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Antimalarial medications or simply antimalarials are a type of
antiparasitic Antiparasitics are a class of medications which are indicated for the treatment of parasitic diseases, such as those caused by helminths, amoeba, ectoparasites, parasitic fungi, and protozoa, among others. Antiparasitics target the parasitic ag ...
chemical agent, often naturally derived, that can be used to treat or to prevent
malaria Malaria is a mosquito-borne infectious disease that affects humans and other animals. Malaria causes symptoms that typically include fever, tiredness, vomiting, and headaches. In severe cases, it can cause jaundice, seizures, coma, or deat ...
, in the latter case, most often aiming at two susceptible target groups, young children and pregnant women. As of 2018, modern treatments, including for severe malaria, continued to depend on therapies deriving historically from
quinine Quinine is a medication used to treat malaria and babesiosis. This includes the treatment of malaria due to '' Plasmodium falciparum'' that is resistant to chloroquine when artesunate is not available. While sometimes used for nocturnal leg ...
and artesunate, both
parenteral A route of administration in pharmacology and toxicology is the way by which a drug, fluid, poison, or other substance is taken into the body. Routes of administration are generally classified by the location at which the substance is applied. ...
(injectable) drugs, expanding from there into the many classes of available modern drugs. Incidence and distribution of the disease ("malaria burden") is expected to remain high, globally, for many years to come; moreover, known antimalarial drugs have repeatedly been observed to elicit resistance in the malaria parasite—including for combination therapies featuring
artemisinin Artemisinin () and its semisynthetic derivatives are a group of drugs used in the treatment of malaria due to '' Plasmodium falciparum''. It was discovered in 1972 by Tu Youyou, who shared the 2015 Nobel Prize in Physiology or Medicine for her ...
, a drug of last resort, where resistance has now been observed in Southeast Asia. As such, the needs for new antimalarial agents and new strategies of treatment (e.g., new combination therapies) remain important priorities in tropical medicine. As well, despite very positive outcomes from many modern treatments, serious
side effect In medicine, a side effect is an effect, whether therapeutic or adverse, that is secondary to the one intended; although the term is predominantly employed to describe adverse effects, it can also apply to beneficial, but unintended, consequence ...
s can impact some individuals taking standard doses (e.g., retinopathy with
chloroquine Chloroquine is a medication primarily used to prevent and treat malaria in areas where malaria remains sensitive to its effects. Certain types of malaria, resistant strains, and complicated cases typically require different or additional medi ...
, acute haemolytic anaemia with tafenoquine). Specifically, antimalarial drugs may be used to treat malaria in three categories of individuals, (i) those with suspected or confirmed infection, (ii) those visiting a malaria-endemic regions who have no immunity, to prevent infection via malaria prophylaxis, and (iii) or in broader groups of individuals, in routine but intermittent preventative treatment in regions where malaria is endemic via intermittent preventive therapy. Practice in treating cases of malaria is most often based on the concept of combination therapy (e.g., using agents such as artemether and lumefantrine against chloroquine-resistant ''
Plasmodium falciparum ''Plasmodium falciparum'' is a unicellular protozoan parasite of humans, and the deadliest species of ''Plasmodium'' that causes malaria in humans. The parasite is transmitted through the bite of a female '' Anopheles'' mosquito and causes the d ...
'' infection), since this offers advantages including reduced risk of treatment failure, reduced risk of developed resistance, as well as the possibility of reduced side-effects. Prompt parasitological confirmation by microscopy, or alternatively by rapid diagnostic tests, is recommended in all patients suspected of malaria before treatment is started. Treatment solely on the basis of clinical suspicion is considered when a parasitological diagnosis is not possible. Anti-malaria aid campaigns have a globally positive impact for health outcomes and beyond.


Medications

It is practical to consider antimalarials by chemical structure since this is associated with important properties of each drug, such as mechanism of action.


Quinine and related agents

Quinine Quinine is a medication used to treat malaria and babesiosis. This includes the treatment of malaria due to '' Plasmodium falciparum'' that is resistant to chloroquine when artesunate is not available. While sometimes used for nocturnal leg ...
has a long history stretching from
Peru , image_flag = Flag of Peru.svg , image_coat = Escudo nacional del Perú.svg , other_symbol = Great Seal of the State , other_symbol_type = Seal (emblem), National seal , national_motto = "Fi ...
, and the discovery of the
cinchona ''Cinchona'' (pronounced or ) is a genus of flowering plants in the family Rubiaceae containing at least 23 species of trees and shrubs. All are native to the tropical Andean forests of western South America. A few species are reportedly natu ...
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 Alkaloids are a class of basic BASIC (Beginners' All-purpose Symbolic Instruction Code) is a family of general-purpose, high-level programming languages designed for ease of use. The original version was created by John G. Kemeny and Th ...
that acts as a blood schizonticidal and weak gametocide against ''
Plasmodium vivax ''Plasmodium vivax'' is a protozoal parasite and a human pathogen. This parasite is the most frequent and widely distributed cause of recurring malaria. Although it is less virulent than '' Plasmodium falciparum'', the deadliest of the five huma ...
'' and '' Plasmodium malariae''. As an alkaloid, it is accumulated in the food
vacuole A vacuole () is a membrane-bound organelle which is present in plant and fungal cells and some protist, animal, and bacterial cells. Vacuoles are essentially enclosed compartments which are filled with water containing inorganic and organic ...
s of ''Plasmodium'' species, especially ''
Plasmodium falciparum ''Plasmodium falciparum'' is a unicellular protozoan parasite of humans, and the deadliest species of ''Plasmodium'' that causes malaria in humans. The parasite is transmitted through the bite of a female '' Anopheles'' mosquito and causes the d ...
''. It acts by inhibiting the
hemozoin Haemozoin is a disposal product formed from the digestion of blood by some blood-feeding parasites. These hematophagous organisms such as malaria parasites (''Plasmodium spp.''), ''Rhodnius'' and '' Schistosoma'' digest haemoglobin and release h ...
biocrystallization, thus facilitating an aggregation of
cytotoxic Cytotoxicity is the quality of being toxic to cells. Examples of toxic agents are an immune cell or some types of venom, e.g. from the puff adder (''Bitis arietans'') or brown recluse spider (''Loxosceles reclusa''). Cell physiology Treating ...
heme. Quinine is less effective and more toxic as a blood schizonticidal agent than
chloroquine Chloroquine is a medication primarily used to prevent and treat malaria in areas where malaria remains sensitive to its effects. Certain types of malaria, resistant strains, and complicated cases typically require different or additional medi ...
; 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 Sulfonamide is a functional group (a part of a molecule) that is the basis of several groups of drugs, which are called sulphonamides, sulfa drugs or sulpha drugs. The original antibacterial sulfonamides are synthetic (nonantibiotic) antimi ...
combinations with pyrimethamine. Quinine is also used in post-exposure treatment of individuals returning from an area where malaria is
endemic Endemism is the state of a species being found in a single defined geographic location, such as an island, state, nation, country or other defined zone; organisms that are indigenous to a place are not endemic to it if they are also found els ...
. 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 The World Health Organization (WHO) is a specialized agency of the United Nations responsible for international public health. The WHO Constitution states its main objective as "the attainment by all peoples of the highest possible level o ...
recommendation for quinine is 20 mg/kg first times and 10 mg/kg every eight hours for five days where parasites are sensitive to quinine, combined with doxycycline,
tetracycline Tetracycline, sold under various brand names, is an oral antibiotic in the tetracyclines family of medications, used to treat a number of infections, including acne, cholera, brucellosis, plague, malaria, and syphilis. Common side effects ...
or
clindamycin Clindamycin is an antibiotic medication used for the treatment of a number of bacterial infections, including osteomyelitis (bone) or joint infections, pelvic inflammatory disease, strep throat, pneumonia, acute otitis media (middle ear infe ...
. Doses can be given by oral, intravenous or
intramuscular Intramuscular injection, often abbreviated IM, is the injection of a substance into a muscle. In medicine, it is one of several methods for parenteral administration of medications. Intramuscular injection may be preferred because muscles have ...
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 Cinchonism is a pathological condition caused by an overdose of quinine or its natural source, cinchona bark. Quinine and its derivatives are used medically to treat malaria and lupus erythematosus. In much smaller amounts, quinine is an ingredie ...
.
Tinnitus Tinnitus is the perception of sound when no corresponding external sound is present. Nearly everyone experiences a faint "normal tinnitus" in a completely quiet room; but it is of concern only if it is bothersome, interferes with normal hearin ...
(a hearing impairment), rashes,
vertigo Vertigo is a condition where a person has the sensation of movement or of surrounding objects moving when they are not. Often it feels like a spinning or swaying movement. This may be associated with nausea, vomiting, sweating, or difficulties ...
, nausea, vomiting and abdominal pain are the most common symptoms. Neurological effects are experienced in some cases due to the drug's
neurotoxic Neurotoxicity is a form of toxicity in which a biological, chemical, or physical agent produces an adverse effect on the structure or function of the central and/or peripheral nervous system. It occurs when exposure to a substance – specifical ...
properties. These actions are mediated through the interactions of quinine causing a decrease in the excitability of the
motor neuron A motor neuron (or motoneuron or efferent neuron) is a neuron whose cell body is located in the motor cortex, brainstem or the spinal cord, and whose axon (fiber) projects to the spinal cord or outside of the spinal cord to directly or indirectly ...
end plate A neuromuscular junction (or myoneural junction) is a chemical synapse between a motor neuron and a muscle fiber. It allows the motor neuron to transmit a signal to the muscle fiber, causing muscle contraction. Muscles require innervation t ...
s. This often results in functional impairment of the
eighth cranial nerve The vestibulocochlear nerve or auditory vestibular nerve, also known as the eighth cranial nerve, cranial nerve VIII, or simply CN VIII, is a cranial nerve that transmits sound and equilibrium (balance) information from the inner ear to the b ...
, resulting in confusion,
delirium Delirium (also known as acute confusional state) is an organically caused decline from a previous baseline of mental function that develops over a short period of time, typically hours to days. Delirium is a syndrome encompassing disturbances ...
and coma. Quinine can cause
hypoglycaemia Hypoglycemia, also called low blood sugar, is a fall in blood sugar to levels below normal, typically below 70 mg/dL (3.9 mmol/L). Whipple's triad is used to properly identify hypoglycemic episodes. It is defined as blood glucose be ...
through its action of stimulating
insulin Insulin (, from Latin ''insula'', 'island') is a peptide hormone produced by beta cells of the pancreatic islets encoded in humans by the ''INS'' gene. It is considered to be the main anabolic hormone of the body. It regulates the metabol ...
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
kidney failure Kidney failure, also known as end-stage kidney disease, is a medical condition in which the kidneys can no longer adequately filter waste products from the blood, functioning at less than 15% of normal levels. Kidney failure is classified as eit ...
and death through depression of the
respiratory system The respiratory system (also respiratory apparatus, ventilatory system) is a biological system consisting of specific organs and structures used for gas exchange in animals and plants. The anatomy and physiology that make this happen varies grea ...
. 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, cinchonine and cinchonidine). This combination has been shown in several studies to be more effective than quinine, supposedly due to a synergistic action among 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.
Warburg's tincture Warburg's tincture was a pharmaceutical drug, now obsolete. It was invented in 1834 by Dr. Carl Warburg. Warburg's tincture was well known in the Victorian era as a medicine for fevers, especially tropical fevers, including malaria. It was conside ...
was a febrifuge developed by
Carl Warburg Carl Warburg (c. 1805–1892), also known as Charles Warburg, was a physician and scientist. He was the inventor of 'Warburg's Tincture', a medicine well known in the 19th century for treating fevers, including malaria.Sparkes, Roland. Article ...
in 1834, which included quinine as a key ingredient. In the 19th-century it was a well-known anti-malarial drug. Although originally sold as a secret medicine, Warburg's tincture was highly regarded by many eminent medical professionals who considered it as being superior to quinine (e.g. Surgeon-General W. C. Maclean, Professor of Military Medicine at British Army Medical School, Netley). Warburg's tincture appeared in '' Martindale: The complete drug reference'' from 1883 until about 1920. The formula was published in ''The Lancet'' 1875.


Chloroquine

Chloroquine was, until recently, the most widely used anti-malarial. It was the original prototype from which most 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. Popular drugs based on chloroquine phosphate (also called nivaquine) are Chloroquine FNA, Resochin and Dawaquin. Chloroquine is a
4-aminoquinolone 4-Aminoquinoline is a form of aminoquinoline with the amino group at the 4-position of the quinoline. The compound has been used as a precursor for the synthesis of its derivatives. A variety of derivatives of 4-aminoquinoline are antimalarial ag ...
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 Heme, or haem (pronounced / hi:m/ ), is a precursor to hemoglobin, which is necessary to bind oxygen in the bloodstream. Heme is biosynthesized in both the bone marrow and the liver. In biochemical terms, heme is a coordination complex "consis ...
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 acid Nucleic acids are biopolymers, macromolecules, essential to all known forms of life. They are composed of nucleotides, which are the monomers made of three components: a 5-carbon sugar, a phosphate group and a nitrogenous base. The two main ...
s and 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
gametocyte A gametocyte is a eukaryotic germ cell that divides by mitosis into other gametocytes or by meiosis into gametids during gametogenesis. Male gametocytes are called '' spermatocytes'', and female gametocytes are called '' oocytes''. Developme ...
s of ''P. vivax'', ''P. malariae'', ''
P. ovale ''Plasmodium ovale'' is a species of parasitic protozoon that causes tertian malaria in humans. It is one of several species of ''Plasmodium'' parasites that infect humans, including ''Plasmodium falciparum'' and ''Plasmodium vivax'' which are ...
'' as well as the immature gametocytes of ''P. falciparum''. Chloroquine also has a significant
anti-pyretic An antipyretic (, from ''anti-'' 'against' and ' 'feverish') is a substance that reduces fever. Antipyretics cause the hypothalamus to override a prostaglandin-induced increase in temperature. The body then works to lower the temperature, which r ...
and
anti-inflammatory Anti-inflammatory is the property of a substance or treatment that reduces inflammation or swelling. Anti-inflammatory drugs, also called anti-inflammatories, make up about half of analgesics. These drugs remedy pain by reducing inflammation as ...
effect when used to treat ''P. vivax'' infections, and 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. Children and adults should receive 25 mg of chloroquine per kg given over three days. A
pharmacokinetic Pharmacokinetics (from Ancient Greek ''pharmakon'' "drug" and ''kinetikos'' "moving, putting in motion"; see chemical kinetics), sometimes abbreviated as PK, is a branch of pharmacology dedicated to determining the fate of substances administered ...
ally 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 two days. For chemoprophylaxis: 5 mg/kg/week (single dose) or 10 mg/kg/week divided into six daily doses is advised. 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 An abortifacient ("that which will cause a miscarriage" from Latin: '' abortus'' "miscarriage" and '' faciens'' "making") is a substance that induces abortion. This is a nonspecific term which may refer to any number of substances or medications ...
or
teratogenic Teratology is the study of abnormalities of physiological development in organisms during their life span. It is a sub-discipline in medical genetics which focuses on the classification of congenital abnormalities in dysmorphology. The relat ...
effects have been reported during this time; therefore, it is considered very safe to use during pregnancy. However, itching can occur at intolerable level and Chloroquinine can be a provocation factor of
psoriasis Psoriasis is a long-lasting, noncontagious autoimmune disease characterized by raised areas of abnormal skin. These areas are red, pink, or purple, dry, itchy, and scaly. Psoriasis varies in severity from small, localized patches to complet ...
.


Hydroxychloroquine

Hydroxychloroquine Hydroxychloroquine, sold under the brand name Plaquenil among others, is a medication used to prevent and treat malaria in areas where malaria remains sensitive to chloroquine. Other uses include treatment of rheumatoid arthritis, lupus, a ...
was derived in the 1950s by adding a
hydroxy group In chemistry, a hydroxy or hydroxyl group is a functional group with the chemical formula and composed of one oxygen atom covalently bonded to one hydrogen atom. In organic chemistry, alcohols and carboxylic acids contain one or more hydrox ...
to existing
Chloroquine Chloroquine is a medication primarily used to prevent and treat malaria in areas where malaria remains sensitive to its effects. Certain types of malaria, resistant strains, and complicated cases typically require different or additional medi ...
, making it more tolerable than Chloroquine by itself.


Amodiaquine

Amodiaquine is a 4-aminoquinolone anti-malarial drug similar in structure and mechanism of action to chloroquine. Amodiaquine has tended to be administered in areas of chloroquine resistance while some patients prefer its tendency to cause less itching than chloroquine. Amodiaquine is now available in a combined formulation with artesunate (
ASAQ Artesunate/amodiaquine, sold under the trade name Camoquin among others, is a medication used for the treatment of malaria. It is a fixed-dose combination of artesunate and amodiaquine. Specifically it recommended for acute uncomplicated ''Plasmo ...
) and is among the artemisinin-combination therapies recommended by the World Health Organization. Combination with sulfadoxine=pyrimethamine is not recommended. The drug should be given in doses between 25 mg/kg and 35 mg/kg over three 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 Bradycardia (also sinus bradycardia) is a slow resting heart rate, commonly under 60 beats per minute (BPM) as determined by an electrocardiogram. It is considered to be a normal heart rate during sleep, in young and healthy or elderly adults, ...
, itching, nausea, vomiting and some abdominal pain have been recorded. Some blood and
hepatic The liver is a major organ only found in vertebrates which performs many essential biological functions such as detoxification of the organism, and the synthesis of proteins and biochemicals necessary for digestion and growth. In humans, it ...
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
sulfadoxine Sulfadoxine (also spelled sulphadoxine) is an ultra-long-lasting sulfonamide used in combination with pyrimethamine to treat malaria.
. It acts by inhibiting dihydrofolate reductase in the parasite thus preventing the biosynthesis of
purine Purine is a heterocyclic aromatic organic compound that consists of two rings ( pyrimidine and imidazole) fused together. It is water-soluble. Purine also gives its name to the wider class of molecules, purines, which include substituted purin ...
s and
pyrimidine Pyrimidine (; ) is an aromatic, heterocyclic, organic compound similar to pyridine (). One of the three diazines (six-membered heterocyclics with two nitrogen atoms in the ring), it has nitrogen atoms at positions 1 and 3 in the ring. The othe ...
s, thereby halting the processes of
DNA replication In molecular biology, DNA replication is the biological process of producing two identical replicas of DNA from one original DNA molecule. DNA replication occurs in all living organisms acting as the most essential part for biological inherita ...
,
cell division Cell division is the process by which a parent cell divides into two daughter cells. Cell division usually occurs as part of a larger cell cycle in which the cell grows and replicates its chromosome(s) before dividing. In eukaryotes, there ar ...
and reproduction. It acts primarily on the schizonts during the erythrocytic phase, and nowadays is only used in concert with a
sulfonamide In organic chemistry, the sulfonamide functional group (also spelled sulphonamide) is an organosulfur group with the structure . It consists of a sulfonyl group () connected to an amine group (). Relatively speaking this group is unreactiv ...
.


Proguanil

Proguanil Proguanil, also known as chlorguanide and chloroguanide, is a medication used to treat and prevent malaria. It is often used together with chloroquine or atovaquone. When used with chloroquine the combination will treat mild chloroquine resistan ...
(chloroguanide) is a
biguanide Biguanide () is the organic compound with the formula HN(C(NH)NH2)2. It is a colorless solid that dissolves in water to give highly basic solution. These solutions slowly hydrolyse to ammonia and urea. Synthesis Biguanide can be obtained from ...
; 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 In biochemistry, a metabolite is an intermediate or end product of metabolism. The term is usually used for small molecules. Metabolites have various functions, including fuel, structure, signaling, stimulatory and inhibitory effects on enzymes, ...
cycloguanil Cycloguanil is a dihydrofolate reductase inhibitor, and is a metabolite of the antimalarial drug proguanil; its formation in vivo has been thought to be primarily responsible for the antimalarial activity of proguanil. However, more recent wor ...
. 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 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 Preventive healthcare, or prophylaxis, consists of measures taken for the purposes of disease prevention.Hugh R. Leavell and E. Gurney Clark as "the science and art of preventing disease, prolonging life, and promoting physical and mental hea ...
when combined with
atovaquone Atovaquone, sold under the brand name Mepron, is an antimicrobial medication for the prevention and treatment of ''Pneumocystis jirovecii'' pneumonia (PCP). Atovaquone is a chemical compound that belongs to the class of naphthoquinones. Atovaq ...
or
chloroquine Chloroquine is a medication primarily used to prevent and treat malaria in areas where malaria remains sensitive to its effects. Certain types of malaria, resistant strains, and complicated cases typically require different or additional medi ...
(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. 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. Proguanil hydrochloride is marketed as Paludrine by
AstraZeneca AstraZeneca plc () is a British-Swedish multinational pharmaceutical and biotechnology company with its headquarters at the Cambridge Biomedical Campus in Cambridge, England. It has a portfolio of products for major diseases in areas includ ...
.


Sulfonamides

Sulfadoxine Sulfadoxine (also spelled sulphadoxine) is an ultra-long-lasting sulfonamide used in combination with pyrimethamine to treat malaria.
and sulfamethoxypyridazine are specific inhibitors of the enzyme dihydropteroate synthetase in the tetrahydrofolate synthesis pathway of malaria parasites. They are structural analogs of ''p''-aminobenzoic acid (PABA) and compete with PABA to block its conversion to dihydrofolic acid. Sulfonamides act on the schizont stages of the erythrocytic (asexual) cycle. When administered alone sulfonamides are not efficacious in treating malaria but co-administration with the antifolate pyrimethamine, most commonly as fixed-dose sulfadoxine-pyrimethamine ( Fansidar), produces synergistic effects sufficient to cure sensitive strains of malaria. Sulfonamides are not recommended for chemoprophylaxis because of rare but severe skin reactions experienced. However it is used frequently for clinical episodes of the disease.


Mefloquine

Mefloquine was developed during the
Vietnam War The Vietnam War (also known by #Names, other names) was a conflict in Vietnam, Laos, and Cambodia from 1 November 1955 to the fall of Saigon on 30 April 1975. It was the second of the Indochina Wars and was officially fought between North Vie ...
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 Half-life (symbol ) is the time required for a quantity (of substance) to reduce to half of its initial value. The term is commonly used in nuclear physics to describe how quickly unstable atoms undergo radioactive decay or how long stable at ...
. It is thought to act by forming toxic heme complexes that damage parasitic food vacuoles. Mefloquine is effective in
prophylaxis Preventive healthcare, or prophylaxis, consists of measures taken for the purposes of disease prevention.Hugh R. Leavell and E. Gurney Clark as "the science and art of preventing disease, prolonging life, and promoting physical and mental hea ...
and for acute therapy. It is now used solely for the prevention of resistant strains of ''P. falciparum'' (usually combined with Artesunate) despite being effective against ''P. vivax'', ''P. ovale'' and ''P. marlariae''. Chloroquine/proguanil or sulfa 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 Mefloquine, sold under the brand name Lariam among others, is a medication used to prevent or treat malaria. When used for prevention it is typically started before potential exposure and continued for several weeks after potential exposure. It ...
". Lariam is fairly expensive at around three € 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 esophagitis. It was not recommended for use during the first trimester, although considered safe during the second and third trimesters; nevertheless, in October 2011, the Centers for Disease Control and Prevention (CDC) changed its recommendation and approved use of Mefloquine for both prophylaxis and treatment of malaria in all trimesters, after the Food and Drug Administration (FDA) changed its categorization from C to B. Mefloquine frequently produces side effects, including nausea, vomiting, diarrhea, abdominal pain and dizziness. Several associations with neurological events have been made, namely
affective Affect, in psychology, refers to the underlying experience of feeling, emotion or mood. History The modern conception of affect developed in the 19th century with Wilhelm Wundt. The word comes from the German ''Gefühl'', meaning "feeling." ...
and
anxiety disorder Anxiety disorders are a cluster of mental disorders characterized by significant and uncontrollable feelings of anxiety and fear such that a person's social, occupational, and personal function are significantly impaired. Anxiety may cause physi ...
s, hallucinations, sleep disturbances,
psychosis Psychosis is a condition of the mind that results in difficulties determining what is real and what is not real. Symptoms may include delusions and hallucinations, among other features. Additional symptoms are incoherent speech and behavior ...
, toxic encephalopathy, convulsions and
delirium Delirium (also known as acute confusional state) is an organically caused decline from a previous baseline of mental function that develops over a short period of time, typically hours to days. Delirium is a syndrome encompassing disturbances ...
.
Cardiovascular The blood circulatory system is a system of organs that includes the heart, blood vessels, and blood which is circulated throughout the entire body of a human or other vertebrate. It includes the cardiovascular system, or vascular system, tha ...
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 six months due to side effects. After this, other drugs (such as those based on paludrine/nivaquine) again need to be taken.


Atovaquone

Atovaquone Atovaquone, sold under the brand name Mepron, is an antimicrobial medication for the prevention and treatment of ''Pneumocystis jirovecii'' pneumonia (PCP). Atovaquone is a chemical compound that belongs to the class of naphthoquinones. Atovaq ...
is available in combination with proguanil under the name
Malarone Atovaquone/proguanil, sold under the brand name Malarone among others, is a fixed-dose combination medication used to treat and prevent malaria, including chloroquine-resistant malaria. It contains atovaquone and proguanil. It is not recommended f ...
, albeit at a price higher than
Lariam Mefloquine, sold under the brand name Lariam among others, is a medication used to prevent or treat malaria. When used for prevention it is typically started before potential exposure and continued for several weeks after potential exposure. It ...
. It is commonly used in
prophylaxis Preventive healthcare, or prophylaxis, consists of measures taken for the purposes of disease prevention.Hugh R. Leavell and E. Gurney Clark as "the science and art of preventing disease, prolonging life, and promoting physical and mental hea ...
by travelers and used to treat falciparum malaria in developed countries. A liquid oral suspension of Atovaquone is available under the name Mepron.


Primaquine

Primaquine Primaquine is a medication used to treat and prevent malaria and to treat ''Pneumocystis'' pneumonia. Specifically it is used for malaria due to ''Plasmodium vivax'' and ''Plasmodium ovale'' along with other medications and for prevention if othe ...
is a highly active 8-aminoquinolone that is effective against ''P. falcipraum'' gametocytes but also acts on merozoites in the bloodstream and on hypnozoites, the dormant hepatic forms of ''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 block oxidative metabolism in Plasmodia. It can also be combined with methylene blue. 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 seven 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 it has been shown that primaquine may cause anorexia, nausea, vomiting, cramps, chest weakness,
anaemia Anemia or anaemia (British English) is a blood disorder in which the blood has a reduced ability to carry oxygen due to a lower than normal number of red blood cells, or a reduction in the amount of hemoglobin. When anemia comes on slowly, t ...
, some suppression of myeloid activity and abdominal pains. In cases of over-dosage granulocytopenia may occur.


Artemisinin and derivatives

Artemisinin Artemisinin () and its semisynthetic derivatives are a group of drugs used in the treatment of malaria due to '' Plasmodium falciparum''. It was discovered in 1972 by Tu Youyou, who shared the 2015 Nobel Prize in Physiology or Medicine for her ...
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 Ge Hong (; b. 283 – d. 343 or 364), courtesy name Zhichuan (稚川), was a Chinese linguist, Taoist practitioner, philosopher, physician, politician, and writer during the Eastern Jin dynasty. He was the author of '' Essays on Chinese Charact ...
in his book ''Zhou Hou Bei Ji Fang'' (''A Handbook of Prescriptions for Emergencies''). Ge Hong extracted the artemesinin using a simple macerate, and this method is still in use today. The active compound was isolated first in 1971 and named artemisinin. It is a
sesquiterpene lactone Sesquiterpene lactones (SLs) are a class of sesquiterpenoids that contain a lactone ring. They are most often found in plants of the family Asteraceae (daisies, asters). Other plant families with SLs are Umbelliferae (celery, parsley, carrots ...
with a chemically rare peroxide bridge linkage. It 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 behaviors associated with the development of resistance. It is also only given in combination with other anti-malarials. *
Artemisinin Artemisinin () and its semisynthetic derivatives are a group of drugs used in the treatment of malaria due to '' Plasmodium falciparum''. It was discovered in 1972 by Tu Youyou, who shared the 2015 Nobel Prize in Physiology or Medicine for her ...
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 trophozoite 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 is often given, and the dose then reduced to 10 mg/kg per day for the six 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 In organic chemistry, ethers are a class of compounds that contain an ether group—an oxygen atom connected to two alkyl or aryl groups. They have the general formula , where R and R′ represent the alkyl or aryl groups. Ethers can again b ...
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 three days, followed by 1.6 mg/kg for three 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 five or seven day course (depending on the predicted adherence level) of 4 mg/kg for three days (usually given in combination with mefloquine) followed by 2 mg/kg for the remaining two or four days. In large studies carried out on over 10,000 patients in Thailand no adverse effects have been shown. *
Dihydroartemisinin Dihydroartemisinin (also known as dihydroqinghaosu, artenimol or DHA) is a drug used to treat malaria. Dihydroartemisinin is the active metabolite of all artemisinin compounds (artemisinin, artesunate, artemether, etc.) and is also available ...
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 six 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 three days given by IM injections. With the exception of a small number of cases demonstrating neurotoxicity following
parenteral A route of administration in pharmacology and toxicology is the way by which a drug, fluid, poison, or other substance is taken into the body. Routes of administration are generally classified by the location at which the substance is applied. ...
administration no side effects have been recorded.


Halofantrine

Halofantrine is a relatively new drug developed by the
Walter Reed Army Institute of Research The Walter Reed Army Institute of Research (WRAIR) is the largest biomedical research facility administered by the U.S. Department of Defense (DoD). The institute is centered at the Forest Glen Annex, in the Forest Glen Park part of the u ...
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 that have 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, diarrhea, 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

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 Tetracycline, sold under various brand names, is an oral antibiotic in the tetracyclines family of medications, used to treat a number of infections, including acne, cholera, brucellosis, plague, malaria, and syphilis. Common side effects ...
compound derived from oxytetracycline. The tetracyclines were one of the earliest groups of antibiotics to be 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 Protein biosynthesis (or protein synthesis) is a core biological process, occurring inside cells, balancing the loss of cellular proteins (via degradation or export) through the production of new proteins. Proteins perform a number of critical ...
by binding to the
30S The prokaryotic small ribosomal subunit, or 30 S subunit, is the smaller subunit of the 70S ribosome found in prokaryotes. It is a complex of the 16S ribosomal RNA (rRNA) and 19 proteins. This complex is implicated in the binding of transfer RN ...
ribosomal Ribosomes ( ) are macromolecular machines, found within all cells, that perform biological protein synthesis (mRNA translation). Ribosomes link amino acids together in the order specified by the codons of messenger RNA (mRNA) molecules to ...
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 of doxycycline should be given per day for seven 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 Photosensitivity is the amount to which an object reacts upon receiving photons, especially visible light. In medicine, the term is principally used for abnormal reactions of the skin, and two types are distinguished, photoallergy and phototoxici ...
. 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 five or seven days depending on the level of adherence and compliance expected. Oesophageal ulceration, gastrointestinal upset and interferences with the process of
ossification Ossification (also called osteogenesis or bone mineralization) in bone remodeling is the process of laying down new bone material by cells named osteoblasts. It is synonymous with bone tissue formation. There are two processes resulting in ...
and depression of bone growth are known to occur. The majority of side effects associated with doxycycline are also experienced.


Clindamycin

Clindamycin Clindamycin is an antibiotic medication used for the treatment of a number of bacterial infections, including osteomyelitis (bone) or joint infections, pelvic inflammatory disease, strep throat, pneumonia, acute otitis media (middle ear infe ...
is a derivative of
lincomycin Lincomycin is a lincosamide antibiotic that comes from the actinomycete ''Streptomyces lincolnensis''. A related compound, clindamycin, is derived from lincomycin by using thionyl chloride to replace the 7-hydroxy group with a chlorine atom wit ...
, 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 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 five 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 Colitis is swelling or inflammation of the large intestine ( colon). Colitis may be acute and self-limited or long-term. It broadly fits into the category of digestive diseases. In a medical context, the label ''colitis'' (without qualification ...
(caused by ''
Clostridium difficile ''Clostridioides difficile'' (syn. ''Clostridium difficile'') is a bacterium that is well known for causing serious diarrheal infections, and may also cause colon cancer. Also known as ''C. difficile'', or ''C. diff'' (), is Gram-positive spec ...
'') has also developed in some patients; this condition may be fatal in a small number of cases.


Resistance

Anti-malarial
drug resistance Drug resistance is the reduction in effectiveness of a medication such as an antimicrobial or an antineoplastic in treating a disease or condition. The term is used in the context of resistance that pathogens or cancers have "acquired", that is, ...
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 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." Resistance to antimalarial drugs is common. In most instances this refers to parasites that remain following on from an observed treatment; thus, it excludes all cases where anti-malarial prophylaxis has failed. In order for a case to be defined as resistant, the patient in question must have received a known and observed anti-malarial therapy while the blood drug and metabolite concentrations are monitored concurrently; techniques used to demonstrate this include ''in vivo'', ''in vitro'', and
animal model An animal model (short for animal disease model) is a living, non-human, often genetic-engineered animal used during the research and investigation of human disease, for the purpose of better understanding the disease process without the risk of ha ...
testing, and more 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 Parasitemia is the quantitative content of parasites in the blood. It is used as a measurement of parasite load in the organism and an indication of the degree of an active parasitic infection. Systematic measurement of parasitemia is important in ...
and recover from an acute clinical episode when a suitable treatment has been given is 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
evolution Evolution is change in the heritable characteristics of biological populations over successive generations. These characteristics are the expressions of genes, which are passed on from parent to offspring during reproduction. Variation ...
ary benefit, thus giving the anti-malarial used a reduced level of sensitivity. This can be caused by a single
point mutation A point mutation is a genetic mutation where a single nucleotide base is changed, inserted or deleted from a DNA or RNA sequence of an organism's genome. Point mutations have a variety of effects on the downstream protein product—consequences ...
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 buildup of the toxic byproducts 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 amodiaquine, 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 Folate, also known as vitamin B9 and folacin, is one of the B vitamins. Manufactured folic acid, which is converted into folate by the body, is used as a dietary supplement and in food fortification as it is more stable during processing and ...
synthesis. Regional variations of specific mutations give differing levels of resistance.
Atovaquone Atovaquone, sold under the brand name Mepron, is an antimicrobial medication for the prevention and treatment of ''Pneumocystis jirovecii'' pneumonia (PCP). Atovaquone is a chemical compound that belongs to the class of naphthoquinones. Atovaq ...
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-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, pharmacokinetics, and the biology of
vector Vector most often refers to: *Euclidean vector, a quantity with a magnitude and a direction *Vector (epidemiology), an agent that carries and transmits an infectious pathogen into another living organism Vector may also refer to: Mathematic ...
s and parasites. The most influential causes are examined below: #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 Immunodeficiency, also known as immunocompromisation, is a state in which the immune system's ability to fight infectious diseases and cancer is compromised or entirely absent. Most cases are acquired ("secondary") due to extrinsic factors that a ...
individuals, pregnant women and young children. #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. #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 amodiaquine, 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. #The resistance to anti-malarials may be increased by a process found in some species of ''Plasmodium'', where a degree of
phenotypic plasticity Phenotypic plasticity refers to some of the changes in an organism's behavior, morphology and physiology in response to a unique environment. Fundamental to the way in which organisms cope with environmental variation, phenotypic plasticity encompa ...
was exhibited, allowing the rapid development of resistance to a new drug, even if the drug has not been previously experienced. #The pharmacokinetics 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. #The pharmacokinetics 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. #Ecologically there is a linkage between the level of transmission and the development of resistance, however at present this still remains unclear. #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 pharmacokinetic and dynamic properties.


Prevention

The prevention of anti-malarial drug resistance is of enormous
public health Public health is "the science and art of preventing disease, prolonging life and promoting health through the organized efforts and informed choices of society, organizations, public and private, communities and individuals". Analyzing the det ...
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 existing 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 need 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 travelers). 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 also could be diversified by combining a potentially effective vaccine 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 A disease is a particular abnormal condition that negatively affects the structure or function of all or part of an organism, and that is not immediately due to any external injury. Diseases are often known to be medical conditions that ...
and mortality. Thus a balance must be reached that attempts to achieve both goals while 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-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

Artemisinin-based combination therapies should be used in preference to amodiaquine plus sulfadoxine-pyrimethamine for the treatment of uncomplicated ''P. falciparum'' malaria.


Artemisinin-based combination therapies (ACTs)

Artemesinin has a very different mode of action than conventional anti-malarials (see information above), which makes it particularly useful in the treatment of resistant infections. However, 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 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.


Other combinations

Several other anti-malarial combinations have been used or are in development. For example,
Chlorproguanil Chlorproguanil is an antimalarial drug. References See also * Proguanil * Chlorproguanil hydrochloride-dapsone-artesunate Chlorproguanil/dapsone/artesunate (abbreviated CDA) was an experimental antimalarial treatment that entered Phase III ...
-
dapsone Dapsone, also known as 4,4'-sulfonyldianiline (SDA) or diaminodiphenyl sulfone (DDS), is an antibiotic commonly used in combination with rifampicin and clofazimine for the treatment of leprosy. It is a second-line medication for the treatment ...
and artesunate (''CDA'') appears efficacious but the problem of haemolysis in patients with
glucose-6-phosphate dehydrogenase Glucose-6-phosphate dehydrogenase (G6PD or G6PDH) () is a cytosolic enzyme that catalyzes the chemical reaction : D-glucose 6-phosphate + NADP+ + H2O 6-phospho-D-glucono-1,5-lactone + NADPH + H+ This enzyme participates in the pentose phos ...
(G6PD) deficiency is likely to prevent widespread use.


By type of malaria

Antimalarial drugs and combinations may also be sorted according to the type of malaria in which they are used.


''Falciparum'' malaria

Artemisinin-based combination therapies (ACTs) are the recommended antimalarial treatments for uncomplicated malaria caused by
P. falciparum ''Plasmodium falciparum'' is a Unicellular organism, unicellular protozoan parasite of humans, and the deadliest species of ''Plasmodium'' that causes malaria in humans. The parasite is transmitted through the bite of a female ''Anopheles'' mosqu ...
. The choice of ACT in a country or region will be based on the level of resistance to the constituents in the combination. For pregnant women, the recommended first-line treatment during the
first trimester Pregnancy is the time during which one or more offspring develops ( gestates) inside a woman's uterus (womb). A multiple pregnancy involves more than one offspring, such as with twins. Pregnancy usually occurs by sexual intercourse, but ...
is quinine plus clindamycin to be given for seven days. In second and third trimesters, it is recommended to give ACTs known to be effective in the country/region or artesunate plus clindamycin for seven days, or quinine plus clindamycin to be given for seven days. Lactating women should receive standard antimalarial treatment (including ACTs) except for
dapsone Dapsone, also known as 4,4'-sulfonyldianiline (SDA) or diaminodiphenyl sulfone (DDS), is an antibiotic commonly used in combination with rifampicin and clofazimine for the treatment of leprosy. It is a second-line medication for the treatment ...
,
primaquine Primaquine is a medication used to treat and prevent malaria and to treat ''Pneumocystis'' pneumonia. Specifically it is used for malaria due to ''Plasmodium vivax'' and ''Plasmodium ovale'' along with other medications and for prevention if othe ...
and
tetracycline Tetracycline, sold under various brand names, is an oral antibiotic in the tetracyclines family of medications, used to treat a number of infections, including acne, cholera, brucellosis, plague, malaria, and syphilis. Common side effects ...
s. In infants and young children, it is recommended to give ACTs for first-line treatment, with attention to accurate dosing and ensuring the administered dose is retained. In severe ''falciparum'' malaria, it is recommended that rapid clinical assessment and confirmation of the diagnosis is made, followed by administration of full doses of parenteral antimalarial treatment without delay with whichever effective antimalarial is first available. For adults, intravenous (IV) or
intramuscular Intramuscular injection, often abbreviated IM, is the injection of a substance into a muscle. In medicine, it is one of several methods for parenteral administration of medications. Intramuscular injection may be preferred because muscles have ...
(IM) artesunate is recommended. Quinine is an acceptable alternative if parenteral artesunate is not available. Parenteral antimalarials should be administered for a minimum of 24 h in the treatment of severe malaria, irrespective of the patient's ability to tolerate oral medication earlier. Thereafter, it is recommended to complete treatment by giving a complete course of any of the following: * an ACT * artesunate plus clindamycin or doxycycline; * quinine plus clindamycin or doxycycline.


''Vivax'' malaria

Chloroquine Chloroquine is a medication primarily used to prevent and treat malaria in areas where malaria remains sensitive to its effects. Certain types of malaria, resistant strains, and complicated cases typically require different or additional medi ...
remains the treatment of choice for ''vivax'' malaria, except in Indonesia's Irian Jaya (
Western New Guinea Western New Guinea, also known as Papua, Indonesian New Guinea, or Indonesian Papua, is the western half of the Melanesian island of New Guinea which is administered by Indonesia. Since the island is alternatively named as Papua, the region ...
) region and the geographically contiguous
Papua New Guinea Papua New Guinea (abbreviated PNG; , ; tpi, Papua Niugini; ho, Papua Niu Gini), officially the Independent State of Papua New Guinea ( tpi, Independen Stet bilong Papua Niugini; ho, Independen Stet bilong Papua Niu Gini), is a country i ...
, where chloroquine resistance is common (up to 20% resistance).


Malaria in poultry

No medications are approved in the
United States The United States of America (U.S.A. or USA), commonly known as the United States (U.S. or US) or America, is a country primarily located in North America. It consists of 50 U.S. state, states, a Washington, D.C., federal district, five ma ...
for treatment of malaria in
poultry Poultry () are domesticated birds kept by humans for their eggs, their meat or their feathers. These birds are most typically members of the superorder Galloanserae (fowl), especially the order Galliformes (which includes chickens, quail ...
.


See also

* '' Diospyros melanoxylon'', tree with possible antiplasmodial properties * Malaria prophylaxis * Medicines for Malaria Venture (MMV) – a not-for-profit organization which is managing the largest–ever portfolio of over 50 antimalarial projects in collaboration with over 100 pharmaceutical, academic, and endemic-country partners in 38 countries. *
Amazon Malaria Initiative The Amazon Malaria Initiative (AMI) is a regional program that was created in 2001 by several countries sharing the Amazon basin with technical support from PAHO/WHO and financial support from the U.S. Agency for International Development (USAID), a ...
– a regional USAID project in 11 countries in the Latin America and the Caribbean region. * RAVREDA – a regional network of national malaria control programs that conduct antimalarial drug efficacy surveillance and other activities to address malaria. * Project 523


References


Further reading

* *


External links

* Medicines for Malaria Venture (MMV
[MMV] " MMV Science "
– for information on the largest–ever portfolio of over 50 antimalarial projects, working in collaboration with over 100 pharmaceutical, academic, and endemic-country partners in 38 countries. * Th
Worldwide Antimalarial Resistance Network (WWARN)
is a global collaboration generating quality-assured, timely information to track the emergence and spread of antimalarial resistance — critical information for ensuring that anyone infected with malaria receives safe and effective treatment. * 2007 guidelines are available from th

website as a PDF file and includes detailed country-specific information for UK travelers. * Th
World Health Organization
provides country-specific advice on malaria prevention. HPA and WHO advice are broadly in line with each other (although there are some differences). * Th
Centers for Disease Control and Prevention
website hosts constantly updated country-specific information on malaria. The advice on this website is less detailed, is very cautious and may not be appropriate for all areas within a given country. This is the preferred site for travelers from the US. {{Portal bar , Medicine *