature gametocytes of P. falciparum. Chloroquine also has a significant anti-pyretic and anti-inflammatory effect when used to treat P. vivax infections, thus it may still remain useful even when resistance is more widespread. According to a report on the Science and Development Network website's sub-Saharan Africa section, there is very little drug resistance among children infected with malaria on the island of Madagascar, but what drug resistance there is, exists against chloroquinine.

A slightly different drug called nivaquine or chloroquine phosphate has also been invented. Popular drugs that make use of this compound are Chloroquine FNA, Resochin and Dawaquin.

Route of administration: It can be given orally, or intramuscularly. Formulation/Strength: Tablet contains 250mg of chloroquine

diphosphate, corresponding to 150mg of chloroquine base. Ampoule. Chloroquine injection, 40mg/ml.

Chloroqine injection: (I.M.I.)

- 40mg/ml - I.M. injection only. (NEVER I.V.) For more serious cases, i.e. if the patient is vomiting, fitting,

not fully conscious, temp. over 39.5 degrees or severe diarrhea.



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- 0.1ml/kg given I.M.I. and repeated 6 hours later. Repeat 0.1ml/kg daily for up to 2 days if still

unconscious, but change to oral treatment as soon as possible. Small adult: 5ml (Under 50kg) Large adult. 7ml (Over 50kg) Children: Give 0.1ml/kg I.M.I. Weight (kg) Dose per ml (I.M.I.) 3 – 5 ¼ 5 – 7 ¼ 8 – 9 ¾ 10 – 14 1 15 – 19 1½ 20 – 24 2 25 – 29 2½ 30 - 39 3 Change to amodiaquine or chloroquine tablet as soon as possible

Children and adults should receive 25 mg of chloroquine per kg given over 3 days. A pharmacokinetically superior regime, recommended by the WHO, involves giving an initial dose of 10 mg/kg followed 6–8 hours later by 5 mg/kg, then 5 mg/kg on the following 2 days. For chemoprophylaxis: 5 mg/kg/week (single dose) or 10 mg/kg/week divided into 6 daily doses is advised. It should be noted that chloroquine is only recommended as a prophylactic drug in regions only affected by P. vivax and sensitive P. falciparum strains. Chloroquine has been used in the treatment of malaria for many years and no abortifacient or teratogenic effects have been reported during this time, therefore it is considered very safe to use during pregnancy. However, itching can occur at intolerable level.

Amodiaquine

Amodiaquine is a 4-aminoquinolone anti-malarial drug similar in structure and mechanism of action to Chloroquine. It is most frequently used in combination with Chloroquine, but is also very effective when used alone. It is thought to be more effective in clearing parasites in uncomplicated malarial than Chloroquine, thus leading to a faster rate of recovery. However, some fatal adverse effects of the drug were noted during the 1980s, thus reducing its usage in chemoprophylaxis. The WHO's most recent advice on the subject still maintains that the drug should be used when the potential risk of not treating an infection outweighs the risk of developing side effects. It has also been suggested that it is particularly effective, and less toxic than other combination treatments in HIV positive patients.



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Dosage

Weight (kg) Dose in tab/mg 3 – 5.9 ½ (50mg) 6 – 9.9 1 (100mg) 10 – 14.9 1½ (150mg) 15 – 18.9 2 (200mg) 19 & over give chloroquine

The drug should be given in doses between 25 mg/kg and 35 mg/kg over 3 days in a similar method to that used in Chloroquine administration. Adverse reactions are generally similar in severity and type to that seen in Chloroquine treatment. In addition, bradycardia, itching, nausea, vomiting and some abdominal pain have been recorded. Some blood and hepatic disorders have also been seen in a small number of patients.

Pyrimethamine

Pyrimethamine is used in the treatment of uncomplicated malaria. It is particularly useful in cases of chloroquine-resistant P. Falciparum strains when combined with Sulphadoxine. It acts by inhibiting dihydrofolate reductase in the parasite thus preventing the biosynthesis of purines and pyrimidines. Therefore halting the processes of DNA synthesis, cell division and reproduction. It acts primarily on the schizonts during the hepatic and erythrocytic phases.

Sulphadoxine

The action of Sulphadoxine is focused on inhibiting the use of para-aminobenzoic acid during the synthesis of dihydropteroic acid. When combined with Pyrimethamine the two key stages in DNA synthesis in the plasmodia are prevented. It also acts on the schizonts during the hepatic and erythrocytic phases. It is mainly used for treating P. falciparum infections and is less active against other Plasmodium strains. However usage is restricted due to the long half life of the combination which exerts a potentially large selection pressure on the parasite hence encouraging the possibility of resistance developing. This combination is not recommended for chemoprophylaxis because of the severe skin reactions commonly experienced. However it is used frequently for clinical episodes of the disease.

Proguanil

Proguanil (Chloroguanadine) is a biguanide; a synthetic derivative of pyrimidine. It was developed in 1945 by a British Antimalarial research group. It has many mechanisms of action but primarily is mediated through conversion to the active metabolite cycloguanil pamoate. This inhibits the malarial dihydrofolate reductase enzyme. Its most prominent effect is on the primary tissue stages of P. falciparum, P. vivax and P. ovale. It has no



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known effect against hypnozoites therefore is not used in the prevention of relapse. It has a weak blood schizonticidal activity and is not recommended for therapy of acute infection. However it is useful in prophylaxis when combined with Atovaquone or chloroquine (in areas where there is no chloroquine resistance). 3 mg/kg is the advised dosage per day, (hence approximate adult dosage is 200 mg). The pharmacokinetic profile of the drugs indicates that a half dose, twice daily maintains the plasma levels with a greater level of consistency, thus giving a greater level of protection. It should be noted that the Proguanil- Chloroquine combination does not provide effective protection against resistant strains of P. falciparum. There are very few side effects to Proguanil, with slight hair loss and mouth ulcers being occasionally reported following prophylactic use.

Mefloquine

Mefloquine was developed during the Vietnam War and is chemically related to quinine. It was developed to protect American troops against multi-drug resistant P. falciparum. It is a very potent blood schizonticide with a long half-life. It is thought to act by forming toxic heme complexes that damage parasitic food vacuoles. It is now used solely for the prevention of resistant strains of P. falciparum despite being effective against P. vivax, P. ovale and P. marlariae. Mefloquine is effective in prophylaxis and for acute therapy. It is now strictly used for resistant strains (and is usually combined with Artesunate). Chloroquine/Proguanil or sufha drug-pyrimethamine combinations should be used in all other Plasmodia infections.

The major commercial manufacturer of mefloquine-based malaria treatment is Roche Pharmaceuticals, which markets the drug under the trade name "Lariam". Lariam is fairly expensive at around 3 € per tablet (pricing of the year 2000).

A dose of 15–25 mg/kg is recommended, depending on the prevalence of Mefloquine resistance. The increased dosage is associated with a much greater level of intolerance, most noticeably in young children; with the drug inducing vomiting and oesophagitis. The effects during pregnancy are unknown, although it has been linked with an increased number of stillbirths. It is not recommended for use during the first trimester, although considered safe during the second and third trimesters. Mefloquine frequently produces side effects, including nausea, vomiting, diarrhea, abdominal pain and dizziness. Several associations with neurological events have been made, namely affective and anxiety disorders, hallucinations, sleep disturbances, psychosis, toxic encephalopathy, convulsions and delirium. Cardiovascular effects have been recorded with bradycardia and sinus arrhythmia being consistently recorded in 68% of patients treated with Mefloquine (in one hospital-based study).

Mefloquine can only be taken for a period up to 6 months (due to side effects, ...). After this, other drugs (such as those based on paludrine/nivaquine) again need to be taken.



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Atovaquone

Atovaquone is only available in combination with Proguanil under the name Malarone, albeit at a price higher than Lariam. It is most commonly used in prophylaxis by travellers.

Primaquine

Primaquine is a highly active 8-aminoquinolone that is used in treating all types of malaria infection. It is most effective against gametocytes but also acts on hypnozoites, blood schizonticytes and the dormant plasmodia in P. vivax and P. ovale. It is the only known drug to cure both relapsing malaria infections and acute cases. The mechanism of action is not fully understood but it is thought to mediate some effect through creating oxygen free radicals that interfere with the plasmodial electron transport chain during respiration.

Formulation/Strength: Tablet – 7.5mg Route of administration: Administered orally. Dosage: Adult. For single dose on the first day of treatment for P. falciparum. - Small adult 4 tablet (30mg)

(Under 50kg) - Large adult 6 tablet (45mg)

(Over 50kg) Children. For single dose on the first day of treatment. Weight (kg) Dose in tab./mg 3 – 5.9 - 6 – 9.9 ½ (3.75mg) 10 – 14.9 1 (7.5mg) 15 – 18.9 1½ (11.25mg) 19 – 27.9 2 (15mg) 28 – 36.9 3 (22.5mg) 37 – 49.9 4 (30mg)

For the prevention of relapse in P. vivax and P. ovale 0.15 mg/kg should be given for 14 days. As a gametocytocidal drug in P. falciparum infections a single dose of 0.75 mg/kg repeated 7 days later is sufficient. This treatment method is only used in conjunction with another effective blood schizonticidal drug. There are few significant side effects although is has been shown that Primaquine may cause anorexia, nausea, vomiting, cramps, chest weakness, anaemia, some suppression of myeloid activity and abdominal pains. In cases of over-dosage granulocytopenia may occur.



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Artemesinin and derivatives

Artemesinin is a Chinese herb (Qinghaosu) that has been used in the treatment of fevers for over 1,000 years, thus predating the use of Quinine in the western world. It is derived from the plant Artemisia annua, with the first documentation as a successful therapeutic agent in the treatment of malaria is in 340 AD by Ge Hong in his book Zhou Hou Bei Ji Fang (A Handbook of Prescriptions for Emergencies). The active compound was isolated first in 1971 and named Artemsinin. It is a sesquiterpene lactone with a chemically rare peroxide bridge linkage. It is this that is thought to be responsible for the majority of its anti-malarial action, although the target within the parasite remains controversial. At present it is strictly controlled under WHO guidelines as it has proven to be effective against all forms of multi-drug resistant P. falciparum, thus every care is taken to ensure compliance and adherence together with other behaviours associated with the development of resistance. It is also only given in combination with other anti-malarials.

• Artemisinin has a very rapid action and the vast majority of acute patients treated show significant improvement within 1–3 days of receiving treatment. It has demonstrated the fastest clearance of all anti-malarials currently used and acts primarily on the trophozite phase, thus preventing progression of the disease. Semi-synthetic artemisinin derivatives (e.g. artesunate, artemether) are easier to use than the parent compound and are converted rapidly once in the body to the active compound dihydroartemesinin. On the first day of treatment 20 mg/kg should be given, this dose is then reduced to 10 mg/kg per day for the 6 following days. Few side effects are associated with artemesinin use. However, headaches, nausea, vomiting, abnormal bleeding, dark urine, itching and some drug fever have been reported by a small number of patients. Some cardiac changes were reported during a clinical trial, notably non specific ST changes and a first degree atrioventricular block (these disappeared when the patients recovered from the malarial fever).

• Artemether is a methyl ether derivative of Dihydroartemesinin. It is similar to Artemesinin in mode of action but demonstrates a reduced ability as a hypnozoiticidal compound, instead acting more significantly to decrease gametocyte carriage. Similar restrictions are in place, as with Artemesinin, to prevent the development of resistance, therefore it is only used in combination therapy for severe acute cases of drug-resistant P. falciparum. It should be administered in a 7 day course with 4 mg/kg given per day for 3 days, followed by 1.6 mg/kg for 3 days. Side effects of the drug are few but include potential neurotoxicity developing if high doses are given.

• Artesunate is a hemisuccinate derivative of the active metabolite Dihydroartemisin. Currently it is the most frequently used of all the Artemesinin-type drugs. Its only effect is mediated through a reduction in the gametocyte transmission. It is used in combination therapy and is effective in cases of uncomplicated P. falciparum. The dosage recommended by the WHO is a 5 or 7 day course (depending on the predicted adherence level) of 4 mg/kg for 3 days (usually given in combination with Mefloquine) followed by 2 mg/kg for the



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remaining 2 or 4 days. In large studies carried out on over 10,000 patients in Thailand no adverse effects have been shown.

• Dihydroartemisinin is the active metabolite to which Artemesinin is reduced. It is the most effective Artemesinin compound and the least stable. It has a strong blood schizonticidal action and reduces gametocyte transmission. It is used for therapeutic treatment of cases of resistant and uncomplicated P. falciparum. 4 mg/kg doses are recommended on the first day of therapy followed by 2 mg/kg for 6 days. As with Artesunate, no side effects to treatment have thus far been recorded.

• Arteether is an ethyl ether derivative of Dihydroartemisinin. It is used in combination therapy for cases of uncomplicated resistant P. falciparum. The recommended dosage is 150 mg/kg per day for 3 days given by IM injections. With the exception of a small number of cases demonstrating neurotoxicity following parenteral administration no side effects have been recorded.

Halofantrine

Halofantrine is a relatively new drug developed by the Walter Reed Army Institute of Research in the 1960s. It is a phenanthrene methanol, chemically related to Quinine and acts acting as a blood schizonticide effective against all plasmodium parasites. Its mechanism of action is similar to other anti-malarials. Cytotoxic complexes are formed with ferritoporphyrin XI that cause plasmodial membrane damage. Despite being effective against drug resistant parasites, Halofantrine is not commonly used in the treatment (prophylactic or therapeutic) of malaria due to its high cost. It has very variable bioavailability and has been shown to have potentially high levels of cardiotoxicity. It is still a useful drug and can be used in patients that are known to be free of heart disease and are suffering from severe and resistant forms of acute malaria. A popular drug based on halofantrine is Halfan. The level of governmental control and the prescription-only basis on which it can be used contributes to the cost, thus Halofantrine is not frequently used.

A dose of 8 mg/kg of Halofantrine is advised to be given in three doses at six hour intervals for the duration of the clinical episode. It is not recommended for children under 10 kg despite data supporting the use and demonstrating that it is well tolerated. The most frequently experienced side-effects include nausea, abdominal pain, diarrhoea, and itch. Severe ventricular dysrhythmias, occasionally causing death are seen when high doses are administered. This is due to prolongation of the QTc interval. Halofantrine is not recommended for use in pregnancy and lactation, in small children, or in patients that have taken Mefloquine previously. Lumefantrine is a relative of halofantrine that is used in some combination antimalarial regimens.

Doxycycline

Probably one of the more prevalent antimalarial drugs prescribed, due to its relative effectiveness and cheapness, Doxycycline is a Tetracycline compound derived from Oxytetracycline. The tetracyclines were one of the earliest groups of antibiotics to be



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developed and are still used widely in many types of infection. It is a bacteriostatic agent that acts to inhibit the process of protein synthesis by binding to the 30S ribosomal subunit thus preventing the 50s and 30s units from bonding. Doxycycline is used primarily for chemoprophylaxis in areas where chloroquine resistance exists. It can also be used in combination with quinine to treat resistant cases of P. falciparum but has a very slow action in acute malaria, and should not be used as monotherapy.

When treating acute cases and given in combination with Quinine; 100 mg/kg of Doxycycline should be given per day for 7 days. In prophylactic therapy, 100 mg (adult dose) of Doxycycline should be given every day during exposure to malaria.

The most commonly experienced side effects are permanent enamel hypoplasia, transient depression of bone growth, gastrointestinal disturbances and some increased levels of photosensitivity. Due to its effect of bone and tooth growth it is not used in children under 8, pregnant or lactating women and those with a known hepatic dysfunction.

Tetracycline is only used in combination for the treatment of acute cases of P.Falciparum infections. This is due to its slow onset. Unlike Doxycycline it is not used in chemoprophylaxis. For Tetracycline, 250 mg is the recommended adult dosage (it should not be used in children) for 5 or 7 days depending on the level of adherence and compliance expected. Oesophageal ulceration, gastrointestinal upset and interferences with the process of ossification and depression of bone growth are known to occur. The majority of side effects associated with Doxycycline are also experienced.

Clindamycin

Clindamycin is a derivative of Lincomycin, with a slow action against blood schizonticides. It is only used in combination with Quinine in the treatment of acute cases of resistant P. falciparum infections and not as a prophylactic. Being more expensive and toxic than the other antibiotic alternatives, it is used only in cases where the Tetracyclines are contraindicated (for example in children).

Clindamycin should be given in conjunction with Quinine as a 300 mg dose (in adults) four times a day for 5 days. The only side effects recorded in patients taking Clindamycin are nausea, vomiting and abdominal pains and cramps. However these can be alleviated by consuming large quantities of water and food when taking the drug. Pseudomembranous colitis (caused by Clostridium difficile) has also developed in some patients; this condition may be fatal in a small number of cases.

Resistance to antimalarials

Antimalarial resistance is common.

Anti-malarial drug resistance has been defined as: "the ability of a parasite to survive and/or multiply despite the administration and absorption of a drug given in doses equal to or higher than those usually recommended but within tolerance of the subject. The



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drug in question must gain access to the parasite or the infected red blood cell for the duration of the time necessary for its normal action." In most instances this refers to parasites that remaining following on from an observed treatment. Thus excluding all cases where anti-malarial prophylaxis has failed. In order for a case to be defined as resistant, the patient under question must have received a known and observed anti-malarial therapy whilst the blood drug and metabolite concentrations are monitored concurrently. The techniques used to demonstrate this are: in vivo, in vitro, animal model testing and the most recently developed molecular techniques.

Drug resistant parasites are often used to explain malaria treatment failure. However, they are two potentially very different clinical scenarios. The failure to clear parasitemia and recover from an acute clinical episode when a suitable treatment has been given and anti-malarial resistance in its true form. Drug resistance may lead to treatment failure, but treatment failure is not necessarily caused by drug resistance despite assisting with its development. A multitude of factors can be involved in the processes including problems with non-compliance and adherence, poor drug quality, interactions with other pharmaceuticals, poor absorption, misdiagnosis and incorrect doses being given. The majority of these factors also contribute to the development of drug resistance.

The generation of resistance can be complicated and varies between plasmodium species. It is generally accepted to be initiated primarily through a spontaneous mutation that provides some evolutionary benefit, thus giving an anti-malarial used a reduced level of sensitivity. This can be caused by a single point mutation or multiple mutations. In most instances a mutation will be fatal for the parasite or the drug pressure will remove parasites that remain susceptible, however some resistant parasites will survive. Resistance can become firmly established within a parasite population, existing for long periods of time.

The first type of resistance to be acknowledged was to Chloroquine in Thailand in 1957. The biological mechanism behind this resistance was subsequently discovered to be related to the development of an efflux mechanism that expels Chloroquine from the parasite before the level required to effectively inhibit the process of haem polymerization (that is necessary to prevent build up of the toxic by products formed by haemoglobin digestion). This theory has been supported by evidence showing that resistance can be effectively reversed on the addition of substances which halt the efflux. The resistance of other quinolone anti-malarials such as amiodiaquine, mefloquine, halofantrine and quinine are thought to have occurred by similar mechanisms.

Plasmodium have developed resistance against antifolate combination drugs, the most commonly used being sulfadoxine and pyrimethamine. Two gene mutations are thought to be responsible, allowing synergistic blockages of two enzymes involved in folate synthesis. Regional variations of specific mutations give differing levels of resistance.

Atovaquone is recommended to be used only in combination with another anti-malarial compound as the selection of resistant parasites occurs very quickly when used in mono-



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therapy. Resistance is thought to originate from a single-point mutation in the gene coding for cytochrome-b.

Spread of resistance There is no single factor that confers the greatest degree of influence on the spread of drug resistance, but a number of plausible causes associated with an increase have been acknowledged. These include aspects of economics, human behaviour, pharmokinetics, and the biology of vectors and parasites.

The most influential causes are examined below:

1. The biological influences are based on the parasites ability to survive the presence of an anti-malarial thus enabling the persistence of resistance and the potential for further transmission despite treatment. In normal circumstances any parasites that persist after treatment are destroyed by the host's immune system, therefore any factors that act to reduce the elimination of parasites could facilitate the development of resistance. This attempts to explain the poorer response associated with immunocompromised individuals, pregnant women and young children.

2. There has been evidence to suggest that certain parasite-vector combinations can alternatively enhance or inhibit the transmission of resistant parasites, causing 'pocket-like' areas of resistance.

3. The use of anti-malarials developed from similar basic chemical compounds can increase the rate of resistance development, for example cross-resistance to chloroquine and amiodiaquine, two 4-aminoquinolones and mefloquine conferring resistance to quinine and halofantrine. This phenomenon may reduce the usefulness of newly developed therapies prior to large-scale usage.

4. The resistance to anti-malarials may be increased by a process found in some species of plasmodium, where a degree of phenotypic plasticity was exhibited, allowing the rapid development of resistance to a new drug, even if the drug has not been previously experienced.

5. The pharmokinetics of the chosen anti-malarial are key; the decision of choosing a long-half life over a drug that is metabolised quickly is complex and still remains unclear. Drugs with shorter half-life's require more frequent administration to maintain the correct plasma concentrations, therefore potentially presenting more problems if levels of adherence and compliance are unreliable, but longer-lasting drugs can increase the development of resistance due to prolonged periods of low drug concentration.

6. The pharmokinetics of anti-malarials is important when using combination therapy. Mismatched drug combinations, for example having an 'unprotected' period where one drug dominates can seriously increase the likelihood of selection for resistant parasites.

7. Ecologically there is a linkage between the level of transmission and the development of resistance, however at present this still remains unclear.



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8. The treatment regime prescribed can have a substantial influence on the development of resistance. This can involve the drug intake, combination and interactions as well as the drug's pharmokinetic and dynamic properties.

Prevention of resistance The prevention of anti-malarial drug resistance is of enormous public health importance. It can be assumed that no therapy currently under development or to be developed in the foreseeable future will be totally protective against malaria. In accordance with this, there is the possibility of resistance developing to any given therapy that is developed. This is a serious concern, as the rate at which new drugs are produced by no means matches the rate of the development of resistance. In addition, the most newly developed therapeutics tend to be the most expensive and are required in the largest quantities by some of the poorest areas of the world. Therefore it is apparent that the degree to which malaria can be controlled depends on the careful use of the current drugs to limit, insofar as it is possible, any further development of resistance.

Provisions essential to this process include the delivery of fast primary care where staff are well trained and supported with the necessary supplies for efficient treatment. This in itself is inadequate in large areas where malaria is endemic thus presenting an initial problem. One method proposed that aims to avoid the fundamental lack in certain countries health care infrastructure is the privatisation of some areas, thus enabling drugs to be purchased on the open market from sources that are not officially related to the health care industry. Although this is now gaining some support there are many problems related to limited access and improper drug use, which could potentially increase the rate of resistance development to an even greater extent.

There are two general approaches to preventing the spread of resistance: preventing malaria infections and, preventing the transmission of resistant parasites.

Preventing malaria infections developing has a substantial effect on the potential rate of development of resistance, by directly reducing the number of cases of malaria thus decreasing the requirement for anti-malarial therapy. Preventing the transmission of resistant parasites limits the risk of resistant malarial infections becoming endemic and can be controlled by a variety of non-medical methods including insecticide-treated bed nets, indoor residual spraying, environmental controls (such as swamp draining) and personal protective methods such as using mosquito repellent. Chemoprophylaxis is also important in the transmission of malaria infection and resistance in defined populations (for example travellers).

A hope for future of anti-malarial therapy is the development of an effective malaria vaccine. This could have enormous public health benefits, providing a cost-effective and easily applicable approach to preventing not only the onset of malaria but the transmission of gametocytes, thus reducing the risk of resistance developing. Anti-malarial therapy could be also be diversified by combining a potentially effective vaccine



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with current chemotherapy, thereby reducing the chance of vaccine resistance developing.

Combination therapy

The problem of the development of malaria resistance must be weighed against the essential goal of anti-malarial care; that is to reduce morbidity and mortality. Thus a balance must be reached that attempts to achieve both goals whilst not compromising either too much by doing so. The most successful attempts so far have been in the administration of combination therapy. This can be defined as, 'the simultaneous use of two or more blood schizonticidal drugs with independent modes of action and different biochemical targets in the parasite'. There is much evidence to support the use of combination therapies, some of which has been discussed previously, however several problems prevent the wide use in the areas where its use is most advisable. These include: problems identifying the most suitable drug for different epidemiological situations, the expense of combined therapy (it is over 10 times more expensive than traditional mono-therapy), how soon the programmes should be introduced and problems linked with policy implementation and issues of compliance.

The combinations of drugs currently prescribed can be divided into two categories: Non-artemesinin and Quinine based combinations and, Artemesinin based combinations. It is also important to distinguish fixed-dose combination therapies (in which two or more drugs are co-formulated into a single tablet) from combinations achieved by taking two separate antimalarials.

Non-Artemisinin based combinations

Components Description Dose

Sulfadoxine-Pyrimethamine (SP) (Fansidar)

This fixed-dose combination has been used for many years and has widespread resistance. It causes few adverse effects but is cheap and is available in a single dose, thus decreasing problems associated with adherence and compliance.

25 mg/kg of sulfadoxine and 1.25 mg/kg of pyrimethamine.

SP plus Chloroquine

This is another cost-effective combination, which benefits from the drugs having similar pharmacokinetic profiles but different biochemical parasitic targets. High levels of resistance to one or both components means it is not effective in most locations.

Chloroquine 25 mg/kg over 3 days with a single dose of SP as described above.



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SP plus Amodiaquine

This combination has been shown to produce a faster rate of clinical recovery than SP and Chloroquine, however there are certain adverse reactions associated with use that have limited its distribution. It is thought to have a longer therapeutic lifetime than other combinations and may be a more cost-effective option to introduce in areas where resistance is likely to develop. This is unlikely to occur until more information regarding its safety has been obtained.

10 mg/kg of Amodiaquine per day for 3 days with a single standard dose of SP.

SP plus Mefloquine (Fansimef)

This is a single dose pill and offered obvious advantages over more complex regimes but it has not been recommended for used since 1990 due to widespread resistance to the components.

Tetracycline or Doxycycline plus Quinine

Despite the increasing levels of resistance to Quinine this combination has proven to be particularly efficacious. The longer half-life of the Tetracycline component ensures a high cure rate. Problems with this regime include the relatively complicated drug regimen, where Quinine must be taken every 8 hours for 7 days. Additionally, there are severe side effects to both drugs (Cinchonism in Quinine) and Tetracyclines are contraindicated in children and pregnant women. For these reasons this combination is not recommended as first-line therapy but can be used for non-responders who remain able to take oral medication.

Quinine 10 mg/kg doses every 8 hours and Tetracycline in 4 mg/kg doses every 6 hours for 7 days.

Artemesinin-based combination therapies (ACTs)

Artemesinin has a very different mode of action than conventional anti-malarials (see information above), this makes is particularly useful in the treatment of resistant infections, however in order to prevent the development of resistance to this drug it is only recommended in combination with another non-artemesinin based therapy. It produces a very rapid reduction in the parasite biomass with an associated reduction in clinical symptoms and is known to cause a reduction in the transmission of gametocytes



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thus decreasing the potential for the spread of resistant alleles. At present there is no known resistance to Artemesinin (though some resistant strains may be emerging) and very few reported side-effects to drug usage, however this data is limited.


Artesunate and Chloroquine

This combination has been thoroughly tested in randomised controlled trials and has demonstrated that it is well tolerated with few side effects. However, chloroquine resistance means that it is frequently ineffective(i n one study there was less than 85% cure in areas where chloroquine resistance was known). It is therefore not approved by the WHO for use in combination therapy.

Artesunate and Amodiaquine (Coarsucam and ASAQ)

This combination has also been tested and proved to be more efficacious and similarly well tolerated to the Chloroquine combination. The cure rate was greater than 90%, potentially providing a viable alternative where levels of Chloroquine resistance are high. The main disadvantage is a suggested link with neutropenia.

Dosage is as a fixed-dose combination (ASAQ) recommended as 4 mg/kg of Artesunate and 10 mg/kg of Amodiaquine per day for 3 days.

Artesunate and Mefloquine (Artequin and ASMQ)

This has been used as an efficacious first-line treatment regimen in areas of Thailand for many years. Mefloquine is known to cause vomiting in children and induces some neuropsychiatric and cardiotoxic effects, interestingly these adverse reactions seem to be reduced when the drug is combined with Artesunate, it is

The standard dose required is 4 mg/kg per day of Artesunate plus 25 mg/kg of Mefloquine as a split dose of 15 mg/kg on day 2 and 10 mg/kg on day three.



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suggested that this is due to a delayed onset of action of Mefloquine. This is not considered a viable option to be introduced in Africa due to the long half-life of Mefloquine, which potentially could exert a high selection pressure on parasites.

Artemether and Lumefantrine (Coartem Riamet, and Lonart)

This combination has been extensively tested in 16 clinical trials, proving effective in children under 5 and has been shown to be better tolerated than Artesunate plus Mefloquine combinations. There are no serious side effects documented but the drug is not recommended in pregnant or lactating women due to limited safety testing in these groups. This is the most viable option for widespread use and is available in fixed-dose formulas thus increasing compliance and adherence.

Artesunate and Sulfadoxine/Pyrimethamine (Ariplus)

This is a well tolerated combination but the overall level of efficacy still depends on the level of resistance to Sulfadoxine and Pyrimethamine thus limiting is usage.

It is recommended in doses of 4 mg/kg of Artesunate per day for 3 days and a single dose of 25 mg/kg of SP.

Other combinations

There are several anti-malarial combinations currently being developed that are hoped to be highly efficacious, cost-effective, safe and well tolerated. These are to be newly developed compounds and not derivatives of currently used drugs, thus decreasing the likelihood of resistance.



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dihydroartemisinin-piperaquine (Duo-Cotecxin, Artekin)

Has been studied mainly in China, Vietnam and other countries in SEAsia. The drug has been shown to be highly efficacious (greater than 90%).

pyronaridine and artesunate (Pyramax)

Has been tested and demonstrated a clinical response rate of 100% in one trial in Hainan (an area with high levels of P. falciparum resistance to Pyronaridine).

Chlorproguanil-Dapsone and Artesunate (CDA)

Is the most tested drug currently under development and could be introduced in African countries imminently. It is not recommended as a monotherapy due to concerns of resistance developing thus threatening the future use of related compounds.

Experimental drugs In 1996, Geoff McFadden became aware of the work of the biologist Ian Wilson, who had discovered that the plasmodia responsible for causing malaria retained parts of chloroplasts, an organelle usually found in plants, complete with their own functioning genomes. This led Professor McFadden to the realisation that herbicides may be useful lead compounds for the development of drugs against malaria. These "apicoplasts" are thought to have originated through the endosymbiosis of algae and play a crucial role in fatty acid bio-synthesis in plasmodia. To date, 466 proteins have been found to be produced by apicoplasts and these are now being looked at as possible targets for novel anti-malarial drugs.

Coartem Coartem (artemether 20 mg/lumefantrine 120 mg) is an artemisinin-based combination therapy (ACT) indicated for the treatment of acute uncomplicated plasmodium falciparum malaria, the most dangerous form of the disease. Coartem is produced by the Swiss pharmaceutical company, Novartis.

Coartem is comprised of two key ingredients; artemether, which is a derivative of artemisinin, and lumefantrine (or benflumetol) an antimalarial drug. The combination of these two ingredients has led to one of the most successful malaria treatments of its kind. Coartem is a highly effective and well-tolerated malaria treatment, providing cure



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rates of up to 97%, even in areas of multi-drug resistance. In 2001, Coartem became the first fixed dose ACT to meet the World Health Organization's (WHO) pre-qualification criteria for efficacy, safety and quality.

In 2002, artemether-lumefantrine tablets were added to the WHO's Essential Medicines list, , an index of essential drugs which help guide the purchasing decisions of Member States and UN agencies.

Access To Treatment

Coartem is provided without profit to developing countries using grants from the Global Fund to Fight AIDS, Tuberculosis and Malaria, US President’s Malaria Initiative along with other donors. These broad partnerships have provided millions of children and adults with access to a high-quality treatment for malaria.

Novartis has lowered the price of Coartem by 50% since 2001, increasing access to patients around the world. The first significant price reduction occurred in 2006, when the price of Coartem decreased from an average of US $1.57 to US $1.00. In 2006, due to an improved supply situation for the natural ingredient artemisinin, Novartis was able to undertake the pharmaceutical industry’s most aggressive manufacturing scale-up of its kind from 4 million treatments in 2004 to 62 million treatments in 2006. Novartis and its partners invested heavily in expanding production capacity at their state-of-the-art facilities in China, and Suffern, New York. This increase in production capacity ensured that supplies of Coartem met demand which enabled Novartis to further decrease the price of Coartem.

In April 2008, Novartis further reduced the public sector price of Coartem by approximately 20%, to an average of US $0.80 (or US $0.37 for a child’s treatment pack). This price reduction was made possible through production efficiency gains.

Innovation of Coartem Dispersible

In January 2009, Novartis and Medicines for Malaria Venture (MMV) launched Coartem Dispersible, the first ACT developed specifically for children suffering from malaria. Coartem Dispersible contains the same amount of artemether and lumefantrine as Coartem. A phase III study published in The Lancet showed that Coartem Dispersible provides a high cure rate of 97.8%, which is comparable to that of Coartem (98.5%). Investigators also reported that it had a good safety profile.

According to the WHO, there were 247 million cases of malaria in 2006, causing about 880,000 deaths, mostly among African children. In Africa alone, a child dies every 30 seconds from malaria. Before Coartem Dispersible, many parents and healthcare workers crushed bitter-tasting antimalarial tablets for their children to swallow. The sweet-tasting Coartem Dispersible tablets disperse quickly in small amounts of water, easing administration and ensuring effective dosing.



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Novartis and MMV provide malaria case management educational programs, which include hands-on training for local healthcare workers, customized training manuals, and user-friendly packaging to ensure that Coartem Dispersible is properly used and to improve patient compliance. Like Coartem, Coartem Dispersible is provided to the public sector without profit to benefit those people most in need in the developing world.

Artemisinin

Pharmacokinetic data

Routes Oral

Artemisinin is a drug used to treat multi-drug resistant strains of falciparum malaria. The compound (a sesquiterpene lactone) is isolated from the plant Artemisia annua. Not all plants of this species contain artemisinin. Apparently it is only produced when the plant is subjected to certain conditions, most likely biotic or abiotic stress. It can be synthesized from artemisinic acid The drug is derived from a herb used in Chinese traditional medicine, though it is usually chemically modified and combined with other medications.

Use of the drug by itself as a monotherapy is explicitly discouraged by the World Health Organization as there have been signs that malarial parasites are developing resistance to the drug. Combination therapies that include artemisinin are the preferred treatment for malaria and are both effective and well tolerated in patients. The drug is also being studied as a treatment for cancer.

History



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Artemisia has been used by Chinese herbalists for more than a thousand years in the treatment of many illnesses, such as skin diseases and malaria. The earliest record dates back to 200 BC, in the "Fifty-two Prescriptions" unearthed from the Mawangdui Han Dynasty Tombs. Its antimalarial application was first described in Zhouhou Beji Fang ("The Handbook of Prescriptions for Emergencies"), edited in the middle of the fourth century by Ge Hong. In the 1960s a research program was set up by the Chinese army to find an adequate treatment for malaria. In 1972, in the course of this research, Tu Youyou discovered artemisinin in the leaves of Artemisia annua (annual wormwood). The drug is named Qinghaosu in Chinese. It was one of many candidates then tested by Chinese scientists from a list of nearly 200 traditional Chinese medicines for treating malaria. It was the only one that was effective, but it was found that it cleared malaria parasites from their bodies faster than any other drug in history. Artemisia annua is a common herb and has been found in many parts of the world, including along the Potomac River, in Washington, D.C.

It remained largely unknown to the rest of the world for about ten years, until results were published in a Chinese medical journal. The report was met with skepticism at first, because the Chinese had made unsubstantiated claims about having found treatments for malaria before. In addition, the chemical structure of artemisinin, particularly the peroxide, appeared to be too unstable to be a viable drug.

Artemisinin derivatives Because artemisinin itself has physical properties such as poor bioavailability that limit its effectiveness, semi-synthetic derivatives of artemisinin, including artemether and artesunate, have been developed.

Chemically modified analogues

There are a number of derivatives and analogues within the artemisinin family:

• Artesunate (water-soluble: for oral, rectal, intramuscular, or intravenous use) • Artemether (lipid-soluble: for oral, rectal or intramuscular use) • Dihydroartemisinin • Artelinic acid • Artenimol • Artemotil

There are also simplified analogs in preclinical research.

Purely synthetic analogues

To counter the present shortage in leaves of Artemisia annua, researchers have been searching for a way to develop artemisinin artificially in the laboratory. A 2006 paper in Nature presented a genetically engineered yeast that can synthesize a precursor called artemisinic acid which can be chemically converted to artemisinin.



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Indications

Malaria

Artemisinins can be used alone, but this leads to a high rate of recrudescence (return of parasites) and other drugs are required to clear the body of all parasites and prevent recurrence. The World Health Organization is pressuring manufacturers to stop making the uncompounded drug available to the medical community at large, saying it would be a significant loss if the malaria parasite developed resistance to Artemisinin.

The World Health Organisation has recommended that a switch to artemisinin combination therapies (ACT) be made in all countries where the malaria parasite has developed resistance to chloroquine. Artemisinin and its derivatives are now standard components of malaria treatment in China, Vietnam, and some other countries in Asia and Africa, where it has been proven to be a safe and effective anti-malarial treatment. Fixed-dose combinations are preferred as this guarantees that the partner drug is present to eradicate the last parasites while the artemisinin component removes the majority at the start of the treatment.

A large number of fixed-dose ACTs are now available containing an artemisinin component and a partner drug which has a long half-life, such as mefloquine (ASMQ), lumefantrine (Coartem), amodiaquine (ASAQ), piperaquine (Duo-Cotecxin) and antifolates (Ariplus). Most are made to GMP standard. A separate issue concerns the quality of some artemisinin-containing products being sold in Africa and South-East Asia.

Artemisinins are not used for malaria prophylaxis (prevention) because of the extremely short activity of the drug. To be effective, it would have to be administered multiple times each day.

Cancer treatment

Artemisinin is undergoing early research and testing for the treatment of cancer, primarily by researchers at the University of Washington. Artemisinin has a peroxide lactone group in its structure. It is thought that when the peroxide comes into contact with high iron concentrations (common in cancerous cells), the molecule becomes unstable and releases reactive oxygen species. It has been shown to reduce angiogenesis and the expression of vascular endothelial growth factor in some tissue cultures.

Resistance A study published in 2008 by Noedl and colleagues in the New England Journal of Medicine suggests a consensus among researchers that artemisinin is losing its potency in Cambodia and increased efforts are required to prevent drug-resistant malaria from



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spreading across the globe.. These findings were subsequently supported by a detailed study from Western Cambodia.

Adverse effects Artemisinins are generally well tolerated at the doses used to treat malaria. The side effects from the artemisinin class of medications are similar to the symptoms of malaria: nausea, vomiting, anorexia, and dizziness. Mild blood abnormalities have also been noted. The only serious adverse effect is an allergic reaction. The drugs that are used in combination therapies can contribute to the adverse effects that are experienced by those undergoing treatment. Adverse effects in patients with acute falciparum malaria treated with artemisinin derivatives tend to be higher.

Mechanism of action There is no consensus regarding the mechanism through which artemisinin derivatives kill the parasites. Their site of action within the parasite also remains controversial.

At the chemical level, one theory states that when the parasite that causes malaria infects a red blood cell, it consumes hemoglobin within its digestive vacuole, liberating free heme, an iron-porphyrin complex. The iron reduces the peroxide bond in artemisinin generating high-valent iron-oxo species, resulting in a cascade of reactions that produce reactive oxygen radicals which damage the parasite leading to its death.

Numerous studies have investigated the type of damage that oxygen radicals may induce. For example, Pandey et al. have observed inhibition of digestive vacuole cysteine protease activity of malarial parasite by artemisinin. These observations were supported by ex vivo experiments showing accumulation of hemoglobin in the parasites treated with artemisinin and inhibition of hemozoin formation by malaria parasites. Electron microscopic evidence linking artemisinin action to the parasite's digestive vacuole has been obtained showing that the digestive vacuole membrane suffers damage soon after parasites are exposed to artemisinin.

Artemisinins have been reported to inhibit PfATP6, the parasite's SERCA-type enzyme (calcium transporter), expressed in Xenopus oocytes. In this isolated system, resistance to artemisinin is reported to be conferred by a single mutation in PfATP6. A study from French Guiana in field isolates of malaria parasites identified an unrelated mutation in PfATP6 that was associated with resistance to artemether. However this series of studies does not constitute convincing evidence that PfATP6 is a site of action of artemisinins, or that mutations in PfATP6 cause reduced artemisinin susceptibility. Robust evidence in this context can be obtained by a transfection study, and it is notable that data from such a study were presented at the Molecular Approaches to Malaria Conference (Lorne, Australia) in February, 2008 yet remain unpublished. There is no evidence to suggest a role for PfATP6 in mediating the artemisinin resistance that appears to be emerging in Cambodia.



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A 2005 study investigating the mode of action of artemisinin using a yeast model demonstrated that the drug acts on the electron transport chain, generates local reactive oxygen species, and causes the depolarization of the mitochondrial membrane.

Dosing The WHO approved adult dose of co-artemether (artemether-lumefantrine) for malaria is 4 tablets at 0, 8, 24, 36, 48 and 60 hours (six doses).This has been proven to be superior to regimens based on amodiaquine. Artemesinin is not soluble in water and therefore Artemisia annua tea was postulated not to contain pharmacologically significant amounts of artemesinin. However, this conclusion was rebuked by several experts who stated that hot water (85 oC), and not boiling water, should be used to prepare the tea. Although Artemisia tea is not recommended as a substitute for the ACT (artemisinin combination therapies) more clinical studies on artemisia tea preparation have been suggested.

Artesunate

Artesunate

Routes oral, IV, IM

Artesunate (INN) is part of the artemisinin group of drugs that treat malaria. It is a semi-synthetic derivative of artemisinin that is water-soluble and may therefore be given by injection. It is sometimes abbreviated AS.

Uses Artesunate is used primarily as treatment for malaria; but it has also been shown to be >90% efficacious at reducing egg production in Schistosoma haematobium infection.

Dosing Intravenous dose of IV artesunate:



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• 2.4 mg/kg loading dose over 5 minutes • 1.2 mg/kg dose 12 hours later • 1.2 mg/kg once daily after that

Artesunate must always be given with another antimalarial such as mefloquine or amodiaquine so as to avoid the development of resistance. The combination of artesunate/amodiaquine has been found to be of equivalence to co-artemether.

Synthesis Artesunate is prepared from dihydroartemisinin (DHA) by reacting it with succinic acid anhydride in basic medium. Pyridine as base/solvent, sodium bicarbonate in chloroform and catalyst DMAP (N,N-dimethylaminopyridine) and triethylamine in 1,2-dichloroethane have been used, with yields of up to 100%. A large scale process involves treatment of DHA in dichloromethane with a mixture of pyridine, a catalytic amount of DMAP and succinic anhydride. The dichloromethane mixture is stirred for 6–9 h to get artesunate in quantitative yield. The product is further re-crystallized from dichloromethane. alpha-Artesunate is exclusively formed (m.p 135–137˚C).

Drug resistance Clinical evidence of drug resistance has appeared in Western Cambodia, where artemesinin monotherapy is common. There are as yet no reports of resistance emerging elsewhere

Quinine

Pharmacokinetic data

Bioavailability 76 to 88%

Protein

binding

~70%

Metabolism Hepatic (mostly CYP3A4 and CYP2C19-

mediated)

Half life ~18 hours



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Excretion Renal (20%)

Routes Oral, intravenous

Quinine is a natural white crystalline alkaloid having antipyretic (fever-reducing), antimalarial, analgesic (painkilling), and anti-inflammatory properties and a bitter taste. It is a stereoisomer of quinidine which, unlike quinine, is an anti-arrhythmic.

Though it has been synthesized in the lab, the bark of the cinchona tree is the only natural source of quinine. The medicinal properties of the cinchona tree were originally discovered by the Quechua Indians of Peru and Bolivia; later, the Jesuits were the first to bring the cinchona to Europe.

Quinine was the first effective treatment for malaria caused by Plasmodium falciparum, appearing in therapeutics in the 17th century. It remained the antimalarial drug of choice until the 1940s, when other drugs replaced it. Since then, many effective antimalarials have been introduced, although quinine is still used to treat the disease in certain critical situations. Quinine is available with a prescription in the United States and over-the-counter, in very small quantities, in tonic water. Quinine is also used to treat lupus, nocturnal leg cramps and arthritis.

Chemical structure

Quinine contains two major fused-ring systems: the aromatic quinoline and the bicyclic quinuclidine.

Mechanism of action against P. falciparum As with other quinoline anti-malarial drugs, the action of quinine has not been fully resolved. The most widely accepted hypothesis of quinine action is based on the well-studied and closely related quinoline drug, chloroquine. This model involves the inhibition of hemozoin biocrystallization, which facilitates the aggregation of cytotoxic heme. Toxic free heme accumulates in the parasites, leading to their death.

History

Quinine is an effective muscle relaxant, long used by the Quechua Indians of Peru to halt shivering due to low temperatures. The Peruvians would mix the ground bark of cinchona trees with sweetened water to offset the bark's bitter taste, thus producing tonic water.

Quinine has been used in unextracted form by Europeans since at least the early 1600s. Quinine was first used to treat malaria in Rome in 1631. During the 1600s, malaria was endemic to the swamps and marshes surrounding the city of Rome. Malaria was



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responsible for the death of several popes, many cardinals and countless common Roman citizens. Most of the priests trained in Rome had seen malaria victims and were familiar with the shivering brought on by the febrile phase of the disease. The Jesuit brother Agostino Salumbrino (1561-1642), an apothecary by training who lived in Lima, observed the Quechua using the bark of the cinchona tree for that purpose. While its effect in treating malaria (and hence malaria-induced shivering) was unrelated to its effect in controlling shivering from rigors, it was still a successful medicine for malaria. At the first opportunity, Salumbrino sent a small quantity to Rome to test as a malaria treatment. In the years that followed, cinchona bark was known as Jesuit's bark and became one of the most valuable commodities shipped from Peru to Europe.

Synthetic quinine

Cinchona trees remain the only economically practical source of quinine. However, under wartime pressure, research towards its synthetic production was undertaken. A formal chemical synthesis was accomplished in 1944 by American chemists R.B. Woodward and W.E. Doering. Since then, several more efficient quinine total syntheses have been achieved, but none of them can compete in economic terms with isolation of the alkaloid from natural sources. The first synthetic organic dye, mauveine, was discovered by William Henry Perkin in 1856 while he was attempting to synthesize quinine.

Dosing and indication

As of 2006, quinine is no longer recommended by the WHO as first line treatment for malaria and should only be used when artemesinins are not available.

Quinine is a basic amine and is therefore always presented as a salt. Various preparations that exist include the hydrochloride, dihydrochloride, sulfate, bisulfate and gluconate. This makes quinine dosing complicated since each of the salts has a different weight.

The following amounts of each form are equal:

• quinine base 100 mg • quinine bisulfate 169 mg • quinine dihydrochloride 122 mg • quinine hydrochloride 111 mg • quinine sulfate (actually (quinine)2H2SO4·2H2O) 121 mg • quinine gluconate 160 mg.

All quinine salts may be given orally or intravenously (IV); quinine gluconate may also be given intramuscularly (IM) or rectally (PR). The main problem with the rectal route is that the dose can be expelled before it is completely absorbed; this can be corrected by giving a half dose again.



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The IV dose of quinine is 8 mg/kg of quinine base every eight hours; the IM dose is 12.8 mg/kg of quinine base twice daily; the PR dose is 20 mg/kg of quinine base twice daily. Treatment should be given for seven days.

Route of administration: Quinine is given either orally, intramuscular or intravenously. Formulation/Strength: Tablet. 300mg

Ampoule I.M.I. 120mg/2ml or 600mg/10ml Dosage: Adult Give I.M. quinine (600mg/10ml) every 8 hours. (Three times daily) - Small adult. 450mg (7.5ml) (Under 50kg) - Large adult. 600mg/10ml) every 8 hours. (Over 50kg) When the patients improves change to quinine tablet (300mg base) for 3 more days. - Small adult. (Under 50kg) 450mg (1½ tab.) t.d.s. - Large adults. (Over 50kg) 600mg (2 tab.) t.d.s. NB: If quinine is given I.V. it must be diluted in dextrose/saline and SLOWLY infuse over 4 hours. Children: __________________________________________ Weight (kg) Quinine I.M/ml Quinine tab.

b.d t.d.s

3 – 3.9 ½ ¼ 4 – 5.9 1 ¼ 6 – 9.9 2 ½ 15 – 19.9 3 ½ 20 – 24.9 4 1 25 – 29.9 5 2 30 – 39.9 6 2½

The preparations available in the UK are quinine sulfate (200 mg or 300 mg tablets) and quinine hydrochloride (300 mg/ml for injection). Quinine is not licensed for IM or PR use in the UK. The adult dose in the UK is 600 mg quinine dihydrochloride IV or 600 mg quinine sulfate orally every eight hours. For nocturnal leg cramps, the dosage is 200–300 mg at night.



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In the United States, quinine sulfate is commercially available in 324-mg tablets under the brand name Qualaquin; the adult dose is two tablets every eight hours. There is no injectable preparation of quinine licensed in the U.S.: quinidine is used instead.

Side-effects It is usual for quinine in therapeutic doses to cause cinchonism; in rare cases, it may even cause death (usually by pulmonary edema). The development of mild cinchonism is not a reason for stopping or interrupting quinine therapy and the patient should be reassured. Blood glucose levels and electrolyte concentrations must be monitored when quinine is given by injection. The patient should ideally be in cardiac monitoring when the first quinine injection is given (these precautions are often unavailable in developing countries where malaria is endemic).

Cinchonism is much less common when quinine is given by mouth, but oral quinine is not well tolerated (quinine is exceedingly bitter and many patients will vomit after ingesting quinine tablets): Other drugs such as Fansidar (sulfadoxine (sulfonamide antibiotic) with pyrimethamine) or Malarone (proguanil with atovaquone) are often used when oral therapy is required. Quinine ethyl carbonate is tasteless and odourless, but is only commercially available in Japan. Blood glucose, electrolyte and cardiac monitoring are not necessary when quinine is given by mouth.

Quinine can cause paralysis if accidentally injected into a nerve. It is extremely toxic in overdose, and the advice of a poisons specialist should be sought immediately.

Quinine in some cases can lead to constipation, erectile dysfunction and diarrhea.

The New York Times Magazine described a case, presenting with fever, hypotension, and blood abnormalities mimicking septic shock.

Abortifacient

Despite popular belief, quinine is an ineffective abortifacient (in the US, quinine is listed as Pregnancy category D. Pregnant women who take toxic doses of quinine will suffer from renal failure before experiencing any kind of quinine-induced abortion. Indeed, quinine is the only drug recommended by the WHO as firstline treatment for uncomplicated malaria in pregnancy.

Disease interactions

Quinine can cause hemolysis in G6PD deficiency, but again this risk is small and the physician should not hesitate to use quinine in patients with G6PD deficiency when there is no alternative. Quinine can also cause drug-induced immune thrombocytopenic purpura (ITP). Symptoms can be severe enough to require hospitalisation and platelet transfusion, with several cases resulting in death.



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Quinine can cause abnormal heart rhythms and should be avoided if possible in patients with atrial fibrillation, conduction defects or heart block.

Quinine can worsen hemoglobinuria, myasthenia gravis and optic neuritis.

Hearing impairment

Some studies have related the use of quinine and hearing impairment, in particular high-frequency loss, but it has not been conclusively established whether such impairment is temporary or permanent.

Dihydroartemisinin (Second line drug) Dihydroartemisinin (or dihydroqinghaosu) is a drug used to treat malaria. Dihydroartemisinin is the active metabolite of all artemisinin compounds (artemisinin, artesunate, artemether, etc.) and is also available as a drug in itself. The lactone of artemisinin could selectively be reduced with mild hydride-reducing agents, such as sodium borohydride, potassium borohydride, and lithium borohydride to dihydroartemisinin (a lactol) in over 90% yield. It is a novel reduction, because normally lactone cannot be reduced with sodium borohydride under the same reaction conditions (0-5˚C, in methanol). Reduction with LiAlH4 leads to some rearranged products. It was surprising to find that the lactone was reduced, but that the peroxy group survived. However, the lactone of deoxyartemisinin resisted reduction with sodium borohydride and could only be reduced with isobutylaluminium hydride to the lactol, (deoxydihydroartimisinin). These results show that the peroxy group assists the reduction of lactone with sodium borohydride to a lactol, but not to the alcohol which is the over-reduction product. No clear evidence for this reduction process exists.

Dosing Dihydroartemisinin is available as a fixed drug combination with piperaquine (each tablet contains 40 mg of dihydroartemisinin and 320 mg of piperaquine; trade name Artekin, manufactured by Holleykin Pharmaceuticals).

The adult dose is 1.6/12.8 mg/kg per dose (rounded up or down to the nearest half tablet) given at 0 h, 8 h, 24 h, and 48 h. Alternatively, the same total dose may be given once daily for three days.

Dihydroartemisinin is also sold in Africa as Cotecxin in 60 mg tablets, which is manufactured by Zhejiang Holley Nanhu Pharmaceutical Co., Ltd., in China.

Piperaquine: (Second line drug) Affiliation(s) du ou des auteurs / Author(s) Affiliation(s)



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Medicine Unit Fremantle and Pharmacology Unit Nedlands, School of Medicine and Pharmacology, University of Western Australia, Crawley, Western Australia, AUSTRALIE Résumé / Abstract

Piperaquine is a bisquinoline antimalarial drug that was first synthesised in the 1960s, and used extensively in China and Indochina as prophylaxis and treatment during the next 20 years. A number of Chinese research groups documented that it was at least as effective as, and better tolerated than, chloroquine against falciparum and vivax malaria, but no pharmacokinetic characterisation was undertaken. With the development of piperaquine-resistant strains of Plasmodium falciparum and the emergence of the artemisinin derivatives, its use declined during the 1980s. However, during the next decade, piperaquine was rediscovered by Chinese scientists as one of a number of compounds suitable for combination with an artemisinin derivative. The rationale for such artemisinin combination therapies (ACTs) was to provide an inexpensive, short-course treatment regimen with a high cure rate and good tolerability that would reduce transmission and protect against the development of parasite resistance. This approach has now been endorsed by the WHO. Piperaquine-based ACT began as China-Vietnam 4 (CV4®: dihydroartemisinin [DHA], trimethoprim, piperaquine phosphate and primaquine phosphate), which was followed by CV8® (the same components as CV4 but in increased quantities), Artecom® (in which primaquine was omitted) and Artekin® or Duo-Cotecxin® (DHA and piperaquine phosphate only). Recent Indochinese studies have confirmed the excellent clinical efficacy of piperaquine-DHA combinations (28-day cure rates >95%), and have demonstrated that currently recommended regimens are not associated with significant cardiotoxicity or other adverse effects. The pharmacokinetic properties of piperaquine have also been characterised recently, revealing that it is a highly lipid-soluble drug with a large volume of distribution at steady state/bioavailability, long elimination half-life and a clearance that is markedly higher in children than in adults. The tolerability, efficacy, pharmacokinetic profile and low cost of piperaquine make it a promising partner drug for use as part of an ACT.

Artemisia annua (Plant)

Artemisia annua



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Artemisia annua, also known as Sweet Wormwood, Sweet Annie, Sweet Sagewort or Annual Wormwood (Chinese: pinyin: qīnghāo), is a common type of wormwood that is native to temperate Asia, but naturalized throughout the world.

Medicinal uses Sweet Wormwood was used by Chinese herbalists in ancient times to treat fever, but had fallen out of common use, but was rediscovered in 1970 when the Chinese Handbook of Prescriptions for Emergency Treatments (340 AD) was found. This pharmacopeia contained recipes for a tea from dried leaves, prescribed for fevers (not specifically malaria).

Extractions

In 1971, scientists demonstrated that the plant extracts had antimalarial activity in primate models, and in 1972 the active ingredient, artemisinin (formerly referred to as arteannuin), was isolated and its chemical structure described. Artemisinin may be extracted using a low boiling point solvent such as diethylether and is found in the glandular trichomes of the leaves, stems, and inflorescences, and it is concentrated in the upper portions of plant within new growth.

Parasite treatment

It is commonly used in tropical nations which can afford it, preferentially as part of a combination-cocktail with other antimalarials in order to prevent the development of parasite resistance.

Malaria treatment



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Artemisinin itself is a sesquiterpene lactone with an endoperoxide bridge and has been produced semi-synthetically as an antimalarial drug. The efficacy of tea made from A. annua in the treatment of malaria is contentious. According to some authors, artemesinin is not soluble in water and the concentrations in these infusions are considered insufficient to treatment malaria. Other researchers have claimed that Artemisia annua contains a cocktail of anti-malarial substances, and insist that clinical trials be conducted to demonstrate scientifically that artemisia tea is effective in treating malaria. This simpler use may be a cheaper alternative to commercial pharmaceuticals, and may enable health dispensaries in the tropics to be more self-reliant in their malaria treatment. In In 2004, the Ethiopian Ministry of Health changed Ethiopia’s first line anti-malaria drug from Fansidar, a Sulfadoxine agent which has an average 36% treatment failure rate, to CoArtem, an agent created from A. annua and which is 100% effective when used correctly, despite a worldwide shortage at the time of the needed derivative from A. annua.

Cancer treatment

The plant has also been shown to have anti-cancer properties. It is said to have the ability to be selectively toxic to some breast cancer cells [Cancer Research 65:(23).Dec 1, 2005] and some form of prostate cancer, there have been exciting preclinical results against leukemia, and other cancer cells.

Mechanism

The proposed mechanism of action of artemisinin involves cleavage of endoperoxide bridges by iron producing free radicals (hypervalent iron-oxo species, epoxides, aldehydes, and dicarbonyl compounds) which damage biological macromolecules causing oxidative stress in the cells of the parasite. Malaria is caused by the Apicomplexan, Plasmodium falciparum, which largely resides in red blood cells and itself contains iron-rich heme-groups (in the from of hemozoin).

Other uses In modern-day central China, specifically Hubei Province, the stems of this wormwood are used as food in a salad-like form. The final product, literally termed "cold-mixed wormwood" is a slightly bitter salad with strong acid overtones from the spiced rice vinegar used as a marinade. It is considered a delicacy and is typically more expensive to buy than meat.



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Life Cycle of the Malaria Parasite

Credit: NIAID

Glossary

Diploid: Cells containing a full set of chromosomes. Gametes: Reproductive elements, male and female. Gametocytes: Precursors of the sexual forms of the malaria



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Life Cycle of the Malaria Parasite

1. A female Anopheles mosquito carrying malaria-causing parasites feeds on a human and injects the parasites in the form of sporozoites into the bloodstream. The sporozoites travel to the liver and invade liver cells.

2. Over 5-16 days*, the sporozoites grow, divide, and produce tens of thousands of haploid forms, called merozoites, per liver cell. Some malaria parasite species remain dormant for extended periods in the liver, causing relapses weeks or months later.

3. The merozoites exit the liver cells and re-enter the bloodstream, beginning a cycle of invasion of red blood cells, asexual replication, and release of newly formed merozoites from the red blood cells repeatedly over 1-3 days*. This multiplication can result in thousands of parasite-infected cells in the host bloodstream, leading to illness and complications of malaria that can last for months if not treated.

4. Some of the merozoite-infected blood cells leave the cycle of asexual multiplication. Instead of replicating, the merozoites in these cells develop into sexual forms of the parasite, called male and female gametocytes, that circulate in the bloodstream.

5. When a mosquito bites an infected human, it ingests the gametocytes. In the mosquito gut, the infected human blood cells burst, releasing the gametocytes, which develop further into mature sex cells called gametes. Male and female gametes fuse to form diploid zygotes, which develop into actively moving ookinetes that burrow into the mosquito midgut wall and form oocysts.

6. Growth and division of each oocyst produces thousands of active haploid forms called sporozoites. After 8-15 days*, the oocyst bursts, releasing sporozoites into the body cavity of the mosquito, from which they travel to and invade the mosquito salivary glands. The cycle of human infection re-starts when the mosquito takes a blood meal, injecting the sporozoites from its salivary glands into the human bloodstream .

or female gametes within the stomach of the mosquito. Haploid: Cells containing a half set of chromosomes. Merozoite: The form of the malaria parasite that invades red blood cells. Oocyst: A stage of the malaria parasite within the mosquito which is produced when male and female gametes combine. Ookinete: The actively moving zygote of the malarial organism that penetrates the mosquito stomach to form an oocyst under the outer gut lining. Sporozoite: The infectious form of the malaria parasite, which is injected into people by mosquitoes. Zygote: The diploid cell resulting from union of a male and a female gamete.



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FANSIDER Fansidar is an antimalarial agent, each tablet containing 500 mg N1-(5,6-dimethoxy-4-pyrimidinyl) sulfanilamide (sulfadoxine) and 25 mg 2,4-diamino-5-(p-chlorophenyl)-6-ethylpyrimidine (pyrimethamine). Each tablet also contains cornstarch, gelatin, lactose, magnesium stearate and talc.

INDICATION

Treatment of Acute Malaria

Fansidar is indicated for the treatment of acute, uncomplicated P. falciparum malaria for those patients in whom chloroquine resistance is suspected. However, strains of P. falciparum (see CLINICAL PHARMACOLOGY: Microbiology) may be encountered which have developed resistance to Fansidar, in which case alternative treatment should be administered.

Prevention of Malaria

Malaria prophylaxis with Fansidar is not routinely recommended and should only be considered for travelers to areas where chloroquine-resistant P. falciparum malaria is endemic and sensitive to Fansidar, and when alternative drugs are not available or are contraindicated (see CONTRAINDICATIONS). However, strains of P. falciparum may be encountered which have developed resistance to Fansidar.

DOSAGE AND ADMINISTRATION

The dosage should be swallowed whole, and not chewed, with plenty of fluids after a meal.

Route of administration: The drug is given by oral route.



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Formulations/strength: Tablet. Fansider tablet containing sulphadoxine 500mg with pyriethamine 25mg. Dosage: Children. Weight (kg) Dose in Tablet 3 – 5 ¼ 6 – 9 ½ 10 – 19 1 20 – 29 1½ 30 – 49 2 (adult) - One single dose is given after quinine course. - Used with quinine in the treatment of chloroquine resistant - Do not use fansider by itself. Give it on day one with quinine.

Prevention of Malaria

The malaria risk must be carefully weighed against the risk of serious adverse drug reactions (see INDICATIONS AND USAGE). If Fansidar is prescribed for prophylaxis, it is important that the physician inquires about sulfonamide intolerance and points out the risk and the need for immediate drug withdrawal if skin reactions do occur.

The first dose of Fansidar should be taken 1 or 2 days before arrival in an endemic area; administration should be continued during the stay and for 4 to 6 weeks after return.

SIDE EFFECTAS

For completeness, all major reactions to sulfonamides and to pyrimethamine are included below, even though they may not have been reported with Fansidar (see WARNINGS and PRECAUTIONS: Information For The Patient).

Hematological Changes

Agranulocytosis, aplastic anemia, megaloblastic anemia, thrombocytopenia, leukopenia, hemolytic anemia, purpura, hypoprothrombinemia, methemoglobinemia, and eosinophilia.

Skin and Miscellaneous Sites Allergic Reactions

Erythema multiforme, Stevens-Johnson syndrome, generalized skin eruptions, toxic epidermal necrolysis, urticaria, serum sickness, pruritus, exfoliative dermatitis, anaphylactoid reactions, periorbital edema, conjunctival and scleral injection, photosensitization, arthralgia, allergic myocarditis, slight hair loss, Lyell's syndrome,



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Gastrointestinal Reactions

Glossitis, stomatitis, nausea, emesis, abdominal pains, hepatitis, hepatocellular necrosis, diarrhea, pancreatitis, feeling of fullness, and transient rise of liver enzymes.

Central Nervous System Reactions

Headache, peripheral neuritis, mental depression, convulsions, ataxia, hallucinations, tinnitus, vertigo, insomnia, apathy, fatigue, muscle weakness, nervousness, and polyneuritis.

Respiratory Reactions

Pulmonary infiltrates resembling eosinophilic or allergic alveolitis.

Genitourinary

Renal failure, interstitial nephritis, BUN and serum creatinine elevation, toxic nephrosis with oliguria and anuria, and crystalluria.

Pregnancy

Teratogenic Effects: Pregnancy Category C Fansidar has been shown to be teratogenic in rats when given in weekly doses approximately 12 times the weekly human prophylactic dose. Teratology studies with pyrimethamine plus sulfadoxine (1:20) in rats showed the minimum oral teratogenic dose to be approximately 0.9 mg/kg pyrimethamine plus 18 mg/kg sulfadoxine. In rabbits, no teratogenic effects were noted at oral doses as high as 20 mg/kg pyrimethamine plus 400 mg/kg sulfadoxine.

There are no adequate and well-controlled studies in pregnant women. However, due to the teratogenic effect shown in animals and because pyrimethamine plus sulfadoxine may interfere with folic acid metabolism, Fansidar therapy should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Overdosage & Contraindications WARNING

FATALITIES ASSOCIATED WITH THE ADMINISTRATION OF FANSIDAR HAVE OCCURRED DUE TO SEVERE REACTIONS, INCLUDING STEVENS-JOHNSON SYNDROME AND TOXIC EPIDERMAL NECROLYSIS. FANSIDAR PROPHYLAXIS MUST BE DISCONTINUED AT THE FIRST APPEARANCE OF SKIN RASH, IF A SIGNIFICANT REDUCTION IN THE COUNT OF ANY FORMED BLOOD ELEMENTS IS NOTED, OR UPON THE OCCURRENCE OF ACTIVE BACTERIAL OR FUNGAL INFECTIONS. DRUG DESCRIPTION



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FATALITIES ASSOCIATED WITH THE ADMINISTRATION OF FANSIDAR HAVE OCCURRED DUE TO SEVERE REACTIONS, INCLUDING STEVENS-JOHNSON SYNDROME AND TOXIC EPIDERMAL NECROLYSIS. FANSIDAR PROPHYLAXIS MUST BE DISCONTINUED AT THE FIRST APPEARANCE OF SKIN RASH, IF A SIGNIFICANT REDUCTION IN THE COUNT OF ANY FORMED BLOOD ELEMENTS IS NOTED, OR UPON THE OCCURRENCE OF ACTIVE BACTERIAL OR FUNGAL INFECTIONS. OVERDOSE Acute intoxication may be manifested by headache, nausea, anorexia, vomiting and central nervous system stimulation (including convulsions), followed by megaloblastic anemia, leukopenia, thrombocytopenia, glossitis and crystalluria. In acute intoxication, emesis and gastric lavage followed by purges may be of benefit. The patient should be adequately hydrated to prevent renal damage. The renal, hepatic, and hematopoietic systems should be monitored for at least 1 month after an overdosage. If the patient is having convulsions, the use of parenteral diazepam or a barbiturate is indicated. For depressed platelet or white blood cell counts, folinic acid (leucovorin) should be administered in a dosage of 5 mg to 15 mg intramuscularly daily for 3 days or longer.

CONTRAINDICATIONS

• Repeated prophylactic (prolonged) use of Fansidar is contraindicated in patients with renal or hepatic failure or with blood dyscrasias;

• Hypersensitivity to pyrimethamine, sulfonamides, or any other ingredient of Fansidar;

• Patients with documented megaloblastic anemia due to folate deficiency; • Infants less than 2 months of age; • Prophylactic use of Fansidar in pregnancy at term and during the nursing period.

Mechanism of Action Sulfadoxine and pyrimethamine, the constituents of Fansidar, are folic acid antagonists. Sulfadoxine inhibits the activity of dihydropteroate synthase whereas pyrimethamine inhibits dihydrofolate reductase.



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Activity in vitro Sulfadoxine and pyrimethamine are active against the asexual erythrocytic stages of Plasmodium falciparum. Fansidar may also be effective against strains of P. falciparum resistant to chloroquine.

Pharmacokinetics

Absorption After administration of 1 tablet, peak plasma levels for pyrimethamine (approximately 0.2 mg/L) and for sulfadoxine (approximately 60 mg/L) are reached after about 4 hours.

Distribution The volume of distribution for sulfadoxine and pyrimethamine is 0.14 L/kg and 2.3 L/kg, respectively.

Patients taking 1 tablet a week (recommended adult dose for malaria prophylaxis) can be expected to have mean steady state plasma concentrations of about 0.15 mg/L for pyrimethamine after about four weeks and about 98 mg/L for sulfadoxine after about seven weeks. Plasma protein binding is about 90% for both pyrimethamine and sulfadoxine. Both pyrimethamine and sulfadoxine cross the placental barrier and pass into breast milk.

Metabolism About 5% of sulfadoxine appears in the plasma as acetylated metabolite, about 2 to 3% as the glucuronide. Pyrimethamine is transformed to several unidentified metabolites.

Elimination A relatively long elimination half-life is characteristic of both components. The mean values are about 100 hours for pyrimethamine and about 200 hours for sulfadoxine. Both pyrimethamine and sulfadoxine are eliminated mainly via the kidneys.

SIDE EFFECTS: See also Warning section. Nausea, vomiting, and loss of appetite may occur. This product may make you more sensitive to the sun and sunburn (see also Precautions section). Less common side effects may include headache, lightheadedness, trouble sleeping, tiredness, or irritability.

ARTEMISININ AND ITS DERIVATIVES

Artemisinin (qinghaosu) is the antimalarial principle isolated by Chinese scientists from Artemisia annua L. It is a sesquiterpene lactone with a peroxide bridge linkage. Artemisinin is poorly soluble in oils or water but the parent compound has yielded dihydroartemisinin, the oil-soluble derivatives artemether and arteether, and the more water-soluble derivatives sodium artesunate and artelinic acid. These derivatives have more potent blood schizonticidal activity than the parent compound and are the most rapidly effective antimalarial drugs known. They are used for the treatment of severe and



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uncomplicated malaria . They are not hypnozoiticidal but gametocytocidal activity has been observed .

Formulations

A wide variety of formulations for oral or parenteral use or as suppositories are available (see below). China and Viet Nam continue to be the main producers of artemisinin and its derivatives.

Efficacy

The antimalarial activity of artemisinin and its derivatives is extremely rapid and most patients show clinical improvement within 1-3 days after treatment. However, the recrudescence rate is high when the drugs are used in monotherapy, depending on the drug dose administered, the duration of treatment and the severity of disease, but not at present on parasite resistance . Treatment for < 7 days gave unacceptably high recrudescence rates . So far there is no confirmed in vivo evidence of resistance of P. falciparum to artemisinin and its derivatives. The susceptibility of P. falciparum strains from the China-Lao People’s Democratic Republic and China-Myanmar border areas to various antimalarial drugs have been tested in vitro. The results have indicated declining susceptibility of P. falciparum to artemisinin derivatives .

Under exceptional circumstances, such as when there is a history of an adverse reaction to the combination agent, artemisinin monotherapy may be indicated, but a 7-day course of therapy is recommended and efforts should be made to improve adherence to the treatment. Preliminary results from Africa indicate that combinations of artesunate plus amodiaquine or sulfadoxine-pyrimetha-mine are highly efficacious, although efficacy may be compromised in areas with moderate to high levels of resistance to sulfadoxine-pyrimethamine P. Olliaro, personal communication)

These compounds are not recommended for use in the treatment of malaria due to P. vivax, P. malariae or P. ovale since other effective antimalarial drugs are available for this purpose. However, they may be used in the absence of micro-scopic diagnosis if they are the recommended first-line treatment.

Use in pregnancy

Preclinical studies have consistently shown that artemisinin and its derivatives do not exhibit mutagenic or teratogenic activity, but all of these drugs caused fetal resorption in rodents at relatively low doses of 1/200-1/400 of the LD50, i.e. > 10 mg/kg, when given after the sixth day of gestation . Reports on the use of these drugs during pregnancy are limited . However, malaria can be particularly hazardous during pregnancy. Artemisinin and its derivatives are therefore the drugs of choice for severe malaria and can be used for treatment of uncomplicated malaria during the second and third trimester of pregnancy in areas of multiple drug resistance . Owing to lack of



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data, their use in the first trimester is not recommended. The inadequacy of current knowledge on the use of these drugs during pregnancy should be understood by prescribers and all such use should, in principle, be monitored. Clinical outcomes of both a successful and adverse nature should be reported to regulatory authorities.

Drug disposition

High-performance liquid chromatography-electron capture detection (HPLCECD) and bioassay methods for studying the pharmacokinetics of artemisinin and its derivatives have now been validated. HPLC-ECD detects separately the parent compound and the major metabolite, dihydroartemisinin, whereas bioassays measure total activity, i.e. parent compound plus metabolite(s). Both methods are cumbersome and only a limited number of laboratories have the capability of conducting assays, especially using HPLC-ECD, which requires a reductive-mode electrochemical analysis and must be performed under oxygen-free conditions. An alternative HPLC method that uses ultraviolet detection is somewhat easier and quicker to use. So far, all methods are for plasma only; no method is available to measure levels in whole blood. With few exceptions, the lower limit of detection of HPLC-based methods is = or <5mg/ml.

Oral bioavailability varies with the derivative and is influenced by disease status. All derivatives, but not artemisinin itself are metabolized to a common bioactive metabolite, dihydroartemisinin, at variable rates .

Adverse effects

Extensive clinical trials in China, Myanmar, Thailand and Viet Nam demonstrated no acute cardiovascular or other vital organ toxicity. However, animal studies have demonstrated severe neurotoxicity following parenteral administration of very high doses of artemether or arteether. Both drugs produced a unique pattern of selective neuropathy with chromatolysis and necrosis of scattered neurons in vestibular, motor and auditory brain stem nuclei in rats, dogs and rhesus monkeys . Such effects have not been observed with oral administration of any artemisinin derivative or with intravenous artesunate. This has led to the suggestion that the effect is related to specific molecules and their route of administration. The cause, however, appears to be due to sustainable high levels of the drugs and their metabolites, which may occur following intramuscular injection, rather than to the route of administration itself (T.G. Brewer, personal communication, 1996).

There is no clinical evidence to date of serious neurotoxicity resulting from the use of any artemisinin drug in humans in prospective studies of more than 10 000 patients or in the more than 2 million persons who have received these drugs . In Thailand, full neurological examinations in more than 1 100 patients who had received an artemisinin drug showed no specific pattern of neurological abnormalities. Studies in Thailand and Viet Nam provided no evidence of any brain stem toxicity attributable to artemisinin and artesunate . There is some concern about cerebellar dysfunction and prolonged or repetitive treatment with artemisinin and its derivatives, which may occur in areas of high transmission, must be viewed with caution. Additional studies to monitor subtle



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neurological changes and hearing loss are required, especially in patients undergoing repetitive treatment. Post-marketing surveillance in countries where these drugs are marketed and used is recommended.

A. ARTEMISININ

Formulations

• Tablets and capsules containing 250 mg of artemisinin (Viet Nam). • Suppositories containing 100 mg, 200 mg, 300 mg, 400 mg or 500 mg of

artemisinin (Viet Nam).

Efficacy

Artemisinin is a sesquiterpene lactone with a peroxide bridge linkage that appears to be responsible for its antimalarial activity. Artemisinin is a potent and rapidly acting blood schizonticide, eliciting shorter parasite clearance times than chloroquine or quinine and rapid symptomatic responses .

Artemisinin is poorly soluble in oils or water. Preclinical and clinical studies show that artemisinin is effective against parasites resistant to all other operationally used antimalarial drugs . It is not hypnozoiticidal. It reduces gametocyte carriage

Use

To reduce the recrudesence rate and the risk of development of resistance, as well as to improve compliance, artemisinin should preferably be administered in combination with another effective blood schizonticide. The use of artemisinin as monotherapy should be limited to specific indications, such as in patients with a history of adverse reactions to the combination drug. When mono-therapy is used, a 7-day course of therapy is recommended and adherence to the treatment should be ensured.

When given as monotherapy to patients with uncomplicated falciparum malaria who have some degree of immunity, a 5-day oral regimen of artemisinin has generally proven to be curative.

Rectal formulations of artemisinin have a potentially important role to play in the treatment of uncomplicated falciparum infections in children who vomit oral medication, and as emergency treatment prior to referral in situations when parenteral antimalarial drugs are not available or cannot be administered. Studies in Viet Nam have shown the latter to be highly efficacious .

Recommended treatment

Although oral artemisinin has been widely employed in the treatment of uncomplicated multidrug-resistant falciparum infections , very few well-designed dose-finding studies of



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artemisinin and its derivatives have been published. The dosage schedules indicated below are based on available clinical data, as pharmacokinetic data are still insufficient for formulating treatment regimens. When used as monotherapy, a minimum 7-day course is required owing to the problem of recrudescent infections. If regimens of < 7 days are employed, combination with mefloquine is indicated to prevent such recrudescence. Pharmacokinetic modelling suggests that a mefloquine dose of 25 mg/kg provides better protection against development of resistance in combination therapy regimens than one of 15 mg/kg (N. White, personal communication, 2000).

Monotherapy 20 mg/kg in a divided loading dose on the first day, followed by 10 mg/kg once a day for 6 days.

Combination therapy

20 mg/kg in a divided loading dose on the first day, followed by 10 mg/kg once a day for two more days plus mefloquine (15-25 mg of base per kg) as a single or split dose on the second and/or third day.

In outpatient settings where adherence is questionable, combination with mefloquine (15 mg or 25 mg of base per kg) is indicated. Several clinical trials have shown that this is the most effective treatment of multidrug-resistant P. falciparum malaria . Mefloquine is administered on the second or third day because there is less risk of vomiting once the clinical condition has improved.

Rectal administration

In emergency pre-referral treatment of severe malaria or for patients who cannot take oral medication, artemisinin can be given by rectal administration before referral to hospital or before medication becomes possible . This is intended as emergency management of malaria in life-treatening circumstances and may be provided on a presumptive diagnosis of malaria.

A single dose of 40 mg/kg should be given intarectally, then 20 mg/kg 24, 48 and 72 hours later, followed by oral treatment with an effective antimalarial drug.

Chemoprophylaxis

There is no rationale at present for using artemisinin for chemoprophylaxis.

Use in pregnancy

Artemisinin can be used for treatment of uncomplicated malaria during the second and third trimester of pregnancy in areas of multidrug resistance . Owing to lack of data, use in the first trimester of pregnancy is not recommended (see above).

Drug disposition



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Oral artemisinin is rapidly but incompletely absorbed with peak concentrations 1-2 h after administration . Artemisinin is rapidly metabolized in vivo to dihydroartemisinin. The elimination half-life is 2-5 hours . Bioavailability with rectal suppository formulations is 30% less than with oral administration, although there is large inter-individual variation. Studies comparing parasite clearance times following oral and rectal administration have led to the conclusion that therapeutic concentrations should be achieved with suppositories . Suppositories have been shown to be as effective as parenteral anti-malarial drugs in clinical trials for the treatment of severe malaria .

Adverse effects

Adverse effects may include headache, nausea, vomiting, abdominal pain, itching, drug fever abnormal bleeding and dark urine. Minor cardiac changes (mainly non-specific ST changes and first degree atrioventricular block) have been noted during clinical trials. These returned to normal after improvement of malaria symptoms. Experience indicates that artemisinin and its derivatives are less toxic than the quinoline antimalarial drugs, few adverse effects being associated with their use.

Prolonged or repetitive treatment with artemisinin and its derivatives must be treated with caution. Additional studies, which monitor subtle neurological changes and hearing loss, are required especially in patients undergoing repetitive treatment. Post-marketing surveillance is recommended in countries where these drugs are marketed and used.

Contraindications

Artemisinin is not recommended in the first trimester of pregnancy because of limited data.

Overdosage

There is no experience with overdosage with artemisinin.

B. ARTEMETHER

Formulations

• Capsules containing 40 mg of artemether (China). • Composite tablets containing 50 mg of artemether (China). • Ampoules of injectable solution for intramuscular injection containing 80 mg in

1 ml (China and France), or 40 mg in 1 ml for paediatric use (France).

Efficacy



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Artemether is an oil-soluble methyl ether derivative of dihydroartemisinin. As with artemisinin, it is effective against P. falciparum resistant to all other operationally used antimalarial drugs . It is not hypnozoiticidal but it reduces gametocyte carriage .

Use

As with artemisinin, when artemether is used for the treatment of uncomplicated P. falciparum malaria, it should always be administered in combination with another effective blood schizonticide to prevent recrudescence and delay the selection of resistant strains. Monotherapy with oral or intramuscular artemether with a dose of 1-4 mg/kg per day for 3-5 days results in an unacceptable rate of recrudescence . The use of artemether as monotherapy should be limited to specific indications, such as in patients with a history of adverse reactions to the combination drug. When monotherapy is used, a 7-day course is recommended and efforts should be made to ensure adherence.

Artemether is not recommended for the treatment of malaria caused by P. vivax, P. ovale and P. malariae since other effective antimalarial drugs are available for this purpose. However, it may be used in the absence of microscopic diagnosis if the compound is the recommended first-line treatment.


Because well-designed dose-finding studies of artemether are limited, the dosage schedules outlined below for uncomplicated and severe malaria are based on available clinical data. When used as monotherapy, a minimum 7-day course is required to prevent recrudescence. If regimens of less than 7 days are employed, combination with mefloquine or another effective blood schizonticide is indicated.

ARTEMETHER INJECTION: Route of administration: Administered I.M. daily. Formulation / Strength: 80mg Dosage: - Day one 3.6mg/kg

- Day two – seven, 1.6mg/kg - Give fansider on day three.

Weight (kg) Dosage ml (IMI) ml (IMI) Day one Day 2-7 3 – 5.9 0.25 0.25 6 - 2.9 0.5 0.25 13 – 18.9 0.75 0.5 19 – 24.9 1ml 0.5 25 – 30.9 1.25 0.75 31 – 36.9 1.5 0.75



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37 – 43.9 1.75 1 Over 40 kg 2 1

• This drug is given IMI as a daily dose. You can change over to tablet once the patient is able to take oral medication.

• Like the tablet, the first dose of injection is also double.

Uncomplicated malaria

Monotherapy: 4 mg/kg loading dose on the first day, followed by 2 mg/kg once a day for 6 days.

Combination therapy

4 mg/kg once a day for 3 days, plus mefloquine (15 mg or 25 mg of base per kg) as a single dose or split dose on the second and/or third day.

Where adherence to the treatment is questionable, especially in outpatients, combination with mefloquine is indicated . Cure rates of 95-98% have been demonstrated with this combination in multidrug-resistant areas . Mefloquine is administered on the second or third day because there is less risk of vomiting once the clinical condition has improved.

Severe malaria

3.2 mg/kg by the intramuscular route as a loading dose on the first day, followed by 1.6 mg/kg daily for a minimum of 3 days or until the patient can take oral therapy to complete a 7-day course. The daily dose can be given as a single injection. In children, the use of a tuberculin syringe is advisable since the injection volume will be small.

Use in pregnancy

Similar to artemisinin.

Drug disposition

The pharmacokinetics of artemether following oral administration appear to be similar to those for artemisinin with mean peak plasma concentrations and mean plasma half lives of 1-2 h and 2-3 h, respectively . The plasma concentrations of artemether are similar in healthy subjects and those with acute uncomplicated malaria. Plasma antimalarial activity is significantly greater with intramuscular administration than with oral use because the first-pass biotransformation is bypassed . Bioavailability of artemether following intramuscular administration was increased and clearance reduced in patients with acute renal failure .



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Adverse effects

Toxicity studies in dogs and rats indicate that dose-dependent and potentially fatal neurotoxic effects may occur after intramuscular injection of artemether at doses higher than those used for malaria treatment . These changes can be widespread but mainly affect areas associated with vestibular, motor and auditory functions . No similar findings have been reported in humans treated with normal therapeutic doses of artemether.

Contraindications


Overdosage


C. ARTESUNATE

Formulations

• Tablets containing 50 mg of sodium artesunate (China, France and Viet Nam) or 200 mg of sodium artesunate (Switzerland).

• Ampoules for intramuscular or intravenous injection containing 60 mg of sodium artesunate in 1 ml of injectable solution (China and Viet Nam).

• Suppositories of sodium artesunate (China). • Rectal capsules containing 100 mg or 400 mg of sodium artesunate (Switzerland).

Efficacy

Artesunate, a water-soluble hemisuccinate derivative of dihydroartemisinin, is the most widely used member of this family of drugs. It is unstable in neutral solutions and is therefore only available for injections as artesunic acid. It is effective against P. falciparum resistant to all other operationally used anti-malarial drugs . It does not have hypnozoiticidal activity. It reduces gametocyte carriage rate .

Use

As with artemisinin, when artesunate is used for the treatment of uncomplicated

P. falciparum malaria, it should always be administered in combination with another effective blood schizonticide to prevent recrudescence and delay the selection of resistant strains. The use of artesunate as monotherapy should be limited to specific indications, such as in patients with a history of adverse reactions to the combination drug. When monotherapy is used, a 7-day course of therapy is recommended and efforts should be made to ensure adherence.



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Artesunate is not recommended for the treatment of malaria caused by P. vivax, P. ovale and P. malariae since other effective antimalarial drugs are available for this purpose. However, it may be used in the absence of microscopic diagnosis if the compound is the recommended first-line treatment.


Giving a dose twice daily offered no advantage over once daily dosing . While 7-day regimens have a therapeutic advantage over 5-day regimens, this might be offset by decreased patient adherence to the treatment; recrudescence rates of 50% are reported following 3-day regimens regardless of the dosage used . The shorter courses provided higher cure rates when a double dose was given on the first day of treatment or if the drugs were combined with a longer-acting single-dose antimalarial such as mefloquine . A regimen of 3-5 days of artesunate in combination with mefloquine given either concomitantly or sequentially provides cure rates of nearly 100% .

ARTESUNATE TABLET Dosage Route of administration: Administer oral daily. Dosage: Day one – 4mg/kg Day two – seven – 2mg/kg Give fansider on day three (3).

Weight (kg) Day.1.(tab.) Day.2-7 (tab.) 4 – 5.7 ½ ¼ 6 – 8.9 ¾ ½ 9 – 12.5 1 ½ 12.6 – 18.5 1½ ¾ 18.6 – 24.9 2 1 25 – 31.9 2½ 1½ 32 – 37.5 3 1½ Over 37.5 4 2

Because well-designed dose-finding studies of artesunate are limited, dosage schedules are based on available clinical data. When used as monotherapy, a minimum 7-day course is required to prevent recrudescence. If regimens of less than 7 days are employed, combination with mefloquine or another effective blood schizonticide is indicated. A once-daily regimen has been shown to have similar parasite and fever clearance times as a twice-daily regimen .



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Uncomplicated malaria

Monotherapy: 4 mg/kg loading dose on the first day, followed by 2 mg/kg once a day for 6 days.

Combination therapy

4 mg/kg once a day for 3 days, plus mefloquine (15 mg or 25 mg of base per kg) as a single dose or split dose on the second and/or third day .

Where adherence to the treatment is questionable, especially in an outpatient situation, combination with mefloquine (15 or 25 mg of base per kg) is indicated.

Severe malaria

2.4 mg/kg by the intramuscular route followed by 1.2 mg/kg at 12 and 24 h, then 1.2 mg/kg daily for 6 days. If the patient can swallow, the daily dose can be given orally.

2.4 mg/kg intravenously on the first day followed by 1.2 mg/kg daily until the patient can take orally artesunate or another effective antimalarial drug.

Drug disposition

The pharmacokinetics of artesunate following oral administration appear to be similar to those for artemisinin, with mean peak plasma concentrations and mean plasma half-lives of 1-2 h and 2-3 h, respectively. The plasma concentrations of artesunate are more erratic following administration by suppository compared to the intravenous route, but inadequate absorption is unusual .

Adverse effects

Prospective clinical studies of more than 10 000 patients, and post-marketing surveillance of over 4 600 patients in Thailand has not shown any serious drug-related adverse reactions.

Rectal administration

In emergency pre-referral treatment of severe malaria or for patients who cannot take oral medication, artesunate can be given by rectal administration before referral to hospital or before oral medication becomes possible . This is intended as emergency pre-referral management of malaria in life-threatening circumstances and may be provided to patients on a presumptive diagnosis of malaria.

A single dose should be given rectally (rectal capsules/suppositories, 10 mg/kg) as soon as possible once a diagnosis of malaria is made. If the rectal capsule is expelled within the first hour, another rectal capsule should be inserted immediately. A second dose



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might be required 24 h after the first dose if the patient is still unable to take oral medication at that time, and has not been able to access recommended parenteral treatment.

There is no information on efficacy in patients with severe and complicated malaria who have organ and systems failure, including renal failure and liver disease. No studies have been undertaken with this formulation in pregnant or lactating women or in patients with diarrhoea.

Rectal artesunate should not be given for the prevention of malaria.

D. DIHYDROARTEMISININ

Formulations

• Tablets containing 20 mg, 60 mg or 80 mg of dihydroartemisinin (China). • Suppositories containing 80 mg of dihydroartemisinin (China).

Efficacy

Dihydroartemisinin is the active metabolite of artemisinin and its derivatives.

These derivatives have more potent blood schizonticidal activity than the parent compound. Dihydroartemisinin is the most potent antimalarial of this group of compounds but it is also the least stable.

Oral dihydroartemisinin has been shown to be effective in the treatment of multidrug-resistant uncomplicated P. falciparum malaria in China, but experience outside that country is limited . Recent studies in Thailand demonstrated a cure rate of 90% in 52 patients given 120 mg of dihydroartemisinin followed by 60 mg once daily for 7 days, i.e. a total adult dose of 480 mg (S. Looareesuwan, personal communication, 1995).

Dihydroartemisinin does not have activity against hypnozoites. It reduces gametocyte carriage rate.

Use

Dihydroartemisinin appears to offer no advantage over artesunate or artemether for the treatment of uncomplicated or severe malaria.

Dihydroartemisinin is not recommended for the treatment of malaria caused by P. vivax, P ovale and P. malariae since other effective antimalarial drugs are available for this purpose. However, it may be used in the absence of micro-scopic diagnosis if the compound is the recommended first-line treatment.




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4 mg/kg in a divided loading dose on the first day followed by 2 mg/kg daily for 6 days.

Data on dihydroartemisinin are very limited, but the currently recommended dosage is as shown above. Dihydroartemisinin has been used in combination with mefloquine . Short courses of treatment of less than 5 days have higher recrudescence rates .

Drug disposition

Oral dihydroartemisinin is rapidly absorbed and has a short elimination half-life although little is known of its metabolism. Peak plasma concentrations are achieved in 1-2 h and the drug disappears from the circulation within 8-10 h.

E. ARTEETHER

Formulations

Ampoules containing 150 mg of arteether in 2 ml of injectable solution (India, Netherlands).

Efficacy

Arteether is the oil-soluble ethyl derivative of dihydroartemisinin. Clinical trials in India have indicated that it is an effective and rapidly-acting drug for the treatment of uncomplicated (275) and severe falciparum malaria .

Use

When arteether is used for the treatment of uncomplicated P. falciparum malaria, it should always be administered in combination with another effective blood schizonticide to improve its efficacy and delay the selection of resistant strains. A recrudescence rate of 6-14% has been observed with the use of alpha, beta-arteether . The use of arteether as monotherapy should therefore be limited to specific indications, such as in patients with a history of adverse reactions to the combination drug. When given as monotherapy, a 7-day course is recommended and efforts should be made to ensure adherence.

Arteether is not recommended for the treatment of malaria caused by P. vivax, P. ovale and P. malariae since other effective antimalarial drugs are available for this purpose.


The recommended regimen according to the Manufacturer is:

For adults, 150 mg/day administrated once daily by the intramuscular route for 3 days.

For children, 3 mg/kg per day by the intramuscular route for 3 days.



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Drug disposition

Intramuscular arteether has the lowest bioavailability (34%) of all the artemisinin derivatives tested in the rat, with approximately 14% converted to dihydroartemisinin. It has a long elimination half-life (> 20 h) and is more stable and more lipophilic than the other artemisinin compounds.

Adverse effects

Animal studies have demonstrated limited symptomatic and pathological evidence of neurotoxicity following parenteral administration of high doses (8-24 mg/kg per day for 14 days) of either arteether or artemether . Both drugs produced a unique pattern of selective neuronopathy with chromatolysis and necrosis of scattered neurons in vestibular, motor and auditory brain stem nuclei in rats, dogs and rhesus monkeys .

F. ARTELINIC ACID

Efficacy

Artelinic acid is a water-soluble derivative of artemisinin and is thought to be more stable than artesunate in solution thus offering the potential for oral administration. The compound is still under investigation. It is the only preparation undergoing transdermal studies .

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malaria drugs 210

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