Antimalarial drug
Encyclopedia
Antimalarial medications, also known as antimalarials, are designed to prevent or cure malaria
. Such drugs may be used for some or all of the following:
Some antimalarial agents, particularly chloroquine
and hydroxychloroquine
, are also used in the treatment of rheumatoid arthritis
and lupus
-associated arthritis.
Current practice in treating cases of malaria is based around the concept of combination therapy
, since this offers several advantages - reduced risk of treatment failure, reduced risk of developing resistance, enhanced convenience and reduced side-effects. Prompt parasitological confirmation by microscopy or alternatively by RDTs is recommended in all patients suspected of malaria before treatment is started. Treatment solely on the basis of clinical suspicion should only be considered when a parasitological diagnosis is not accessible.
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 vacuole
s 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 20 mg/kg first times and 10 mg/kg 8 hr for 5days where parasites are sensitive to quinine, 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 eighth 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
.
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.
Warburg's Tincture
was a febrifuge developed by Dr Carl Warburg
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.
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 Africa
n 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 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 acid
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
s 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, 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 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. 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, itch
ing can occur at intolerable level and Chloroquinine can be a provocation factor of psoriasis
.
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
) and is among the artemisinin-combination therapies recommended by the World Health Organisation. Combination with sulfadoxine=pyrimethamine is no longer recommended (WHO guidelines 2010).
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.
is used in the treatment of uncomplicated malaria. It is particularly useful in cases of chloroquine-resistant P. falciparum strains when combined with sulfadoxine
. It acts by inhibiting dihydrofolate reductase
in the parasite thus preventing the biosynthesis of purine
s and pyrimidine
s, thereby halting the processes of DNA synthesis
, cell division
and reproduction. It acts primarily on the schizonts during the erythrocytic phase, and nowadays is only used in concert with a sulfonamide
.
(chloroguanide) 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 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. 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
.
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.
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. 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 Adminstration (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 and anxiety disorder
s, 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.
is only available in combination with proguanil under the name Malarone, albeit at a price higher than Lariam. It is commonly used in prophylaxis
by travellers and used to treat falciparum malaria in developed countries.
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 block oxidative metabolism in Plasmodia.
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 it 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.
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). 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 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 behaviors associated with the development of resistance. It is also only given in combination with other anti-malarials.
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, 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
is a relative of halofantrine that is used in some combination antimalarial regimens.
is a tetracycline 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 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 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.
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.
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 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 evolution
ary 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-therapy. Resistance is thought to originate from a single-point mutation in the gene coding for cytochrome-b.
The most influential causes are examined below:
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 with current chemotherapy, thereby reducing the chance of vaccine resistance developing.
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.
According to WHO guidelines 2010, artemisinin-based combination therapies should be used in preference to amodiaquine plus sulfadoxine-pyrimethamine for the treatment of uncomplicated P. falciparum malaria.
-dapsone
and artesunate (CDA) appears efficacious but the problem of haemolysis in patients with glucose-6-phosphate dehydrogenase
(G6PD) deficiency is likely to prevent widespread use.
, primaquine
and tetracyclines. 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 (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:
remains the treatment of choice for vivax malaria, except in Indonesia's Iranian Jaya (Western New Guinea
) region and the geographically contiguous Papua New Guinea, where chloroquine resistance is common (up to 20% resistance).
Malaria
Malaria is a mosquito-borne infectious disease of humans and other animals caused by eukaryotic protists of the genus Plasmodium. The disease results from the multiplication of Plasmodium parasites within red blood cells, causing symptoms that typically include fever and headache, in severe cases...
. Such drugs may be used for some or all of the following:
- Treatment of malaria in individuals with suspected or confirmed infection
- Prevention of infection in individuals visiting a malaria-endemic region who have no immunity (Malaria prophylaxisMalaria prophylaxisMalaria prophylaxis is a preventative treatment of malaria.Most adults from endemic areas have a degree of long-term infection, which tends to recur, and also possess partial immunity ; the resistance reduces with time, and such adults may become susceptible to severe malaria if they have spent a...
) - Routine intermittent treatment of certain groups in endemic regions (Intermittent preventive therapyIntermittent preventive therapyIntermittent preventive therapy is a public health intervention aimed at treating and preventing malaria episodes in infants , children , schoolchildren and pregnant women...
)
Some antimalarial agents, particularly chloroquine
Chloroquine
Chloroquine is a 4-aminoquinoline drug used in the treatment or prevention of malaria.-History:Chloroquine , N'--N,N-diethyl-pentane-1,4-diamine, was discovered in 1934 by Hans Andersag and co-workers at the Bayer laboratories who named it "Resochin". It was ignored for a decade because it was...
and hydroxychloroquine
Hydroxychloroquine
Hydroxychloroquine is an antimalarial drug, sold under the trade names Plaquenil,Axemal, Dolquine, and Quensyl, also used to reduce inflammation in the treatment of rheumatoid arthritis and lupus...
, are also used in the treatment of rheumatoid arthritis
Rheumatoid arthritis
Rheumatoid arthritis is a chronic, systemic inflammatory disorder that may affect many tissues and organs, but principally attacks synovial joints. The process produces an inflammatory response of the synovium secondary to hyperplasia of synovial cells, excess synovial fluid, and the development...
and lupus
Lupus erythematosus
Lupus erythematosus is a category for a collection of diseases with similar underlying problems with immunity . Symptoms of these diseases can affect many different body systems, including joints, skin, kidneys, blood cells, heart, and lungs...
-associated arthritis.
Current practice in treating cases of malaria is based around the concept of combination therapy
Combination therapy
Combination therapy or polytherapy is the use of more than one medication or other therapy. In contrast, monotherapy is any therapy which is taken by itself....
, since this offers several advantages - reduced risk of treatment failure, reduced risk of developing resistance, enhanced convenience and reduced side-effects. Prompt parasitological confirmation by microscopy or alternatively by RDTs is recommended in all patients suspected of malaria before treatment is started. Treatment solely on the basis of clinical suspicion should only be considered when a parasitological diagnosis is not accessible.
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
QuinineQuinine
Quinine is a natural white crystalline alkaloid having antipyretic , antimalarial, analgesic , anti-inflammatory properties and a bitter taste. It is a stereoisomer of quinidine which, unlike quinine, is an anti-arrhythmic...
has a long history stretching from Peru
Peru
Peru , officially the Republic of Peru , is a country in western South America. It is bordered on the north by Ecuador and Colombia, on the east by Brazil, on the southeast by Bolivia, on the south by Chile, and on the west by the Pacific Ocean....
, and the discovery of the cinchona
Cinchona
Cinchona or Quina is a genus of about 38 species in the family Rubiaceae, native to tropical South America. They are large shrubs or small trees growing 5–15 metres in height with evergreen foliage. The leaves are opposite, rounded to lanceolate and 10–40 cm long. The flowers are white, pink...
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
Alkaloid
Alkaloids are a group of naturally occurring chemical compounds that contain mostly basic nitrogen atoms. This group also includes some related compounds with neutral and even weakly acidic properties. Also some synthetic compounds of similar structure are attributed to alkaloids...
that acts as a blood schizonticidal and weak gametocide
Gamete
A gamete is a cell that fuses with another cell during fertilization in organisms that reproduce sexually...
against Plasmodium vivax
Plasmodium vivax
Plasmodium vivax is a protozoal parasite and a human pathogen. The most frequent and widely distributed cause of recurring malaria, P. vivax is one of the four species of malarial parasite that commonly infect humans. It is less virulent than Plasmodium falciparum, which is the deadliest of the...
and Plasmodium malariae
Plasmodium malariae
Plasmodium malariae is a parasitic protozoa that causes malaria in humans. It is closely related to Plasmodium falciparum and Plasmodium vivax which are responsible for most malarial infection. While found worldwide, it is a so-called "benign malaria" and is not nearly as dangerous as that...
. As an alkaloid, it is accumulated in the food vacuole
Vacuole
A vacuole is a membrane-bound organelle which is present in all 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 molecules including enzymes in solution, though in certain...
s of Plasmodium species, especially Plasmodium falciparum
Plasmodium falciparum
Plasmodium falciparum is a protozoan parasite, one of the species of Plasmodium that cause malaria in humans. It is transmitted by the female Anopheles mosquito. Malaria caused by this species is the most dangerous form of malaria, with the highest rates of complications and mortality...
. It acts by inhibiting the hemozoin
Hemozoin
Hemozoin is a disposal product formed from the digestion of blood by some blood-feeding parasites. These hematophagous organisms such as Malaria parasites , Rhodnius and Schistosoma digest hemoglobin and release high quantities of free heme, which is the non-protein component of hemoglobin...
biocrystallization
Biocrystallization
Biocrystallization is the formation of crystals from organic macromolecules by living organisms. This may be a stress response, a normal part of metabolism such as processes that dispose of waste compounds, or a pathology. Template mediated crystallization is qualitatively different from in vitro...
, thus facilitating an aggregation of cytotoxic heme. Quinine is less effective and more toxic as a blood schizonticidal agent than chloroquine
Chloroquine
Chloroquine is a 4-aminoquinoline drug used in the treatment or prevention of malaria.-History:Chloroquine , N'--N,N-diethyl-pentane-1,4-diamine, was discovered in 1934 by Hans Andersag and co-workers at the Bayer laboratories who named it "Resochin". It was ignored for a decade because it was...
; 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
Mefloquine
Mefloquine hydrochloride is an orally administered medication used in the prevention and treatment of malaria. Mefloquine was developed in the 1970s at the United States Department of Defense's Walter Reed Army Institute of Research as a synthetic analogue of quinine...
, and sulfa drug combinations with pyrimethamine
Pyrimethamine
Pyrimethamine is a medication used for protozoal infections. It is commonly used as an antimalarial drug , and is also used in the treatment of Toxoplasma gondii infections in immunocompromised patients, such as HIV-positive individuals.-Mechanism of action:Pyrimethamine interferes with...
. Quinine is also used in post-exposure treatment of individuals returning from an area where malaria is endemic
Endemic (epidemiology)
In epidemiology, an infection is said to be endemic in a population when that infection is maintained in the population without the need for external inputs. For example, chickenpox is endemic in the UK, but malaria is not...
.
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
World Health Organization
The World Health Organization is a specialized agency of the United Nations that acts as a coordinating authority on international public health. Established on 7 April 1948, with headquarters in Geneva, Switzerland, the agency inherited the mandate and resources of its predecessor, the Health...
recommendation for quinine is 20 mg/kg first times and 10 mg/kg 8 hr for 5days where parasites are sensitive to quinine, combined with doxycycline
Doxycycline
Doxycycline INN is a member of the tetracycline antibiotics group, and is commonly used to treat a variety of infections. Doxycycline is a semisynthetic tetracycline invented and clinically developed in the early 1960s by Pfizer Inc. and marketed under the brand name Vibramycin. Vibramycin...
, tetracycline or clindamycin
Clindamycin
Clindamycin rINN is a lincosamide antibiotic. It is usually used to treat infections with anaerobic bacteria but can also be used to treat some protozoal diseases, such as malaria...
. 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
Cinchonism
Cinchonism or quinism is a pathological condition in humans caused by an overdose of quinine or its natural source, cinchona bark. Quinine is medically used to treat malaria. In much smaller amounts, quinine is an ingredient of tonic drinks, acting as a bittering agent...
. Tinnitus
Tinnitus
Tinnitus |ringing]]") is the perception of sound within the human ear in the absence of corresponding external sound.Tinnitus is not a disease, but a symptom that can result from a wide range of underlying causes: abnormally loud sounds in the ear canal for even the briefest period , ear...
(a hearing impairment), rashes, vertigo
Vertigo (medical)
Vertigo is a type of dizziness, where there is a feeling of motion when one is stationary. The symptoms are due to a dysfunction of the vestibular system in the inner ear...
, 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
Motor neuron
In vertebrates, the term motor neuron classically applies to neurons located in the central nervous system that project their axons outside the CNS and directly or indirectly control muscles...
end plates. This often results in functional impairment of the eighth cranial nerve
Vestibulocochlear nerve
The vestibulocochlear nerve is the eighth of twelve cranial nerves, and is responsible for transmitting sound and equilibrium information from the inner ear to the brain...
, resulting in confusion, delirium
Delirium
Delirium or acute confusional state is a common and severe neuropsychiatric syndrome with core features of acute onset and fluctuating course, attentional deficits and generalized severe disorganization of behavior...
and coma. Quinine can cause hypoglycaemia through its action of stimulating insulin
Insulin
Insulin is a hormone central to regulating carbohydrate and fat metabolism in the body. Insulin causes cells in the liver, muscle, and fat tissue to take up glucose from the blood, storing it as glycogen in the liver and muscle....
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
Renal failure
Renal failure or kidney failure describes a medical condition in which the kidneys fail to adequately filter toxins and waste products from the blood...
and death through depression of the respiratory system
Respiratory system
The respiratory system is the anatomical system of an organism that introduces respiratory gases to the interior and performs gas exchange. In humans and other mammals, the anatomical features of the respiratory system include airways, lungs, and the respiratory muscles...
.
Quinimax and quinidine
Quinidine
Quinidine is a pharmaceutical agent that acts as a class I antiarrhythmic agent in the heart. It is a stereoisomer of quinine, originally derived from the bark of the cinchona tree.-Mechanism:...
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.
Warburg's Tincture
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 considered, by some, to be superior to quinine.Warburg's...
was a febrifuge developed by Dr Carl Warburg
Carl Warburg
Carl Warburg, also known as Charles Warburg, was a physician, clinical pharmacologist, pharmaceutical chemist, botanist and manufacturer...
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
Martindale: The complete drug reference
Martindale: The Complete Drug Reference is a reference book published by Pharmaceutical Press listing some 6,000 drugs and medicines used throughout the world, including details of over 161,000 proprietary preparations. It also includes 675 disease treatment reviews...
from 1883 until about 1920. The formula was published in The Lancet 1875.
Chloroquine
ChloroquineChloroquine
Chloroquine is a 4-aminoquinoline drug used in the treatment or prevention of malaria.-History:Chloroquine , N'--N,N-diethyl-pentane-1,4-diamine, was discovered in 1934 by Hans Andersag and co-workers at the Bayer laboratories who named it "Resochin". It was ignored for a decade because it was...
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 Africa
Sub-Saharan Africa
Sub-Saharan Africa as a geographical term refers to the area of the African continent which lies south of the Sahara. A political definition of Sub-Saharan Africa, instead, covers all African countries which are fully or partially located south of the Sahara...
n 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 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
PH
In chemistry, pH is a measure of the acidity or basicity of an aqueous solution. Pure water is said to be neutral, with a pH close to 7.0 at . Solutions with a pH less than 7 are said to be acidic and solutions with a pH greater than 7 are basic or alkaline...
. It controls the conversion of toxic heme
Heme
A heme or haem is a prosthetic group that consists of an iron atom contained in the center of a large heterocyclic organic ring called a porphyrin. Not all porphyrins contain iron, but a substantial fraction of porphyrin-containing metalloproteins have heme as their prosthetic group; these are...
to hemozoin
Hemozoin
Hemozoin is a disposal product formed from the digestion of blood by some blood-feeding parasites. These hematophagous organisms such as Malaria parasites , Rhodnius and Schistosoma digest hemoglobin and release high quantities of free heme, which is the non-protein component of hemoglobin...
by inhibiting the biocrystallization
Biocrystallization
Biocrystallization is the formation of crystals from organic macromolecules by living organisms. This may be a stress response, a normal part of metabolism such as processes that dispose of waste compounds, or a pathology. Template mediated crystallization is qualitatively different from in vitro...
of hemozoin
Hemozoin
Hemozoin is a disposal product formed from the digestion of blood by some blood-feeding parasites. These hematophagous organisms such as Malaria parasites , Rhodnius and Schistosoma digest hemoglobin and release high quantities of free heme, which is the non-protein component of hemoglobin...
, 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 acid
Nucleic acids are biological molecules essential for life, and include DNA and RNA . Together with proteins, nucleic acids make up the most important macromolecules; each is found in abundance in all living things, where they function in encoding, transmitting and expressing genetic information...
s and the formation of a chloroquine-haem or chloroquine-DNA
DNA
Deoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...
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
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....
s of P. vivax, P. malariae, P. ovale
Plasmodium ovale
Plasmodium ovale is a species of parasitic protozoa that causes tertian malaria in humans. It is closely related to Plasmodium falciparum and Plasmodium vivax, which are responsible for most malaria. It is rare compared to these two parasites, and substantially less dangerous than P...
as well as the immature gametocytes of P. falciparum. Chloroquine also has a significant anti-pyretic and anti-inflammatory
Anti-inflammatory
Anti-inflammatory refers to the property of a substance or treatment that reduces inflammation. Anti-inflammatory drugs make up about half of analgesics, remedying pain by reducing inflammation as opposed to opioids, which affect the central nervous system....
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 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
Chemoprophylaxis
Chemoprophylaxis refers to the administration of a medication for the purpose of preventing disease or infection. Antibiotics, for example, may be administered to patients with disorders of immune system function to prevent bacterial infections...
: 5 mg/kg/week (single dose) or 10 mg/kg/week divided into 6 daily doses is advised. Chloroquine is only recommended as a prophylactic drug
Malaria prophylaxis
Malaria prophylaxis is a preventative treatment of malaria.Most adults from endemic areas have a degree of long-term infection, which tends to recur, and also possess partial immunity ; the resistance reduces with time, and such adults may become susceptible to severe malaria if they have spent a...
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
Abortifacient
An abortifacient is a substance that induces abortion. Abortifacients for animals that have mated undesirably are known as mismating shots....
or teratogenic effects have been reported during this time; therefore, it is considered very safe to use during pregnancy. However, itch
Itch
Itch is a sensation that causes the desire or reflex to scratch. Itch has resisted many attempts to classify it as any one type of sensory experience. Modern science has shown that itch has many similarities to pain, and while both are unpleasant sensory experiences, their behavioral response...
ing can occur at intolerable level and Chloroquinine can be a provocation factor of psoriasis
Psoriasis
Psoriasis is an autoimmune disease that appears on the skin. It occurs when the immune system mistakes the skin cells as a pathogen, and sends out faulty signals that speed up the growth cycle of skin cells. Psoriasis is not contagious. However, psoriasis has been linked to an increased risk of...
.
Amodiaquine
AmodiaquineAmodiaquine
Amodiaquine is a 4-aminoquinoline compound related to chloroquine, used as an antimalarial and anti-inflammatory agent....
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
ASAQ
ASAQ is a medication launched in 2007-03-01 which is a pharmaceutical formula combining artesunate and amodiaquine for an affordable treatment of malaria, devised by DNDi in partnership with Sanofi-Aventis. The drug is patent free as well....
) and is among the artemisinin-combination therapies recommended by the World Health Organisation. Combination with sulfadoxine=pyrimethamine is no longer recommended (WHO guidelines 2010).
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
Bradycardia
Bradycardia , in the context of adult medicine, is the resting heart rate of under 60 beats per minute, though it is seldom symptomatic until the rate drops below 50 beat/min. It may cause cardiac arrest in some patients, because those with bradycardia may not be pumping enough oxygen to their heart...
, 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
PyrimethaminePyrimethamine
Pyrimethamine is a medication used for protozoal infections. It is commonly used as an antimalarial drug , and is also used in the treatment of Toxoplasma gondii infections in immunocompromised patients, such as HIV-positive individuals.-Mechanism of action:Pyrimethamine interferes with...
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
Sulfadoxine is an ultra-long-lasting sulfonamide often used in combination with pyrimethamine to treat or prevent malaria....
. It acts by inhibiting dihydrofolate reductase
Dihydrofolate reductase
- Function :Dihydrofolate reductase converts dihydrofolate into tetrahydrofolate, a methyl group shuttle required for the de novo synthesis of purines, thymidylic acid, and certain amino acids...
in the parasite thus preventing the biosynthesis of purine
Purine
A purine is a heterocyclic aromatic organic compound, consisting of a pyrimidine ring fused to an imidazole ring. Purines, including substituted purines and their tautomers, are the most widely distributed kind of nitrogen-containing heterocycle in nature....
s and pyrimidine
Pyrimidine
Pyrimidine is a heterocyclic aromatic organic compound similar to benzene and pyridine, containing two nitrogen atoms at positions 1 and 3 of the six-member ring...
s, thereby halting the processes of DNA synthesis
DNA synthesis
DNA synthesis commonly refers to:*DNA replication - DNA biosynthesis *Polymerase chain reaction - enzymatic DNA synthesis *Oligonucleotide synthesis - chemical synthesis of nucleic acids...
, cell division
Cell division
Cell division is the process by which a parent cell divides into two or more daughter cells . Cell division is usually a small segment of a larger cell cycle. This type of cell division in eukaryotes is known as mitosis, and leaves the daughter cell capable of dividing again. The corresponding sort...
and reproduction. It acts primarily on the schizonts during the erythrocytic phase, and nowadays is only used in concert with a sulfonamide
Sulfonamide
Sulfonamide or sulphonamide may refer to:*Sulfonamide – the sulfonamide functional group. *Sulfonamide – the group of sulfonamide antibacterial drugs....
.
Proguanil
ProguanilProguanil
Proguanil is a prophylactic antimalarial drug.Proguanil is effective against sporozoites.Proguanil hydrochloride is marketed as Paludrine by AstraZeneca.-Mechanism:...
(chloroguanide) is a biguanide
Biguanide
Biguanide can refer to a molecule, or to a class of drugs based upon this molecule. Biguanides can function as oral antihyperglycemic drugs used for diabetes mellitus or prediabetes treatment...
; 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
Metabolite
Metabolites are the intermediates and products of metabolism. The term metabolite is usually restricted to small molecules. A primary metabolite is directly involved in normal growth, development, and reproduction. Alcohol is an example of a primary metabolite produced in large-scale by industrial...
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 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
Malaria prophylaxis
Malaria prophylaxis is a preventative treatment of malaria.Most adults from endemic areas have a degree of long-term infection, which tends to recur, and also possess partial immunity ; the resistance reduces with time, and such adults may become susceptible to severe malaria if they have spent a...
when combined with atovaquone
Atovaquone
Atovaquone is a chemical compound that belongs to the class of naphthalenes. Atovaquone is a hydroxy-1,4-naphthoquinone, an analog of ubiquinone, with antipneumocystic activity. Its average wholesale price is about US$2.13 per standard 250 mg. tablet...
or chloroquine
Chloroquine
Chloroquine is a 4-aminoquinoline drug used in the treatment or prevention of malaria.-History:Chloroquine , N'--N,N-diethyl-pentane-1,4-diamine, was discovered in 1934 by Hans Andersag and co-workers at the Bayer laboratories who named it "Resochin". It was ignored for a decade because it was...
(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
Blood plasma
Blood plasma is the straw-colored liquid component of blood in which the blood cells in whole blood are normally suspended. It makes up about 55% of the total blood volume. It is the intravascular fluid part of extracellular fluid...
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
AstraZeneca plc is a global pharmaceutical and biologics company headquartered in London, United Kingdom. It is the world's seventh-largest pharmaceutical company measured by revenues and has operations in over 100 countries...
.
Sulfonamides
SulfadoxineSulfadoxine
Sulfadoxine is an ultra-long-lasting sulfonamide often used in combination with pyrimethamine to treat or prevent malaria....
and sulfamethoxypyridazine
Sulfamethoxypyridazine
Sulfamethoxypyridazine is a sulfonamide antibacterial.It is prescribed for vaginal irritation, and severe acute thrush....
are specific inhibitors of the enzyme dihydropteroate synthetase
Dihydropteroate synthetase
Dihydropteroate synthetase is an enzyme classified under . It produces dihydropteroate in bacteria, but it is not expressed in most eukaryotes including humans...
in the tetrahydrofolate synthesis pathway of malaria parasites. They are structural analogs of p-aminobenzoic acid
4-Aminobenzoic acid
4-Aminobenzoic acid is an organic compound with the formula H2NC6H4CO2H. PABA is a white grey crystalline substance that is only slightly soluble in water...
(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
Pyrimethamine
Pyrimethamine is a medication used for protozoal infections. It is commonly used as an antimalarial drug , and is also used in the treatment of Toxoplasma gondii infections in immunocompromised patients, such as HIV-positive individuals.-Mechanism of action:Pyrimethamine interferes with...
, most commonly as fixed-dose sulfadoxine-pyrimethamine (Fansidar), produces synergistic
Synergism
In theology, synergism is the position of those who hold that salvation involves some form of cooperation between divine grace and human freedom...
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
MefloquineMefloquine
Mefloquine hydrochloride is an orally administered medication used in the prevention and treatment of malaria. Mefloquine was developed in the 1970s at the United States Department of Defense's Walter Reed Army Institute of Research as a synthetic analogue of quinine...
was developed during the Vietnam War
Vietnam War
The Vietnam War was a Cold War-era military conflict that occurred in Vietnam, Laos, and Cambodia from 1 November 1955 to the fall of Saigon on 30 April 1975. This war followed the First Indochina War and was fought between North Vietnam, supported by its communist allies, and the government of...
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
Half-life, abbreviated t½, is the period of time it takes for the amount of a substance undergoing decay to decrease by half. The name was originally used to describe a characteristic of unstable atoms , but it may apply to any quantity which follows a set-rate decay.The original term, dating to...
. 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
Malaria prophylaxis
Malaria prophylaxis is a preventative treatment of malaria.Most adults from endemic areas have a degree of long-term infection, which tends to recur, and also possess partial immunity ; the resistance reduces with time, and such adults may become susceptible to severe malaria if they have spent a...
and for acute therapy. It is now strictly used for resistant strains (and is usually combined with Artesunate
Artesunate
Artesunate 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...
). 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. 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 Adminstration (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 and anxiety disorder
Anxiety disorder
Anxiety disorder is a blanket term covering several different forms of abnormal and pathological fear and anxiety. Conditions now considered anxiety disorders only came under the aegis of psychiatry at the end of the 19th century. Gelder, Mayou & Geddes explains that anxiety disorders are...
s, hallucinations, sleep disturbances, psychosis
Psychosis
Psychosis means abnormal condition of the mind, and is a generic psychiatric term for a mental state often described as involving a "loss of contact with reality"...
, toxic encephalopathy
Toxic encephalopathy
* Baker, E. . Chronic toxic encephalopathy caused by occupational solvent exposure. Annals of Neurology. 63: 545-547- External links :*****...
, convulsions and delirium
Delirium
Delirium or acute confusional state is a common and severe neuropsychiatric syndrome with core features of acute onset and fluctuating course, attentional deficits and generalized severe disorganization of behavior...
. 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.
Atovaquone
AtovaquoneAtovaquone
Atovaquone is a chemical compound that belongs to the class of naphthalenes. Atovaquone is a hydroxy-1,4-naphthoquinone, an analog of ubiquinone, with antipneumocystic activity. Its average wholesale price is about US$2.13 per standard 250 mg. tablet...
is only available in combination with proguanil under the name Malarone, albeit at a price higher than Lariam. It is commonly used in prophylaxis
Malaria prophylaxis
Malaria prophylaxis is a preventative treatment of malaria.Most adults from endemic areas have a degree of long-term infection, which tends to recur, and also possess partial immunity ; the resistance reduces with time, and such adults may become susceptible to severe malaria if they have spent a...
by travellers and used to treat falciparum malaria in developed countries.
Primaquine
PrimaquinePrimaquine
Primaquine is a medication used in the treatment of malaria and Pneumocystis pneumonia. It is a member of the 8-aminoquinoline group of drugs that includes tafenoquine and pamaquine.-Radical cure:...
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 block oxidative metabolism in Plasmodia.
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 it has been shown that primaquine may cause anorexia
Anorexia (symptom)
Anorexia is the decreased sensation of appetite...
, nausea, vomiting, cramps, chest weakness, anaemia, some suppression of myeloid
Myeloid
The term myeloid suggests an origin in the bone marrow or spinal cord, or a resemblance to the marrow or spinal cord.In hematopoiesis, the term "myeloid cell" is used to describe any leukocyte that is not a lymphocyte...
activity and abdominal pains. In cases of over-dosage granulocytopenia may occur.
Artemisinin and derivatives
ArtemisininArtemisinin
Artemisinin , also known as Qinghaosu , and its derivatives are a group of drugs that possess the most rapid action of all current drugs against falciparum malaria. Treatments containing an artemisinin derivative are now standard treatment worldwide for falciparum malaria...
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
Artemisia annua
Artemisia annua, also known as Sweet Wormwood, Sweet Annie, Sweet Sagewort or Annual Wormwood , is a common type of wormwood that is native to temperate Asia, but naturalized throughout the world.-Characteristics:...
, with the first documentation as a successful therapeutic agent in the treatment of malaria is in 340 AD by Ge Hong
Ge Hong
Ge Hong , courtesy name Zhichuan , was a minor southern official during the Jìn Dynasty of China, best known for his interest in Daoism, alchemy, and techniques of longevity...
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 artemsinin. It is a sesquiterpene lactone
Sesquiterpene lactone
Sesquiterpene lactones are a class of chemical compounds; they are sesquiterpenoids and contain a lactone ring, hence the name....
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 behaviors associated with the development of resistance. It is also only given in combination with other anti-malarials.
- ArtemisininArtemisininArtemisinin , also known as Qinghaosu , and its derivatives are a group of drugs that possess the most rapid action of all current drugs against falciparum malaria. Treatments containing an artemisinin derivative are now standard treatment worldwide for falciparum malaria...
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 blockAtrioventricular blockAn atrioventricular block involves the impairment of the conduction between the atria and ventricles of the heart.The causes of pathological AV block are varied and include ischaemia, infarction, fibrosis or drugs. Certain AV blocks can also be found as normal variants, such as in athletes or...
(these disappeared when the patients recovered from the malarial fever).
- ArtemetherArtemetherArtemether is an antimalarial for the treatment of multi-drug resistant strains of falciparum malaria. It is combined with Lumefantrine and sold by Novartis under the brand names Riamet and Co-Artem.-Chemical nature:...
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. - ArtesunateArtesunateArtesunate 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...
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 remaining 2 or 4 days. In large studies carried out on over 10,000 patients in Thailand no adverse effects have been shown. - DihydroartemisininDihydroartemisininDihydroartemisinin is a drug used to treat malaria. Dihydroartemisinin is the active metabolite of all artemisinin compounds and is also available as a drug in itself...
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 parenteralParenteralParenteral is a route of administration that involves piercing the skin or mucous membrane. Parenteral nutrition refers to providing nutrition via the veins.-Etymology:...
administration no side effects have been recorded.
Halofantrine
HalofantrineHalofantrine
Halofantrine is a drug used to treat malaria. Halofantrine's structure contains a substituted phenanthrene, and is related to the antimalarial drugs quinine and lumefantrine. Marketed as Halfan, halofantrine is never used to prevent malaria and its mode of action is unknown...
is a relatively new drug developed by the Walter Reed Army Institute of Research
Walter Reed Army Institute of Research
This article is about the U.S. Army medical research institute . Otherwise, see Walter Reed .The Walter Reed Army Institute of Research is the largest biomedical research facility administered by the U.S. Department of Defense...
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, 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
Long QT syndrome
The long QT syndrome is a rare inborn heart condition in which delayed repolarization of the heart following a heartbeat increases the risk of episodes of torsade de pointes . These episodes may lead to palpitations, fainting and sudden death due to ventricular fibrillation...
. Halofantrine is not recommended for use in pregnancy and lactation, in small children, or in patients that have taken mefloquine previously. Lumefantrine
Lumefantrine
Lumefantrine is an antimalarial drug. It is only used in combination with artemether. The term "co-artemether" is sometimes used to describe this combination....
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, doxycyclineDoxycycline
Doxycycline INN is a member of the tetracycline antibiotics group, and is commonly used to treat a variety of infections. Doxycycline is a semisynthetic tetracycline invented and clinically developed in the early 1960s by Pfizer Inc. and marketed under the brand name Vibramycin. Vibramycin...
is a tetracycline compound derived from oxytetracycline
Oxytetracycline
Oxytetracycline was the second of the broad-spectrum tetracycline group of antibiotics to be discovered.Oxytetracycline works by interfering with the ability of bacteria to produce proteins that are essential to them. Without these proteins the bacteria cannot grow, multiply and increase in numbers...
. 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 by binding to the 30S
30S
30S is the smaller subunit of the 70S ribosome of prokaryotes. It is a complex of ribosomal RNA and ribonucleoproteins that functions in mRNA translation...
ribosomal
Ribosome
A ribosome is a component of cells that assembles the twenty specific amino acid molecules to form the particular protein molecule determined by the nucleotide sequence of an RNA molecule....
subunit thus preventing the 50s and 30s units from bonding. Doxycycline is used primarily for chemoprophylaxis
Malaria prophylaxis
Malaria prophylaxis is a preventative treatment of malaria.Most adults from endemic areas have a degree of long-term infection, which tends to recur, and also possess partial immunity ; the resistance reduces with time, and such adults may become susceptible to severe malaria if they have spent a...
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 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
Photosensitivity
Photosensitivity is the amount to which an object reacts upon receiving photons, especially visible light.- Human medicine :Sensitivity of the skin to a light source can take various forms. People with particular skin types are more sensitive to sunburn...
. 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
Ossification
Ossification is the process of laying down new bone material by cells called osteoblasts. It is synonymous with bone tissue formation...
and depression of bone growth are known to occur. The majority of side effects associated with doxycycline are also experienced.
Clindamycin
ClindamycinClindamycin
Clindamycin rINN is a lincosamide antibiotic. It is usually used to treat infections with anaerobic bacteria but can also be used to treat some protozoal diseases, such as malaria...
is a derivative of lincomycin
Lincomycin
Lincomycin is a lincosamide antibiotic that comes from the actinomyces Streptomyces lincolnensis. It has been structurally modified by thionyl chloride to its more commonly known 7-chloro-7-deoxy derivative, clindamycin...
, 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
Pseudomembranous colitis
Pseudomembranous colitis, a cause of antibiotic-associated diarrhea , is an infection of the colon. It is often, but not always, caused by the bacterium Clostridium difficile. Because of this, the informal name C. difficile colitis is also commonly used. The illness is characterized by...
(caused by Clostridium difficile
Clostridium difficile
Clostridium difficile , also known as "CDF/cdf", or "C...
) has also developed in some patients; this condition may be fatal in a small number of cases.
Resistance
Antimalarial resistance is common.Anti-malarial drug resistance
Drug resistance
Drug resistance is the reduction in effectiveness of a drug such as an antimicrobial or an antineoplastic in curing a disease or condition. When the drug is not intended to kill or inhibit a pathogen, then the term is equivalent to dosage failure or drug tolerance. More commonly, the term is used...
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." 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
Animal model
An animal model is a living, non-human animal used during the research and investigation of human disease, for the purpose of better understanding the disease without the added risk of causing harm to an actual human being during the process...
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
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...
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 evolution
Evolution
Evolution is any change across successive generations in the heritable characteristics of biological populations. Evolutionary processes give rise to diversity at every level of biological organisation, including species, individual organisms and molecules such as DNA and proteins.Life on Earth...
ary benefit, thus giving an anti-malarial used a reduced level of sensitivity. This can be caused by a single point mutation
Point mutation
A point mutation, or single base substitution, is a type of mutation that causes the replacement of a single base nucleotide with another nucleotide of the genetic material, DNA or RNA. Often the term point mutation also includes insertions or deletions of a single base pair...
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
Antifolate
Antifolates are drugs that impair the function of folic acids. Many are used in cancer chemotherapy, some are used as antibiotics or antiprotozoal agents....
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
Atovaquone
Atovaquone is a chemical compound that belongs to the class of naphthalenes. Atovaquone is a hydroxy-1,4-naphthoquinone, an analog of ubiquinone, with antipneumocystic activity. Its average wholesale price is about US$2.13 per standard 250 mg. tablet...
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, pharmokinetics, and the biology of vectors 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 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 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.
- The resistance to anti-malarials may be increased by a process found in some species of plasmodium, where a degree of phenotypic plasticityPhenotypic plasticityPhenotypic plasticity is the ability of an organism to change its phenotype in response to changes in the environment. Such plasticity in some cases expresses as several highly morphologically distinct results; in other cases, a continuous norm of reaction describes the functional interrelationship...
was exhibited, allowing the rapid development of resistance to a new drug, even if the drug has not been previously experienced. - 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.
- 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.
- 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 pharmokinetic and dynamic properties.
Prevention
The prevention of anti-malarial drug resistance is of enormous public healthPublic 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" . It is concerned with threats to health based on population 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
Infrastructure
Infrastructure is basic physical and organizational structures needed for the operation of a society or enterprise, or the services and facilities necessary for an economy to function...
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
Malaria prophylaxis
Malaria prophylaxis is a preventative treatment of malaria.Most adults from endemic areas have a degree of long-term infection, which tends to recur, and also possess partial immunity ; the resistance reduces with time, and such adults may become susceptible to severe malaria if they have spent a...
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
Insecticide
An insecticide is a pesticide used against insects. They include ovicides and larvicides used against the eggs and larvae of insects respectively. Insecticides are used in agriculture, medicine, industry and the household. The use of insecticides is believed to be one of the major factors behind...
-treated bed nets, indoor residual spraying
Indoor residual spraying
Indoor residual spraying or IRS is the process of spraying the inside of dwellings with an insecticide to kill mosquitoes that spread malaria. A dilute solution of insecticide is sprayed on the inside walls of certain types of dwellings—those with walls made from porous materials such as mud or...
, 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
Malaria vaccine
Malaria vaccines are an area of intensive research. However, there is no effective vaccine that has been introduced into clinical practice.The global burden of P. falciparum malaria increased through the 1990s due to drug-resistant parasites and insecticide-resistant mosquitoes; this is illustrated...
. 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 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-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, causes few adverse effects, is cheap and effective in a single dose, thus decreasing problems associated with adherence and compliance. In technical terms Fansidar is not generally considered a true combination therapy since the components do not possess independent curative activity. Fansidar should no longer be used alone for treatment of falciparum malaria. | 25 mg/kg of sulfadoxine and 1.25 mg/kg of pyrimethamine. |
| SP plus chloroquine | High levels of resistance to one or both components means this combination is effective in few locations and it is no longer recommended by WHO World Health Organization The World Health Organization is a specialized agency of the United Nations that acts as a coordinating authority on international public health. Established on 7 April 1948, with headquarters in Geneva, Switzerland, the agency inherited the mandate and resources of its predecessor, the Health... guidelines. |
Chloroquine 25 mg/kg over 3 days with a single dose of SP as described above. |
| SP plus amodiaquine | This combination has been shown to produce a faster rate of clinical recovery than SP and chloroquine, but is clearly inferior to artemisinin-based combinations (ACTs) for the treatment of malaria. | 10 mg/kg of Amodiaquine per day for 3 days with a single standard dose of SP. |
| SP plus mefloquine (Fansimef) | This single dose pill offered obvious advantages of convenience over more complex regimes but it has not been recommended for use for many years owing to widespread resistance to the components. | |
| Quinine plus tetracycline/doxycycline | This combination retains a high cure rate in many areas. Problems with this regime include the relatively complicated drug regimen, where quinine must be taken every 8 hours for 7 days. Additionally, there are significant side effects with quinine ('cinchonism Cinchonism Cinchonism or quinism is a pathological condition in humans caused by an overdose of quinine or its natural source, cinchona bark. Quinine is medically used to treat malaria. In much smaller amounts, quinine is an ingredient of tonic drinks, acting as a bittering agent... ') and tetracyclines are contraindicated in children and pregnant women (these groups should use clindamycin instead). With the advent of artemisinin-combination therapies, quinine-based treatment is less popular than previously. |
Quinine 10 mg/kg doses every 8 hours and tetracycline in 4 mg/kg doses every 6 hours for 7 days. |
According to WHO guidelines 2010, 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), 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 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.| Components | Description | Dose |
|---|---|---|
| Artesunate and amodiaquine Amodiaquine Amodiaquine is a 4-aminoquinoline compound related to chloroquine, used as an antimalarial and anti-inflammatory agent.... (Coarsucam and ASAQ ASAQ ASAQ is a medication launched in 2007-03-01 which is a pharmaceutical formula combining artesunate and amodiaquine for an affordable treatment of malaria, devised by DNDi in partnership with Sanofi-Aventis. The drug is patent free as well.... ) |
This combination has been tested and proved to be efficacious in many areas where amodiaquine retains some efficacy. A potential disadvantage is a suggested link with neutropenia Neutropenia Neutropenia, from Latin prefix neutro- and Greek suffix -πενία , is a granulocyte disorder characterized by an abnormally low number of neutrophils, the most important type of white blood cell... . It's recommended by the WHO for uncomplicated falciparum malaria. |
Dosage is as a fixed-dose combination (ASAQ ASAQ ASAQ is a medication launched in 2007-03-01 which is a pharmaceutical formula combining artesunate and amodiaquine for an affordable treatment of malaria, devised by DNDi in partnership with Sanofi-Aventis. The drug is patent free as well.... ) recommended as 4 mg/kg of Artesunate and 10 mg/kg of Amodiaquine per day for 3 days. |
| Artesunate and mefloquine Mefloquine Mefloquine hydrochloride is an orally administered medication used in the prevention and treatment of malaria. Mefloquine was developed in the 1970s at the United States Department of Defense's Walter Reed Army Institute of Research as a synthetic analogue of quinine... (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 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. It's recommended by the WHO for uncomplicated falciparum malaria. | 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. |
| Artemether and lumefantrine Lumefantrine Lumefantrine is an antimalarial drug. It is only used in combination with artemether. The term "co-artemether" is sometimes used to describe this combination.... (Coartem Coartem The combination artemether/lumefantrine is an artemisinin-based combination therapy indicated for the treatment of acute uncomplicated plasmodium falciparum malaria. Coartem is produced by the Swiss pharmaceutical company, Novartis.Artemether is a derivative of artemisinin, and lumefantrine is... Riamet, Faverid, Amatem 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. It's recommended by the WHO for uncomplicated falciparum malaria. | |
| Artesunate and sulfadoxine Sulfadoxine Sulfadoxine is an ultra-long-lasting sulfonamide often used in combination with pyrimethamine to treat or prevent malaria.... /pyrimethamine Pyrimethamine Pyrimethamine is a medication used for protozoal infections. It is commonly used as an antimalarial drug , and is also used in the treatment of Toxoplasma gondii infections in immunocompromised patients, such as HIV-positive individuals.-Mechanism of action:Pyrimethamine interferes with... (Ariplus and Amalar plus) |
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 by the WHO for uncomplicated falciparum malaria. | 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. |
| Dihydroartemisinin Dihydroartemisinin Dihydroartemisinin is a drug used to treat malaria. Dihydroartemisinin is the active metabolite of all artemisinin compounds and is also available as a drug in itself... -piperaquine Piperaquine Piperaquine is an antimalarial drug, a bisquinoline first synthesised in the 1960s, and used extensively in China and Indochina as prophylaxis and treatment during the next 20 years. Usage declined in the 1980s as piperaquine-resistant strains of P. falciparum arose and artemisinin-based... (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%). It's recommended by the WHO for uncomplicated falciparum malaria. | |
| Pyronaridine Pyronaridine Pyronaridine is an antimalarial drug. It was first synthesized in 1970 and has been in clinical use in China since the 1980s.... and artesunate Artesunate Artesunate 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... (Pyramax) |
Manufactured by Shin Poong Pharmaceutical. Has been tested and demonstrated a clinical response rate of 100% in one trial in Hainan Hainan Hainan is the smallest province of the People's Republic of China . Although the province comprises some two hundred islands scattered among three archipelagos off the southern coast, of its land mass is Hainan Island , from which the province takes its name... (an area with high levels of P. falciparum resistance to Pyronaridine). A multi-centre phase III trial conducted in Africa found a 99.5% response rate. |
Other combinations
Several other anti-malarial combinations have been used or are in development. For example, ChlorproguanilChlorproguanil
Chlorproguanil is an antimalarial drug.-See also:* Proguanil* Chlorproguanil hydrochloride-dapsone-artesunate...
-dapsone
Dapsone
Dapsone is a medication most commonly used in combination with rifampicin and clofazimine as multidrug therapy for the treatment of Mycobacterium leprae infections . It is also second-line treatment for prophylaxis against Pneumocystis pneumonia caused by Pneumocystis jiroveci Dapsone...
and artesunate (CDA) appears efficacious but the problem of haemolysis in patients with glucose-6-phosphate dehydrogenase
Glucose-6-phosphate dehydrogenase
Glucose-6-phosphate dehydrogenase is a cytosolic enzyme in the pentose phosphate pathway , a metabolic pathway that supplies reducing energy to cells by maintaining the level of the co-enzyme nicotinamide adenine dinucleotide phosphate...
(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
According to WHO guidelines 2010, artemisinin-based combination therapies (ACTs) are the recommended antimalarial treatments for uncomplicated malaria caused by P. falciparum. 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 is quinine plus clindamycin to be given for 7 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 7 days, or quinine plus clindamycin to be given for 7 days. Lactating women should receive standard antimalarial treatment (including ACTs) except for dapsoneDapsone
Dapsone is a medication most commonly used in combination with rifampicin and clofazimine as multidrug therapy for the treatment of Mycobacterium leprae infections . It is also second-line treatment for prophylaxis against Pneumocystis pneumonia caused by Pneumocystis jiroveci Dapsone...
, primaquine
Primaquine
Primaquine is a medication used in the treatment of malaria and Pneumocystis pneumonia. It is a member of the 8-aminoquinoline group of drugs that includes tafenoquine and pamaquine.-Radical cure:...
and tetracyclines. 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 (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
ChloroquineChloroquine
Chloroquine is a 4-aminoquinoline drug used in the treatment or prevention of malaria.-History:Chloroquine , N'--N,N-diethyl-pentane-1,4-diamine, was discovered in 1934 by Hans Andersag and co-workers at the Bayer laboratories who named it "Resochin". It was ignored for a decade because it was...
remains the treatment of choice for vivax malaria, except in Indonesia's Iranian Jaya (Western New Guinea
Western New Guinea
West Papua informally refers to the Indonesian western half of the island of New Guinea and other smaller islands to its west. The region is officially administered as two provinces: Papua and West Papua. The eastern half of New Guinea is Papua New Guinea.The population of approximately 3 million...
) region and the geographically contiguous Papua New Guinea, where chloroquine resistance is common (up to 20% resistance).
See also
- Malaria prophylaxisMalaria prophylaxisMalaria prophylaxis is a preventative treatment of malaria.Most adults from endemic areas have a degree of long-term infection, which tends to recur, and also possess partial immunity ; the resistance reduces with time, and such adults may become susceptible to severe malaria if they have spent a...
- Medicines for Malaria Venture (MMV)Medicines for Malaria Venture (MMV)Medicines for Malaria Venture , a not-for-profit public-private partnership, was established as a foundation in Switzerland in 1999. Its mission is to reduce the burden of malaria in disease-endemic countries by discovering, developing and facilitating delivery of new, effective and affordable...
- 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.
External links
- Medicines for Malaria Venture (MMV) http://www.mmv.org/rubrique.php3?id_rubrique=21 - 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.
- The 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 the UK Health Protection Agency website as a PDF file and includes detailed country-specific information for UK travellers.
- The World Health Organisation provides country-specific advice on malaria prevention. HPA and WHO advice are broadly in line with each other (although there are some differences).
- The 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 travellers from the US. CDC guidance frequently contradicts HPA and WHO guidance.