Clinical Manifestations Of Malaria Biology Essay


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Malaria is a complex disease that varies in epidemiology and clinical manifestations in different parts of the world; factors responsible to this variability includes: species of malaria parasites that are found in a given area, distribution and transmission efficiency of the vector mosquitoes, climate, susceptibility of malaria parasites to commonly used anti-malarial drugs and the level of acquired immunity by the exposed human population (1).

In humans, malaria infection is caused by four species of intracellular protozoan parasites: plasmodium falciparum,p.vivax,p.ovale and p.malariae .These four species differ in geographical distribution, microscopic appearance, periodicity of infection, potential for severe disease and ability to cause relapses, and potential for the development of resistance to anti malarial drugs[1].

About 100 countries in the world are considered malarious,from which nearly half of them are in Africa, south of Sahara and the incidence of malaria world wide is estimated to be 300-500 million clinical cases each year, with about 90% of these occurring in Africa, south of Sahara mostly caused by plasmodium falciparum(2).According to (22) it is estimated that malaria affects more than 500 million people each year, and more than 1 million children die of the disease,mostoftheminsub-SaharanAfrica. About 75% of the total area of Ethiopia and 65% of the population is estimated to be at risk of malaria infection; in this country sever malaria is known to be caused by plasmodium falciparum with fatality rate of about 11% in hospitalized adults and 33% in children less than 12 years old; in Ethiopia the epidemiology of malaria is characterized by the briefness of the transmission season (from June to August and light rains in March and April) that prevents the development of immunity and thus resulting in periodic epidemics attended by high death(22).

Malaria remains a major health problem world wide because of development of resistance to currently available therapies. The impact of drug resistant falciparum malaria is considerable (21).Anti malarial drug resistance has emerged as one of the greatest challenges facing malaria control today, and drug resistance has also played a significant role in the occurrence and severity of epidemics in some parts of the world ;the cause for anti malarial drugs resistance is due to spontaneously-occurring mutations that affect the structure and activity at the molecular level of the drug target in the malaria parasite or affect the access of the drug to that target (1). Development and spread of drug resistance is enhanced by various factors which are relating to drug, parasite and human host interactions. The molecular mechanism of drug action is a critical element in the speed at which resistance develops. In addition, drugs with a long terminal elimination half-life enhance the development of resistance, particularly in areas of high transmission. Similarly, increased drug pressure is a significant contributor to drug resistance. As increased amounts of a drug are used, the likelihood that parasites will be exposed to inadequate drug levels rises and resistant mutants are more readily selected. Parasite factors associated with resistance include the Plasmodium species concerned and the intensity of transmission (23). Most drugs used in treatment of malaria are active against the parasite forms in the blood that actually cause the disease. These include chloroquine, mefloquine, atovaquone-proguanil, quinine, and doxycycline artemisin derivatives. In addition, primaquine is active against the dormant parasite liver forms (hypnozoites) and prevents relapses. The atremisinin based combination therapy is now the first line treatment for malaria worldwide. The methods for malaria treatment depend on multiple factors; such as the species of the infecting parasite, the area where the infection was acquired, its drug-resistance status and the clinical status of the patient, any accompanying illness or conditions, pregnancy, drug allergies, or other medications taken by the patient(5).

2. Some drugs used to treat malaria

2.1. Chloroquine

Chloroquine is a 4-aminoquinolone compound with a complicated and still unclear mechanism of action but it is believed to reach high concentrations in the vacuoles of the parasite, which, due to its alkaline nature, raises the internal pH and controls the conversion of toxic heame to hemozoin by inhibiting the bio crystallization of hemozoin, thus poisoning the parasite through excess levels of toxicity( 23). Other potential mechanisms through which it may act include interfering with the biosynthesis of parasitic nucleic acids 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 gametocytes of P. vivax, P. malariae, and 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 remain useful even when resistance is more widespread (23).

Chloroquine is a weak base that accumulates in the parasite's digestive vacuole,alysosomal compartment in which haemoglobin,taken up from the host cell cytocol via endocytotic feeding mechanism, is degraded to its compartment peptides and haem; within the vacuole chloroquine interferes with the mechanism by which the potentially toxic haem monomers are converted to the inert crystalline substance haemozoin,causing monomeric haem to accumulate to levels that kill the malaria parasite (3). Adults and children should receive 25 mg of chloroquine per kg given over 3 days. A pharmacokinetic ally superior regime, recommended by the WHO, involves giving an initial dose of 10 mg/kg followed 6-8 hours later by 5 mg/kg, then 5 mg/kg on the following 2 days. For chemoprophylaxis: 5 mg/kg/week (single dose) or 10 mg/kg/week divided into 6 daily doses are advised and chloroquine is only recommended as a prophylactic drug in regions only affected by P. vivax and sensitive P. falciparum strains(23).

2.2. Quinine

Quinine is an alkaloid that acts as a blood schizonticidal and weak gametocyte against Plasmodium vivax and Plasmodium malariae. Being an alkaloid, it is accumulated in the food vacuoles of Plasmodium species, especially Plasmodium falciparum and it acts by inhibiting the hemozoin biocrystallization, thus facilitating an aggregation of cytotoxic heme. 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;it is also used in post-exposure treatment of individuals returning from an area where malaria is endemic. The World Health Organization recommendation for quinine is 8 mg/kg three times daily for 3 days in areas where the level of adherence is questionable and for 7 days where parasites are sensitive to quinine. In areas where there is an increased level of resistance to quinine 8 mg/kg three times daily for 7 days is recommended, combined with doxycycline, tetracycline, or clindamycin and doses can be given by oral, intravenous, or intramuscular routes (23).

2.3. Amodiaquine

Amodiaquine is a 4-aminoquinolone anti-malarial drug similar in structure and mechanism of action to Chloroquine; it is most frequently used in combination with Chloroquine, but is also very effective when used alone. It is thought to be more effective in clearing parasites in uncomplicated malarial than Chloroquine, thus leading to a faster rate of recovery. The Amodiaquine 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 (23). The mechanism of plasmodicidal action of amodiaquine is not completely certain, but like other quinoline derivatives, it inhibits heme polymerase activity. This results in accumulation of free heme, which is toxic to the parasites (24). Amodiaquine is an ant malarial with schizonticidal activity and it is effective against the erythrocyte stages of all four species of plasmodium falciparum. In addition, it is effective as chloroquine against chloroquine-sensitive strains of Plasmodium falciparum and some chloroquine-resistant strains. Amodiaquine accumulates in the lysosomes and brings about loss of function so that the parasite is unable to digest haemoglobin on which it depends for its energy (6). Amodiaquine is no longer recommended for chemoprophylaxis because of the risk of severe adverse reactions, generally similar to those to chloroquine, the most common being nausea, vomiting, abdominal pain, diarrhea and itching and bradycardia; however, unlike chloroquine, amodiaquine can induce toxic hepatitis and fatal agranulocytosis following its use for malaria chemoprophylaxis (7).

2.4. Pyrimethamine

Pyrimethamine is used in the treatment of uncomplicated malaria; particularly useful in cases of chloroquine-resistant P. falciparum strains when combined with Sulphadoxine and it acts by inhibiting dihydrofolate reductase in the parasite thus preventing the biosynthesis of purines and pyrimidines; thus halting the processes of DNA synthesis, cell division and reproduction .It acts primarily on the schizonts during the hepatic and erythrocytic phases(23). Pyrimethamine is a folic acid antagonist and has a mechanism of action similar to that of trimethoprim; by binding to and reversibly inhibiting dihydrofolate reductase, pyrimethamine inhibits the reduction of dihydrofolic acid to tetrahydrofolic acid (folinic acid), and it interferes the synthesis of tetrahydrofolic acid in malarial parasites at a point immediately succeeding that where sulphonamides act (8).

2.5. Proguanil

Proguanil is a prophylactic ant malarial drug, which works by stopping the malaria parasite, Plasmodium falciparum and Plasmodium vivax from reproducing once it is in the red blood cells and proguanil inhibits the dihydrofolate reductase of plasmodia and thereby blocks the biosynthesis of purines and pyrimidines, which are essential for DNA synthesis and cell multiplication which leads to failure of nuclear division at the time of schizont formation in erythrocytes and liver (9). Proguanil (Chloroguanadine) is a biguanide: a synthetic derivative of pyrimidine and 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 and its most prominent effect is on the primary tissue stages of P. falciparum, P. vivax and P. ovale. Since it has no known effect against hypnozoites, it is not used in the prevention of relapse but 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.There are very few side effects to Proguanil, with slight hair loss and mouth ulcers being occasionally reported following prophylactic use (23).

2.6. Primaquine

Primaquine is the essential co-drug with chloroquine in treating all cases of malaria and it is highly effective against the gametocytes of all plasmodia and thereby prevents spread of the disease to the mosquito from the patient. It is also effective against the dormant tissue forms of P. vivax and P. ovale malaria, and thereby offers radical cure and prevents relapses. It has insignificant activity against the asexual blood forms of the parasite and therefore it is always used in conjunction with a blood schizonticide and never as a single agent (25).

Mechanism of action is not well understood but it may be acting by generating reactive oxygen species or by interfering with the electron transport in the parasite. At larger doses, it may cause occasional epigastria distress and abdominal cramps. This can be minimized by taking the drug with a meal.Mild anemia cyanosis and methemo globinemia may occur. Severe met hemoglobinemia can occur rarely in patients with deficiency of NADH methemoglobin reductase (25).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 (23).Primaquine should not be taken by pregnant women or by people who are deficient in glucose-6-phosphate dehydrogenase; patients should not take primaquine until a screening test has excluded glucose-6-phosphate dehydrogenase deficiency (5).

2.7. Doxycycline(Tetracycline)

Doxycycline is relatively effective and cheaper, due to this it is likely one of the more prevalent anti-malarial drugs, and it is tetracycline compound derived from tetracycline. Doxycycline is used primarily for chemoprophylaxis in areas where chloroquine resistance exists and 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 mono therapy (23).When treating acute cases and given in combination with quinine; 100 mg/kg of doxycycline should be given per day for seven days but in prophylactic therapy, 100 mg (adult dose) of doxycycline should be given every day during exposure to malaria(23).However,doxycyclin must not be used to children below 12 years (in critical situations 8 years) as tetracycline may give permanently discolored teeth. In addition, pregnant women must not use doxycycline because it is deposited in the bone and teeth of the fetus where it may give permanent discoloration or malformation of the bones (27).

2.8. Antifolate combination drugs

These drugs are various combinations of dihydrofolate- reductase inhibitors (proguanil, chlorproguanil, pyrimethamine, and trimethoprim) and sulfa drugs (dapsone, sulfalene, sulfamethoxazole sulfadoxine, and others).Although these drugs have ant malarial activity when used alone, parasitological resistance can develop rapidly. When used in combination, they produce a synergistic effect on the parasite and can be effective even in the presence of resistance to the individual components. Typical combinationsincludesulfadoxine/pyrimethamine (SP or Fansidar1), sulfalenepyrimethamine, and sulfamethoxazole-trimethoprim (co-trimoxazole).Anew antifolate combination drug is currently being tested in Africa. This drug, combination of chlorproguanil and dapsone, also known as Lap-Dap, has a much more potent synergistic effect on malaria than existing drugs such as SP. Benefits of this combination include, a greater cure rate, even in areas currently experiencing some level of SP resistance, a lower likelihood of resistance developing because of a more advantageous pharmacokinetic and pharmacodynamic profile, (23). Use of combinations of antimalarials that do not share the same resistance mechanisms will reduce the chance of selection because the chance of a resistant mutant surviving is the product of the per parasite mutation rates for the individual drugs, multiplied by the number of parasites in an infection that are exposed to the drugs. Artemisinin derivatives are particularly effective combination partners because (i) they are very active antimalarials, producing up to 10 000-fold reductions in parasite biomass per asexual cycle; (ii) they reduce malaria transmissibility; and (iii) no resistance to these drugs has been reported yet. There are good arguments for no longer using ant malarial drugs alone in treatment, and instead always using a combination with artemisinin or one of its derivatives (11).

3. Mechanism of anti-malarial drug resistance

Anti malarial drug resistance is the ability of a parasite strain 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 the limits of tolerance of the subject and the resistance to anti- malarial drug is caused by spontaneously- occurring mutations which affect the structure and activity at the molecular level of the drug target in the malaria parasite or affect the access of the drug to that target(23).

3.1. Quinine resistance

Quinine resistance appears to share common characteristics with chloroquine resistance; it is associated with mutations in the pfmdr1 and pfcrt genes, but the mechanism of quinine resistance is still unknown. In addition to the pfmdr1 and pfcrt genes, other genetic polymorphisms such as microsatellite length variations in the P. falciparum sodium/hydrogen exchanger (pfnhe-1) gene and mutations in the P. falciparum multidrug resistance protein gene may contribute to quinine resistance (10).

3.2 .Chloroquine resistance

Chloroquine is the most widely used anti malarial drug in the world and it is still the drug of choice for nearly all Plasmodium vivax, P. malaria, and P. ovale malaria, and used extensively to treat falciparum malaria despite widespread resistance; chloroquine resistance results from a reduced parasite accumulation of the drug, although the precise molecular mechanisms responsible have not been elucidated fully. The intra-erythrocytic malaria parasite consumes hemoglobin, detoxifying haem by polymerization to haemozoin or malaria pigment. Chloroquine and related aryl amino alcohols (11) inhibit this process. Mechanism of chloroquine resistance in P. falciparum is associated with a decreased ability of the parasite to accumulate chloroquine; Verapamil, a Ca2+ channel blocker, has been found to restore both the chloroquine concentration ability as well as sensitivity to this drug. Recently an altered chloroquine-transporter protein CG2 of the parasite has been related to chloroquine resistance, but other mechanism of resistance also appears to be involved (12).

When hemoglobin is digested by malaria parasite, large amounts of a toxic by-product are formed and the parasite polymerizes this by-product in its food vacuole, producing non-toxic haemozoin (malaria Pigment). It is believed that resistance of P. falciparum to chloroquine is related to an increased capacity for the parasite to expel chloroquine at a rate that does not allow chloroquine to reach levels required for inhibition of haem polymerization; this chloroquine efflux occurs at a rate of 40 to 50 times faster among resistant parasites than sensitive ones(1).Chloroquine, a dibasic drug, is accumulated several thousand-fold in the food vacuole; the high intravacuolar chloroquine concentration is proposed to interfere with the polymerization of heme and/or the detoxification of the reactive oxygen species, effectively killing the parasite with its own metabolic waste.Chloroquine resistance appears to arise as a result of a decreased level of chloroquine uptake, due to an increased vacuolar pH or to changes in a chloroquine importer or receptor (26).

3.3 .Atovaquone resistance

Atovaquone acts through inhibition of electron transport at the cytochrome bc1 complex .Although resistance to atovaquone develops very rapidly when used alone, when combined with a second drug such as proguanil (the combination used in MalaroneTM) or tetracycline, resistance develops more slowly; résistance is caused by single-point mutations in the cytochrome-b gene (1).Resistance to atovaquone results from point mutations in the gene cytB, coding for cytochrome b (11). Atovaquine is an analog of ubiquinone, which selectively inhibits parasite mitochondrial electron transport and it, has similar activity against both chloroquine-sensitive and chloroquine-resistant P. falciparum isolates, however, when ATQ is used as monotherapy resistance develops rapidly (13).

3.4. Sulfone and sulfonamide resistance

The enzyme dihydropteroate synthase is the target of sulfone and sulfonamide drugs which are used extensively in the control of many infections including P. falciparum and sulfadoxine is the major sulfonamide used for the prophylaxis of P. falciparum infections, and this drug inhibits the enzyme dihydropteroate synthase (DHPS) by direct competition for the substrate binding site;however,identification of amino acid differences in the DHPS enzyme of sulfadoxine-resistant compared with sulfadoxine-sensitive P. falciparum isolates suggested that the mechanism of resistance may involve mutations in DHPS that alter the affinity of binding of the drug ; the amino acid differences in DHPS decrease the efficacy of inhibition by sulfadoxine and that such mutations are important for resistance of P. falciparum toward this drug(14). The mechanism of resistance to sulfonamides and sulfones involves mutations of dihydropteroate synthase (DHPS), their enzyme target impairing their capacity to potentiate antifolinic drug (16).

3.5. Antifolate combination drugs resistance

Antifolate combination drugs, such as sulfadoxine and pyrimethamine, act through sequential and synergistic blockade of two key enzymes involved with folate synthesis. Pyrimethamine and related compounds inhibit the step mediated by dihydrofolate reductase (DHFR) while sulfones and sulfonamides inhibit the step mediated by dihydropteroate synthase (DHPS). Specific gene mutations encoding for resistance to both DHPS and DHFR have been identified. Specific combinations of these mutations have been associated with varying degrees of resistance to antifolate combination drugs (1).P.falciparum resistance to sulfadoxine-pyrimethamine is primarily conferred by successive single-point mutations in parasite dhfr, the gene that encodes the target enzyme dihydrofolate reductase (DHFR), and by additional mutations in dhps, which encodes for the enzyme dihydropteroate synthase (23). Molecular and epidemiological studies of both Plasmodium falciparum and P. vivax have revealed that the dihydrofolate reductase (DHFR) and dihydropteroate synthase (DHFR) enzymes are the therapeutic targets of sulfadoxine-pyrimethamine (SP); as a result, resistance to sulfadoxine-pyrimethamine (SP) is determined by specific point mutations in the parasite dhfr and dhps genes ,so these mutations cause alterations of key amino acid residues in the active sites of these enzymes, which reduce the affinity of the enzyme for the drug (17) .Plasmodium have developed resistance against antifolate combination drugs, the most commonly used being sulfadoxine and pyrimethamine. The resistance to these drugs occurs by mutations at two genes, allowing synergistic blockages of two enzymes, DHFR and DHFR involved in foliate synthesis; however, regional variations of specific mutations give differing levels of resistance (23).

4. Prevention of drug resistance

4.1. Reducing overall drug pressure.

Preventing drug resistance, generally focus on reducing overall drug pressure through more selective use of drugs; improving the way drugs are used through improving prescribing, follow-up practices, and patient compliance; or using drugs or drug combinations which are inherently less likely to foster resistance or have properties that do not facilitate development or spread of resistant parasites(1).Drug pressure is higher where a drug with a long half-life is taken because the drug remains in the patient's blood at low levels for weeks, exposing any newly introduced malarial parasites to sub-therapeutic levels; this is particularly likely to occur in high transmission areas where people are not only infected more frequently, but also take ant malarial drugs frequently whether or not they are have malaria, this form of drug pressure can be reduced by using drugs with a shorter half-life and by restricting the use of the first-line drug to patients with confirmed malaria (19).

4.2. Improving the way drugs are used

Improving the way drugs are used such as restrictive drug use and prescribing practices are helpful for limiting the spread of drug resistance (15).The benefits of using single-dose DOT (directly observed therapy) need to be weighed against the costs of using drugs with long half-lives. Another approach that has not been widely adopted is the close follow-up and re-treatment, if necessary, of patients. The success of this approach is dependant on availability of reliable microscopy (to diagnose the illness initially as well as to confirm treatment failure), and either an infrastructure to locate patients in the community or a community willing to return on a given date, regardless of whether they feel ill or not. With this system, Patients who fail initial treatment, for whatever reason, are identified quickly and re-treated until parasitological cured, decreasing the potential for spread of resistant parasites(1).

4.3. Combination therapy

4.3.1 Artemesinin-based combination therapies (ACTs)

Artemesinin has a very different mode of action than conventional anti-malarial information 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 (23).

Plasmodium falciparum resistance to chloroquine and sulphadoxine-pyrimethamine has led to the recent adoption of artemisinin-based combination therapies (ACTs) as the first line of treatment against malaria. ACTs comprise semisynthetic artemisinin derivatives paired with distinct chemical classes of longer acting drugs. These artemisinins are exceptionally potent against the pathogenic asexual blood stages of Plasmodium parasites and act on the transmissible sexual stages. These combinations increase the rates of clinical and parasitological cures and decrease the selection pressure for the emergence of ant malarial resistance (18).

Artemisinin drugs are highly efficacious, rapidly active, and have action against a broader range of parasite developmental stages. This action apparently yields two notable results: first, artemisinin compounds, used in combination with a longer acting ant malarial, can rapidly reduce parasite densities to very low levels at a time when drug levels of the longer acting ant malarial drug are still maximal. This greatly reduces both the likelihood of parasites surviving initial treatment and the likelihood that parasites will be exposed to suboptimal levels of the longer acting drug; second, the use of artemisinins has been shown to reduce gametocytogenesis by 8- to 18-fold.This reduces the likelihood that gametocytes carrying resistance genes are passed onwards and potentially may reduce malaria transmission rates (1).

Combination therapy with ant malarial drugs is the simultaneous use of two or more blood schizontocidal drugs with independent modes of action and different biochemical targets in the parasite; the concept of combination therapy is based on the synergistic or additive potential of two or more drugs, to improve therapeutic efficacy and also delay the development of resistance to the individual components of the combination. Ant malarial combinations can increase efficacy, shorten duration of treatment (and hence increase compliance), and decrease the risk of resistant parasites arising through mutation during therapy. Artemisinin based combinations are known to improve cure rates, reduce the development of resistance and they might decrease transmission of drug-resistant parasites. The total effect of artemisinin combinations (which can be simultaneous or sequential) is to reduce the chance of parasite recrudescence, reduce the within-patient selection pressure, and prevent transmission (20).Some of the arteminisinin drug combinations with their descriptions are listed in the table as following:

Artemisinin Drug Combinations

Efficacy advantages




Artesunate + Amodiaquine

Better efficacy than amodiaquine alone (cure rate >90%); Well tolerated

Neutropenia; Pharmacokinetic mismatch

Artesunate 4mg/kg and amodiaquine 10mg base/ kg once a day 3 days


Artesunate + Mefloquine

In use for many years and the first-line treatment in several parts of SE Asia

Pharmacokinetic mismatch; Mefloquine induced neuropsychiatric effects, cardiotoxic effects, incidents of vomiting in children; but combination with artesunate results in less adverse reactions than the use of mefloquine alone

Artesunate (4mg/kg once daily) for 3 days + mefloquine (25mg base/kg) as a split dose of 15mg/kg on Day 2 and 10mg/kg on Day 3. (Alternatively 8mg/kg mefloquine daily for three days)

Not approved; Not considered a viable option as first-line therapy in Africa

Artesunate + Sulfadoxine/Pyrimethamine (SP)

Well tolerated; Efficacy dependent on the level of pre-existing resistance to SP

Pharmacokinetic mismatch; adverse effects to SP

Artesunate 4mg/kg once daily for 3 days and SP single dose of 25mg/kg and 1.25mg/kg respectively

Approved (in areas where SP efficacy is high); Resistance to SP limits the use

Artemether + Lumefantrine (Coartem,TM RiametTM)

As effective, and better tolerated, as artesunate plus mefloquine; No serious adverse reactions documented

Irreversible hearing impairment

Artemether 1.5mg/kg and Lumifantrine 9mg/kg at 0, 8, 24, 36, 48 and 60 hours

Approved; Not recommended for use in pregnancy and lactating women

SP + Chloroquine

Cheap;Similar pharmacokinetic profiles, with varied modes of action on different biochemical targets in the parasite

Drug resistance; Serious adverse effects to SP

Chloroquine 25mg/kg over 3 days; SP single dose as above

Not approved; an be used where resistance to SP is not a problem

SP + Amodiaquine

Similar pharmacokinetic profiles

Adverse effects of amodiaquine and SP

Amodiaquine 10mg/kg daily for 3 days; SP single dose as above

Approved (In areas where efficacy of both amodiaquine and SP remain high - countries in West Africa)

SP + Quinine

Effective where resistance to SP is not a problem

Drug resistance; Serious adverse effects

Quinine 15mg/kg 12 hourly for 3 days; SP single dose as above

Not approved

SP + Mefloquin (FansimefTM)

Fixed dose pill, single dose

Not an additive or synergistic combination; Each drug has a different pharmacokinetic profile; Expensive; Resistance known

Mefloquine 15mg/kg and SP as above single dose

Notapproved; recommended for general use since 1990

Quinine + Tetracycline


7-day course, multiple doses daily; Cinchonism; Tetracyclines contraindicated in children and pregnant women; Emergence of resistance

Quinine 10mg/kg 8 hourly and Tetracycline 4mg/kg 6 hourly for 7 days

Not approved; Difficult to recommend as a first-line treatment for uncomplicated malaria

Quinine + Clindamycin

Good efficacy; Safe in children andpregnant women; Lesser risk of resistance


Quinine 15mg/kg 12 hourly and Clindamycin 20mg/kg in three doses for 3 days

Not approved

5. Summary

Malaria remains a major health problem world wide because of development of resistance to currently available therapies. Ant malarial drug resistance usually arises when spontaneously arising mutants are selected by anti- malarial drug concentrations that provide deferential inhibition to distinct genetic parasite types: i.e. the drug concentrations are sufficient to reduce the susceptible parasite population, but inhibit less or do not inhibit multiplication of the mutants. More over, the cause for development of ant malarial drug resistance can be a long terminal elimination half-life, a shallow concentration-effect relationship, and mutations that confer marked reduction in susceptibility. Ant malarial drug resistance can be prevented by combining a well-matched drug pair combining one drug that rapidly reduces parasite biomass with a partner drug that can remove any residual parasites), thus using different drugs in combination with other anti-malarial is to increase its effectiveness by preventing the growth of the infecting parasite in the blood. Ant malarial combinations can increase efficacy, shorten duration of treatment (and hence increase compliance), and decrease the risk of resistant parasites arising through mutation during therapy. For example, using artemisinin-based combinations will improve cure rates, reduce the development of resistance and they might decrease transmission of drug-resistant parasites. Use of combinations of antimalarials that do not share the same resistance mechanisms will reduce the chance of selection because the chance of a resistant mutant surviving is the product of the per parasite mutation rates for the individual drugs, multiplied by the number of parasites in an infection that are exposed to the drugs. More over, reducing overall drug pressure by following restrictive drug use and prescription as well as improving the ways of using drugs are some of the ways to prevent ant malarial drug resistance.

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