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fermer ce livreGuidelines for the Treatment of Malaria (WHO; 2006; 266 pages) Voir le document au format PDF
Afficher le documentGlossary
Afficher le documentAbbreviations
ouvrir ce répertoire et afficher son contenu1. Introduction
Afficher le document2. The clinical disease
ouvrir ce répertoire et afficher son contenu3. Treatment objectives
ouvrir ce répertoire et afficher son contenu4. Diagnosis of malaria
ouvrir ce répertoire et afficher son contenu5. Resistance to antimalarial medicines9
ouvrir ce répertoire et afficher son contenu6. Antimalarial treatment policy
ouvrir ce répertoire et afficher son contenu7. Treatment of uncomplicated P. Falciparum malaria10
ouvrir ce répertoire et afficher son contenu8. Treatment of severe falciparum malaria14
ouvrir ce répertoire et afficher son contenu9. Treatment of malaria caused by P. vivax, P. ovale or P. malariae19
Afficher le document10. Mixed malaria infections
ouvrir ce répertoire et afficher son contenu11. Complex emergencies and epidemics
fermer ce répertoireAnnexes
Afficher le documentAnnex 1. The guidelines development process
Afficher le documentAnnex 2. Adaptation of WHO malaria treatment guidelines for use in countries
Afficher le documentAnnex 3. Pharmacology of antimalarial drugs
Afficher le documentAnnex 4. Antimalarials and malaria transmission
Afficher le documentAnnex 5. Malaria diagnosis
Afficher le documentAnnex 6. Resistance to antimalarials
Afficher le documentAnnex 7. Uncomplicated P. falciparum malaria
Afficher le documentAnnex 8. Malaria treatment and HIV/AIDS
Afficher le documentAnnex 9. Treatment of severe P. falciparum malaria
Afficher le documentAnnex 10. Treatment of P. vivax, P. ovale and P. malariae infections

Annex 3. Pharmacology of antimalarial drugs

A3.1 Chloroquine

Molecular weight: 436.0

Chloroquine is a 4-aminoquinoline that has been used extensively for the treatment and prevention of malaria. Widespread resistance has now rendered it virtually useless against P. falciparum infections in most parts of the world, although it still maintains considerable efficacy for the treatment of P. vivax, P. ovale and P. malariae infections. As with other 4-aminoquinolines, it does not produce radical cure.

Chloroquine interferes with parasite haem detoxification (1, 2). Resistance is related to genetic changes in transporters (PfCRT, PfMDR), which reduce the concentrations of chloroquine at its site of action, the parasite food vacuole.


• Tablets containing 100 mg or 150 mg of chloroquine base as hydrochloride, phosphate or sulfate.


Chloroquine is rapidly and almost completely absorbed from the gastrointestinal tract when taken orally, although peak plasma concentrations can vary considerably. Absorption is also very rapid following intramuscular and subcutaneous administration (3-5). Chloroquine is extensively distributed into body tissues, including the placenta and breast milk, and has an enormous total apparent volume of distribution. The relatively small volume of distribution of the central compartment means that transiently cardiotoxic levels may occur following intravenous administration unless the rate of parenteral delivery is strictly controlled. Some 60% of chloroquine is bound to plasma proteins, and the drug is eliminated slowly from the body via the kidneys, with an estimated terminal elimination half-life of 1-2 months. Chloroquine is metabolized in the liver, mainly to monodesethylchloroquine, which has similar activity against P. falciparum.


Chloroquine has a low safety margin and is very dangerous in overdosage. Larger doses of chloroquine are used for the treatment of rheumatoid arthritis than for malaria, so adverse effects are seen more frequently in patients with arthritis. The drug is generally well tolerated. The principle limiting adverse effects in practice are the unpleasant taste, which may upset children, and pruritus, which may be severe in dark-skinned patients (6). Other less common side effects include headache, various skin eruptions and gastrointestinal disturbances, such as nausea, vomiting and diarrhoea. More rarely central nervous system toxicity including, convulsions and mental changes may occur. Chronic use (>5 years continuous use as prophylaxis) may lead to eye disorders, including keratopathy and retinopathy. Other uncommon effects include myopathy, reduced hearing, photosensitivity and loss of hair. Blood disorders, such as aplastic anaemia, are extremely uncommon (7).

Acute overdosage is extremely dangerous and death can occur within a few hours. The patient may progress from feeling dizzy and drowsy with headache and gastrointestinal upset, to developing sudden visual disturbance, convulsions, hypokalaemia, hypotension and cardiac arrhythmias. There is no specific treatment, although diazepam and epinephrine (adrenaline) administered together are beneficial (8, 9).

Drug interactions

Major interactions are very unusual. There is a theoretical increased risk of arrhythmias when chloroquine is given with halofantrine or other drugs that prolong the electrocardiograph QT interval; a possible increased risk of convulsions with mefloquine; reduced absorption with antacids; reduced metabolism and clearance with cimetidine; an increased risk of acute dystonic reactions with metronidazole; reduced bioavailability of ampicillin and praziquantel; reduced therapeutic effect of thyroxine; a possible antagonistic effect on the antiepileptic effects of carbamazepine and sodium valproate; and increased plasma concentrations of cyclosporine.

A3.2 Amodiaquine

Molecular weight: 355.9

Amodiaquine is a Mannich base 4-aminoquinoline with a mode of action similar to that of chloroquine. It is effective against some chloroquine-resistant strains of P. falciparum, although there is cross-resistance.


• Tablets containing 200 mg of amodiaquine base as hydrochloride or 153.1 mg of base as chlorohydrate.


Amodiaquine hydrochloride is readily absorbed from the gastrointestinal tract. It is rapidly converted in the liver to the active metabolite desethylam-odiaquine, which contributes nearly all of the antimalarial effect (10). There are insufficient data on the terminal plasma elimination half-life of desethy-lamodiaquine. Both amodiaquine and desethylamodiaquine have been detected in the urine several months after administration.


The adverse effects of amodiaquine are similar to those of chloroquine. Amodiaquine is associated with less pruritus and is more palatable than chloroquine, but is associated with a much higher risk of agranulocytosis and, to a lesser degree, of hepatitis when used for prophylaxis (11). The risk of a serious adverse reaction with prophylactic use (which is no longer recommended) appears to be between 1 in 1000 and 1 in 5000. It is not clear whether the risks are lower when amodiaquine is used to treat malaria. Following overdose cardiotoxicity appears to be less frequent than with chloroquine. Large doses of amodiaquine have been reported to cause syncope, spasticity, convulsions and involuntary movements.

Drug interactions

There are insufficient data.

A3.3 Sulfadoxine

Molecular weight: 310.3

Sulfadoxine is a slowly eliminated sulfonamide. It is very slightly soluble in water. Sulfonamides are structural analogues and competitive antagonists of p-aminobenzoic acid. They are competitive inhibitors of dihydropteroate synthase, the bacterial enzyme responsible for the incorporation of p-aminobenzoic acid in the synthesis of folic acid.


Sulfadoxine is used in a fixed-dose combination of 20 parts sulfadoxine with 1 part pyrimethamine and may be administered orally or by the intramuscular route:

• Tablets containing 500 mg of sulfadoxine and 25 mg of pyrimethamine.

• Ampoules containing 500 mg of sulfadoxine and 25 mg of pyrimethamine in 2.5 ml of injectable solution for intramuscular use.


Sulfadoxine is readily absorbed from the gastrointestinal tract. Peak blood concentrations occur about 4 h after an oral dose. The terminal elimination half-life is 4-9 days. Around 90-95% is bound to plasma proteins. It is widely distributed to body tissues and fluids, passes into the fetal circulation and is detectable in breast milk. The drug is excreted in urine, primarily unchanged.


Sulfadoxine shares the adverse effect profile of other sulfonamides, although allergic reactions can be severe because of its slow elimination. Nausea, vomiting, anorexia and diarrhoea may occur. Crystalluria causing lumbar pain, haematuria and oliguria is rare compared with more rapidly eliminated sulphonamides. Hypersensitivity reactions may effect different organ system. Cutaneous manifestations can be severe and include pruritus, photosensitivity reactions, exfoliative dermatitis, erythema nodosum, toxic epidermal necrolysis and Stevens-Johnson syndrome (12). Treatment with sulfadoxine should be stopped in any patient developing a rash because of the risk of severe allergic reactions (13). Hypersensitivity to sulfadoxine may also cause interstitial nephritis, lumbar pain, haematuria and oliguria. This is due to crystal formation in the urine (crystalluria) and may be avoided by keeping the patient well hydrated to maintain a high urine output. Alkalinization of the urine will also make the crystals more soluble. Blood disorders that have been reported include agranulocytosis, aplastic anaemia, thrombocytopenia, leukopenia and hypoprothrombinaemia. Acute haemolytic anaemia is a rare complication, which may be antibody mediated or associated with glucose-6-phosphate dehydrogenase (G6PD) deficiency. Other adverse effects, which may be manifestations of a generalized hypersensitivity reaction include fever, interstitial nephritis, a syndrome resembling serum sickness, hepatitis, myocarditis, pulmonary eosinophilia, fibrosing alveolitis, peripheral neuropathy and systemic vasculitis, including polyarteritis nodosa. Anaphylaxis has been reported only rarely. Other adverse reactions that have been reported include hypo-glycaemia, jaundice in neonates, aseptic meningitis, drowsiness, fatigue, headache, ataxia, dizziness, drowsiness, convulsions, neuropathies, psychosis and pseudomembranous colitis.

A3.4 Pyrimethamine

Molecular weight: 248.7

Pyrimethamine is a diaminopyrimidine used in combination with a sulfonamide, usually sulfadoxine or dapsone. It exerts its antimalarial activity by inhibiting plasmodial dihydrofolate reductase thus indirectly blocking the synthesis of nucleic acids in the malaria parasite. It is a slow-acting blood schizontocide and is also possibly active against pre-erythrocytic forms of the malaria parasite and inhibits sporozoite development in the mosquito vector. It is effective against all four human malarials, although resistance has emerged rapidly. Pyrimethamine is also used in the treatment of toxoplasmosis, and isosporiasis and as prophylaxis against Pneumocystis carinii pneumonia. Pyrimethamine is no longer used alone as an antimalarial, only in synergistic combination with slowly eliminated sulfonamides for treatment (sulfadoxine, sulfalene) or with dapsone for prophylaxis.


Pyrimethamine is currently used mainly in a fixed-dose combination with slowly eliminated sulfonamides, either of 20 parts sulfadoxine with 1 part pyrimethamine for which there are oral and parenteral formulations:

• Tablets containing 500 mg of sulfadoxine and 25 mg of pyrimethamine.
• Ampoules containing 500 mg of sulfadoxine and 25 mg of pyrimethamine in 2.5 ml of injectable solution for intramuscular use.


Pyrimethamine is almost completely absorbed from the gastrointestinal tract and peak plasma concentrations occur 2-6 h after an oral dose. It is mainly concentrated in the kidneys, lungs, liver and spleen, and about 80-90% is bound to plasma proteins. It is metabolized in the liver and slowly excreted via the kidneys. The plasma half-life is around 4 days. Pyrimethamine crosses the blood-brain barrier and the placenta and is detectable in breast milk. Absorption of the intramuscular preparation is incomplete and insufficiently reliable for this formulation to be recommended (14).


Pyrimethamine is generally very well tolerated. Administration for prolonged periods may cause depression of haematopoiesis due to interference with folic acid metabolism. Skin rashes and hypersensitivity reactions also occur. Larger doses may cause gastrointestinal symptoms such as atrophic glossitis, abdominal pain and vomiting, haematological effects including megaloblastic anaemia, leukopenia, thrombocytopenia and pancytopenia, and central nervous system effects such as headache and dizziness.

Acute overdosage of pyrimethamine can cause gastrointestinal effects and stimulation of the central nervous system with vomiting, excitability and convulsions. Tachycardia, respiratory depression, circulatory collapse and death may follow. Treatment of overdosage is supportive.

Drug interactions

Administration of pyrimethamine with other folate antagonists such as cotri-moxazole, trimethoprim, methotrexate or with phenytoin may exacerbate bone marrow depression. Given with some benzodiazepines, there is a risk of hepatotoxicity.

A3.5 Mefloquine

Molecular weight: 378.3

Mefloquine is a 4-methanolquinoline and is related to quinine. It is soluble in alcohol but only very slightly soluble in water. It should be protected from light. The drug is effective against all forms of malaria.


Mefloquine is administered by mouth as the hydrochloride salt (250 mg base equivalent to 274 mg hydrochloride salt):

• Tablets containing either 250 mg salt (United States of America) or 250 mg base (elsewhere).


Mefloquine is reasonably well absorbed from the gastrointestinal tract but there is marked interindividual variation in the time required to achieve peak plasma concentrations. Splitting the 25 mg/kg dose into two parts given at an interval of 6-24 h augments absorption and improves tolerability (15). Mefloquine undergoes enterohepatic recycling. It is approximately 98% bound to plasma proteins and is widely distributed throughout the body. The pharmacokinetics of mefloquine may be altered by malaria infection with reduced absorption and accelerated clearance (16, 17). When administered with artesunate, blood concentrations are increased, probably as an indirect effect of increased absorption resulting from more rapid resolution of symptoms (15). Mefloquine is excreted in small amounts in breast milk. It has a long elimination half-life of around 21 days, which is shortened in malaria to about 14 days, possibly because of interrupted enterohepatic cycling (18-20). Mefloquine is metabolized in the liver and excreted mainly in the bile and faeces. Its pharmacokinetics show enantioselectivity after administration of the racemic mixture, with higher peak plasma concentrations and area under the curve values, and lower volume of distribution and total clearance of the SR enantiomer than its RS antipode (21-23).


Minor adverse effects are common following mefloquine treatment, most frequently nausea, vomiting, abdominal pain, anorexia, diarrhoea, headache, dizziness, loss of balance, dysphoria, somnolence and sleep disorders, notably insomnia and abnormal dreams. Neuropsychiatric disturbances (seizures, encephalopathy, psychosis) occur in approximately 1 in 10 000 travellers receiving mefloquine prophylaxis, 1 in 1000 patients treated in Asia, 1 in 200 patients treated in Africa, and 1 in 20 patients following severe malaria (24-27). Other side effects reported rarely include skin rashes, pruritus and urticaria, hair loss, muscle weakness, liver function disturbances and very rarely thrombocytopenia and leukopenia. Cardiovascular effects have included postural hypotension, bradycardia and, rarely, hypertension, tachycardia or palpitations and minor changes in the electrocardiogram. Fatalities have not been reported following overdosage, although cardiac, hepatic and neurological symptoms may be seen. Mefloquine should not be given with halofantrine because it exacerbates QT prolongation. There is no evidence of an adverse interaction with quinine (28).

Drug interactions

There is a possible increase in the risk of arrhythmias if mefloquine is given together with beta blockers, calcium channel blockers, amiodarone, pimozide, digoxin or antidepressants; there is also a possible increase in the risk of convulsions with chloroquine and quinine. Mefloquine concentrations are increased when given with ampicillin, tetracycline and metoclopramide. Caution should be observed with alcohol.

A3.6 Artemisinin and its derivatives

A3.6.1 Artemisinin

Molecular weight: 282.3

Artemisinin, also known as qinghaosu, is a sesquiterpene lactone extracted from the leaves of Artemisia annua (sweet wormwood). It has been used in China for the treatment of fever for over a thousand years. It is a potent and rapidly acting blood schizontocide and is active against all Plasmodium species. It has an unusually broad activity against asexual parasites, killing all stages from young rings to schizonts. In P. falciparum malaria, artemisinin also kills the gametocytes - including the stage 4 gametocytes, which are otherwise sensitive only to primaquine. Artemisinin and its derivatives inhibit an essential calcium adenosine triphosphatase, PfATPase 6 (29). Artemisinin has now largely given way to the more potent dihydroartemisinin and its derivatives, artemether, artemotil and artesunate. The three latter derivatives are converted back in vivo to dihydroartemisinin. These drugs should be given as combination therapy to protect them from resistance.


A wide variety of formulations for oral, parenteral and rectal use are available. These include:

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


Peak plasma concentrations occur around 3 h and 11 h following oral and rectal administration respectively (30). Artemisinin is converted to inactive metabolites via the cytochrome P450 enzyme CYP2B6 and other enzymes.

Artemisinin is a potent inducer of its own metabolism. The elimination half-life is approximately 1 h (31).


Artemisinin and its derivatives are safe and remarkably well tolerated (32, 33). There have been reports of mild gastrointestinal disturbances, dizziness, tinnitus, reticulocytopenia, neutropenia, elevated liver enzyme values, and electrocardiographic abnormalities, including bradycardia and prolongation of the QT interval, although most studies have not found any electrocardiographic abnormalities. The only potentially serious adverse effect reported with this class of drugs is type 1 hypersensitivity reactions in approximately 1 in 3000 patients (34). Neurotoxicity has been reported in animal studies, particularly with very high doses of intramuscular artemotil and artemether, but has not been substantiated in humans (35-37). Similarly, evidence of death of embryos and morphological abnormalities in early pregnancy have been demonstrated in animal studies (37a). Artemisinin has not been evaluated in the first trimester of pregnancy so should be avoided in first trimester patients with uncomplicated malaria until more information is available.

Drug interactions

None known.

A3.6.2 Artemether

Molecular weight: 298.4

Artemether is the methyl ether of dihydroartemisinin. It is more lipid soluble than artemisinin or artesunate. It can be given as an oil-based intramuscular injection or orally. It is also coformulated with lumefantrine (previously referred to as benflumetol) for combination therapy.


• Capsules containing 40 mg of artemether.

• Tablets containing 50 mg of artemether.

• Ampoules of injectable solution for intramuscular injection containing 80 mg of artemether in 1 ml for adults or 40 mg of artemether in 1 ml for paediatric use.

In a coformulation with lumefantrine:

• Tablets containing 20 mg of artemether and 120 mg of lumefantrine.


Peak plasma concentrations occur around 2-3 h after oral administration (38). Following intramuscular injection, absorption is very variable, especially in children with poor peripheral perfusion: peak plasma concentrations generally occur after around 6 h but absorption is slow and erratic and times to peak can be 18 h or longer in some cases (39-41). Artemether is metabolized to dihydroartemisinin, the active metabolite. After intramuscular administration, artemether predominates, whereas after oral administration dihydroartemisinin predominates. Biotransformation is mediated via the cytochrome P450 enzyme CYP3A4. Autoinduction of metabolism is less than with artemisinin. Artemether is 95% bound to plasma proteins. The elimination half-life is approximately 1 h, but following intramuscular administration the elimination phase is prolonged because of continued absorption. No dose modifications are necessary in renal or hepatic impairment.


In all species of animals tested, intramuscular artemether and artemotil cause an unusual selective pattern of neuronal damage to certain brain stem nuclei. Neurotoxicity in experimental animals is related to the sustained blood concentrations that follow intramuscular administration (42), since it is much less frequent when the same doses are given orally, or with similar doses of water-soluble drugs such as artesunate. Clinical, neurophysiological and pathological studies in humans have not shown similar findings with therapeutic use of these compounds (40). Toxicity is otherwise similar to that of artemisinin.

Drug interactions

None known.

A3.6.3 Artesunate

Molecular weight: 384.4

Artesunate is the sodium salt of the hemisuccinate ester of artemisinin. It is soluble in water but has poor stability in aqueous solutions at neutral or acid pH. In the injectable form, artesunic acid is drawn up in sodium bicarbonate to form sodium artesunate immediately before injection. Artesunate can be given orally, rectally or by the intramuscular or intravenous routes. There are no coformulations currently available.


• Tablets containing 50 mg or 200 mg of sodium artesunate.

• Ampoules: intramuscular or intravenous injection containing 60 mg of anhydrous artesunic acid with a separate ampoule of 5% sodium bicarbonate solution.

• Rectal capsules containing 100 mg or 400 mg of sodium artesunate.


Artesunate is rapidly absorbed, with peak plasma levels occurring 1.5 h and 2 h and 0.5 h after oral, rectal and intramuscular administration, respectively (43-47). It is almost entirely converted to dihydroartemisinin, the active metabolite (30). Elimination of artesunate is very rapid, and antimalarial activity is determined by dihydroartemisinin elimination (half-life approximately 45 min) (40). The extent of protein binding is unknown. No dose modifications are necessary in renal or hepatic impairment.


As for artemisinin.

Drug interactions

None known.

A3.6.4 Dihydroartemisinin

Molecular weight: 284.4

Dihydroartemisinin is the main active metabolite of the artemisinin derivatives, but can also be given orally and rectally as a drug in its own right. It is relatively insoluble in water, and requires formulation with suitable excipients to ensure adequate absorption. It achieves cure rates similar to those of oral artesunate. A fixed-dose formulation with piperaquine is currently undergoing evaluation as a promising new artemisinin-based combination therapy (ACT).


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


Dihydroartemisinin is rapidly absorbed following oral administration, reaching peak levels after around 2.5 h. Absorption via the rectal route is somewhat slower, with peak levels occurring around 4 h after administration. Plasma protein binding is around 55%. Elimination half-life is approximately 45 min via intestinal and hepatic glucuronidation (48).


As for artemisinin.

Drug interactions

None known.

A3.6.5 Artemotil

Molecular weight: 312.4

Artemotil, previously known as arteether, is the ethyl ether of artemisinin, and is closely related to the more widely used artemether. It is oil-based so water insoluble. It is given by intramuscular injection only.


• Ampoules containing 150 mg of artemotil in 2 ml of injectable solution.


There is less published information on artemotil than for artemether. Absorption is slower and more erratic, with some patients having undetectable plasma artemotil until more than 24 h after administration.


As for artemisinin.

Drug interactions

None known.

A3.7 Lumefantrine (benflumetol)

Molecular weight: 528.9

Lumefantrine belongs to the aryl aminoalcohol group of antimalarials, which also includes quinine, mefloquine and halofantrine. It has a similar mechanism of action. Lumefantrine is a racemic fluorine derivative developed in China. It is only available in an oral preparation coformulated with artemether. This ACT is highly effective against multidrug-resistant P. falciparum.


Available only in an oral preparation coformulated with artemether: • Tablets containing 20 mg of artemether and 120 mg of lumefantrine.


Oral bioavailability is variable and is highly dependant on administration with fatty foods (38, 49). Absorption increases by 108% after a meal and is lower in patients with acute malaria than in convalescing patients. Peak plasma levels occur approximately 10 h after administration. The terminal elimination half-life is around 3 days.


Despite similarities with the structure and pharmacokinetic properties of halofantrine, lumefantrine does not significantly prolong the electrocardio-graphic QT interval, and has no other significant toxicity (50). In fact the drug seems to be remarkably well tolerated. Reported side effects are generally mild - nausea, abdominal discomfort, headache and dizziness - and cannot be distinguished from symptoms of acute malaria.

Drug interactions

The manufacturer of artemether-lumefantrine recommends avoiding the following: grapefruit juice; antiarrhythmics, such as amiodarone, disopyramide, flecainide, procainamide and quinidine; antibacterials, such as macrolides and quinolones; all antidepressants; antifungals such as imidazoles and triazoles; terfenadine; other antimalarials; all antipsychotic drugs; and beta blockers, such as metoprolol and sotalol. However, there is no evidence that co-administration with these drugs would be harmful.

A3.8 Primaquine

Molecular weight: 259.4

Primaquine is an 8-aminoquinoline and is effective against intrahepatic forms of all types of malaria parasite. It is used to provide radical cure of P. vivax and P. ovale malaria, in combination with a blood schizontocide for the erythrocytic parasites. Primaquine is also gametocytocidal against P. falciparum and has significant blood stage activity against P. vivax (and some against asexual stages of P. falciparum). The mechanism of action is unknown.


• Tablets containing 5.0 mg, 7.5 mg or 15.0 mg of primaquine base as diphosphate.


Primaquine is readily absorbed from the gastrointestinal tract. Peak plasma concentrations occur around 1-2 h after administration and then decline, with a reported elimination half-life of 3-6 h (51). Primaquine is widely distributed into body tissues. It is rapidly metabolized in the liver. The major metabolite is carboxyprimaquine, which may accumulate in the plasma with repeated administration.


The most important adverse effects are haemolytic anaemia in patients with G6PD deficiency, other defects of the erythrocytic pentose phosphate pathway of glucose metabolism, or some other types of haemoglobinopathy (52). In patients with the African variant of G6PD deficiency, the standard course of primaquine generally produces a benign self-limiting anaemia. In the Mediterranean and Asian variants, haemolysis may be much more severe. Therapeutic doses may also cause abdominal pain if administered on an empty stomach. Larger doses can cause nausea and vomiting. Methaemoglobinaemia may occur. Other uncommon effects include mild anaemia and leukocytosis.

Overdosage may result in leukopenia, agranulocytosis, gastrointestinal symptoms, haemolytic anaemia and methaemoglobinaemia with cyanosis.

Drug interactions

Drugs liable to increase the risk of haemolysis or bone marrow suppression should be avoided.

A3.9 Atovaquone

Molecular weight: 366.8

Atovaquone is a hydroxynaphthoquinone antiparasitic drug active against all Plasmodium species. It also inhibits pre-erythrocytic development in the liver, and oocyst development in the mosquito. It is combined with proguanil for the treatment of malaria - with which it is synergistic. Atovaquone interferes with cytochrome electron transport.


Atovaquone is available for the treatment of malaria in a co-formulation with proguanil:

• Film-coated tablets containing 250 mg of atovaquone and 100 mg of proguanil hydrochloride for adults.

• Tablets containing 62.5 mg of atovaquone and 25 mg of proguanil hydro-chloride for paediatric use.


Atovaquone is poorly absorbed from the gastrointestinal tract but bioavailability following oral administration can be improved by taking the drug with fatty foods. Bioavailabillity is reduced in patients with AIDS. Atovaquone is 99% bound to plasma proteins and has a plasma half-life of around 66-70 h due to enterohepatic recycling. It is excreted almost exclusively in the faeces as unchanged drug. Plasma concentrations are significantly reduced in late pregnancy (53).


Atovaquone is generally very well tolerated (54). Skin rashes, headache, fever, insomnia, nausea, diarrhoea, vomiting, raised liver enzymes, hyponatraemia and, very rarely, haematological disturbances, such as anaemia and neutropenia, have all been reported.

Drug interactions

Reduced plasma concentrations may occur with concomitant administration of metoclopramide, tetracycline and possibly also acyclovir, antidiarrhoeal drugs, benzodiazepines, cephalosporins, laxatives, opioids and paracetamol. Atovaquone decreases the metabolism of zidovudine and cotrimoxazole. Theoretically, it may displace other highly protein-bound drugs from plasma-protein binding sites.

A3.10 Proguanil

Molecular weight: 253.7

Proguanil is a biguanide compound that is metabolized in the body via the polymorphic cytochrome P450 enzyme CYP2C19 to the active metabolite, cycloguanil. Approximately 3% of Caucasian and African populations and 20% of Oriental people are "poor metabolizers" and have considerably reduced biotransformation of proguanil to cycloguanil (55, 56). Cycloguanil inhibits plasmodial dihydrofolate reductase. The parent compound has weak intrinsic antimalarial activity through an unknown mechanism. It is possibly active against pre-erythrocytic forms of the parasite and is a slow blood schizontocide. Proguanil also has sporontocidal activity, rendering the gametocytes non-infective to the mosquito vector. Proguanil is given as the hydrochloride salt in combination with atovaquone. It is not used alone for treatment as resistance to proguanil develops very quickly. Cycloguanil was formerly administered as an oily suspension of the embonate by intramuscular injection.


• Tablets of 100 mg of proguanil hydrochloride containing 87 mg of proguanil base.

In co-formulation with atovaquone:

• Film-coated tablets containing 250 mg of atovaquone and 100 mg of proguanil hydrochloride for adults.

• Tablet containing 62.5 mg of atovaquone and 25 mg of proguanil hydro-chloride for paediatric use.


Proguanil is readily absorbed from the gastrointestinal tract following oral administration. Peak plasma levels occur at about 4 h, and are reduced in the third trimester of pregnancy. Around 75% is bound to plasma proteins. Proguanil is metabolized in the liver to the active antifolate metabolite, cycloguanil, and peak plasma levels of cycloguanil occur 1 h after those of the parent drug. The elimination half-lives of both proguanil and cycloguanil is approximately 20 h (57, 58). Elimination is about 50% in the urine, of which 60% is unchanged drug and 30% cycloguanil, and a further amount is excreted in the faeces. Small amounts are present in breast milk. The elimination of cycloguanil is determined by that of the parent compound. The biotrans-formation of proguanil to cycloguanil via CYP2C19 is reduced in pregnancy and women taking the oral contraceptive pill (59, 60).


Apart from mild gastric intolerance, diarrhoea, occasional aphthous ulceration and hair loss, there are few adverse effects associated with usual doses of proguanil hydrochloride. Haematological changes (megaloblastic anaemia and pancytopenia) have been reported in patients with severe renal impairment. Overdosage may produce epigastric discomfort, vomiting and haematuria. Proguanil should be used cautiously in patients with renal impairment and the dose reduced according to the degree of impairment.

Drug interactions

Interactions may occur with concomitant administration of warfarin. Absorption of proguanil is reduced with concomitant administration of magnesium trisilicate.

A3.11 Chlorproguanil

Molecular weight: 288.2

Chlorproguanil is a biguanide and is given as the hydrochloride salt. Its actions and properties are very similar to those of proguanil. It is available only in combination with a sulfone such as dapsone (co-formulated as Lapdap).


Similar to those of proguanil (61).


As for proguanil.

Drug interactions

As for proguanil.

A3.12 Dapsone

Molecular weight: 248.3

Dapsone is a sulfone widely used for the treatment of leprosy, and sometimes also for treatment or prophylaxis of Pneumocystis carinii pneumonia, and treatment of toxoplasmosis, cutaneous leishmaniasis, actinomycetoma and dermatitis herpetiformis. For malaria, dapsone is given in combination with another antimalarial. It is coformulated with chlorproguanil (as Lapdap™). Dapsone inhibits plasmodial dihydropteroate synthase.


Dapsone is almost completely absorbed from the gastrointestinal tract, with peak plasma concentrations occurring 2-8 h after an oral dose. Dapsone is 50-80% bound to plasma proteins, as is almost 100% of monoacetyldapsone, its major metabolite. Dapsone undergoes enterohepatic recycling. It is widely distributed to body tissues, including breast milk and saliva. Its elimination half-life is 10-50 h. Dapsone is metabolized by acetylation, which exhibits genetic polymorphism. Hydroxylation is the other metabolic pathway, resulting in hydroxylamine dapsone, which may be responsible for dapsone-associated methaemoglobinaemia and haemolysis. Dapsone is mainly excreted in the urine, only 20% as unchanged drug.


Varying degrees of haemolysis and methaemoglobinaemia are the most frequently reported adverse effects and occur in most patients given more than 200 mg of dapsone daily. Doses of up to 100 mg daily do not cause significant haemolysis but patients deficient in G6PD are affected by doses of >50 mg daily. Haemolytic anaemia has been reported following ingestion of dapsone in breast milk. Agranulocytosis has been reported following use of dapsone and pyrimethamine together as malaria prophylaxis - particularly when used twice weekly. Aplastic anaemia has also been reported. Rashes, including pruritus and fixed-drug reactions may occur but serious cutaneous hyper-sensitivity is rare. "Dapsone syndrome" consists of rash, fever, jaundice and eosinophilia, and has been reported in a few patients using dapsone as malaria prophylaxis, but mainly in leprosy patients on long treatment courses. Other rare adverse effects include anorexia, nausea, vomiting, headache, hepatitis, hypoalbuminaemia and psychosis.

Drug interactions

There is an increased risk of dapsone toxicity with concomitant administration of probenecid, trimethoprim and amprenovir. Levels of dapsone are reduced with rifampicin.

A3.13 Quinine

Molecular weight: 324.4

Quinine is an alkaloid derived from the bark of the Cinchona tree. Four anti-malarial alkaloids can be derived from the bark: quinine (the main alkaloid), quinidine, cinchonine and cinchonidine. Quinine is the L-stereoisomer of quinidine.

Quinine acts principally on the mature trophozoite stage of parasite development and does not prevent sequestration or further development of circulating ring stages of P. falciparum. Like other structurally similar antimalarials, quinine also kills the sexual stages of P. vivax, P. malariae and P. ovale, but not mature gametocytes of P. falciparum. It does not kill the pre-erythrocytic stages of malaria parasites. The mechanisms of its antimalarial actions are thought to involve inhibition of parasite haem detoxification in the food vacuole, but are not well understood.


• Tablets of quinine hydrochloride, quinine dihydrochloride, quinine sulfate and quinine bisulfate containing 82%, 82%, 82.6% and 59.2% quinine base, respectively.

• Injectable solutions of quinine hydrochloride, quinine dihydrochloride and quinine sulfate containing 82%, 82% and 82.6% quinine base, respectively.


The pharmacokinetic properties of quinine are altered significantly by malaria infection, with reductions in apparent volume of distribution and clearance in proportion to disease severity (16, 62). In children under 2 years of age with severe malaria, concentrations are slightly higher than in older children and adults (63). There is no evidence for dose-dependent kinetics. Quinine is rapidly and almost completely absorbed from the gastrointestinal tract and peak plasma concentrations occur 1-3 h after oral administration of the sulfate or bisulfate (64). It is well absorbed after intramuscular injection in severe malaria (65, 66). Plasma-protein binding, mainly to alpha 1-acid glycoprotein, is 80% in healthy subjects but rises to around 90% in patients with malaria (67-69). Quinine is widely distributed throughout the body including the cerebrospinal fluid (2-7% of plasma values), breast milk (approximate 30% of maternal plasma concentrations) and the placenta (70). Extensive metabolism via the cytochrome P450 enzyme CYP3A4 occurs in the liver and elimination of more polar metabolites is mainly renal (71, 72). The initial metabolite 3-hydroxyquinine contributes approximately 10% of the antimalarial activity of the parent compound, but may accumulate in renal failure (73). Excretion is increased in acid urine. The mean elimination half-life is around 11 h in healthy subjects, 16 h in uncomplicated malaria and 18 h in severe malaria (62). Small amounts appear in the bile and saliva.


Administration of quinine or its salts regularly causes a complex of symptoms known as cinchonism, which is characterized in its mild form by tinnitus, impaired high tone hearing, headache, nausea, dizziness and dysphoria, and sometimes disturbed vision (7). More severe manifestations include vomiting, abdominal pain, diarrhoea and severe vertigo. Hypersensitivity reactions to quinine range from urticaria, bronchospasm, flushing of the skin and fever, through antibody-mediated thrombocytopenia and haemolytic anaemia, to life-threatening haemolytic-uraemic syndrome. Massive haemolysis with renal failure ("black water fever") has been linked epidemiologically and historically to quinine, but its etiology remains uncertain (74). The most important adverse effect in the treatment of severe malaria is hyperinsulinaemic hypoglycaemia (75). This is particularly common in pregnancy (50% of quinine-treated women with severe malaria in late pregnancy). Intramuscular injections of quinine dihydrochloride are acidic (pH 2) and cause pain, focal necrosis and in some cases abscess formation, and in endemic areas are a common cause of sciatic nerve palsy. Hypotension and cardiac arrest may result from rapid intravenous injection. Intravenous quinine should be given only by infusion, never injection. Quinine causes an approximately 10% prolongation of the electrocardiograph QT interval - mainly as a result of slight QRS widening (75). The effect on ventricular repolarization is much less than that with quinidine. Quinine has been used as an abortifacient, but there is no evidence that it causes abortion, premature labour or fetal abnormalities in therapeutic use.

Overdosage of quinine may cause oculotoxicity, including blindness from direct retinal toxicity, and cardiotoxicity, and can be fatal (76). Cardiotoxic effects are less frequent than those of quinidine and include conduction disturbances, arrhythmias, angina, hypotension leading to cardiac arrest and circulatory failure. Treatment is largely supportive, with attention being given to maintenance of blood pressure, glucose and renal function, and to treating arrhythmias.

Drug interactions

There is a theoretical concern that drugs that may prolong the QT interval should not be given with quinine, although whether or not quinine increases the risk of iatrogenic ventricular tachyarrhythmia has not been established. Antiarrhythmics, such as flecainide and amiodarone, should probably be avoided. There might be an increased risk of ventricular arrhythmias with anti-histamines such as terfenadine, and with antipsychotic drugs such as pimozide and thioridazine. Halofantrine, which causes marked QT prolongation, should be avoided but combination with other antimalarials, such as lumefantrine and mefloquine is safe. Quinine increases the plasma concentration of digoxin. Cimetidine inhibits quinine metabolism, causing increased quinine levels and rifampicin increases metabolic clearance leading to low plasma concentrations and an increased therapeutic failure rate (77).

A3.14 Tetracycline

Molecular weight: 444.4

The tetracyclines are a group of antibiotics originally derived from certain Streptomyces species, but used mostly in synthetic form. Tetracycline itself may be administered orally or intravenously as the hydrochloride salt or phosphate complex. Both are water soluble, although the intravenous preparation is only stable for a few hours. Tetracyclines are inhibitors of aminoacyl-tRNA binding during protein synthesis. They have a broad range of uses, including treatment of some bacterial infections: Chlamydia, Rickettsia, Mycoplasma, Lyme disease, Brucella, tularaemia, plague and cholera. Doxycycline is a synthetic tetracycline with a longer half-life, which makes dosing schedules easier.


• Capsules and tablets containing 250 mg of tetracycline hydrochloride, equivalent to 231 mg of tetracycline base.


Some 60-80% of tetracycline is absorbed from the gastrointestinal tract following oral administration. Absorption is reduced by the presence of divalent and trivalent metal ions with which it forms stable, insoluble complexes. Thus absorption may be impaired with food or milk. Formulation with phosphate may improve absorption. Peak plasma concentrations occur 1-3 h after ingestion. Tetracycline is 20-65% bound to plasma proteins. It is widely distributed throughout the body, although less so than the more lipophilic doxycycline. High concentrations are present in breast milk (around 60% of plasma levels), and also diffuse readily across the placenta, and are retained in sites of new bone formation and teeth development. The half-life of tetracycline is around 8 h;

40-70% is excreted in the urine via glomerular filtration. The remainder is excreted in the faeces and bile. Enterohepatic recycling slows down elimination.


All the tetracyclines have similar adverse effect profiles. Gastrointestinal effects, such as nausea, vomiting and diarrhoea, are common, especially with higher doses, and are due to mucosal irritation. Dry mouth, glossitis, stomatitis, dysphagia and oesophageal ulceration have also been reported. Overgrowth of Candida and other bacteria occurs, presumably due to disturbances in gastrointestinal flora as a result of incomplete absorption of the drug. This effect is seen less frequently with doxycycline, which is better absorbed. Pseudomembranous colitis, hepatotoxicity and pancreatitis have also been reported.

Tetracyclines accumulate in patients with renal impairment and this may cause renal failure. In contrast doxycycline accumulates less and is preferred in patient with renal impairment. The use of out-of-date tetracycline can result in the development of a reversible Fanconi-type syndrome characterized by polyuria and polydipsia with nausea, glycosuria, aminoaciduria, hypophos-phataemia, hypokalaemia, and hyperuricaemia with acidosis and proteinuria. These effects have been attributed to the presence of degradation products, in particular anhydroepitetracycline.

Tetracyclines are deposited in deciduous and permanent teeth during their formation and cause discoloration and enamel hypoplasia. They are also deposited in calcifying areas in bone and the nails and interfere with bone growth in young infants or pregnant women. Raised intracranial pressure in adults and infants has also been documented. Tetracyclines use in pregnancy has also been associated with acute fatty liver. Tetracyclines should therefore not be given to pregnant or lactating women, or children of less than 8 years of age.

Hypersensitivity reactions occur, although they are less common than for ß-lactam antibiotics. Rashes, fixed drug reactions, drug fever, angioedema, urticaria, pericarditis and asthma have all been reported. Photosensitivity may develop and, rarely, haemolytic anaemia, eosinophilia, neutropenia and thrombocytopenia. Pre-existing systemic lupus erythematosus may be worsened and tetracyclines are contraindicated in patients with the established disease.

Drug interactions

There is reduced absorption of tetracyclines with concomitant administration of cations, such as aluminium, bismuth, calcium, iron, zinc and magnesium. Administration with antacids, iron preparations, dairy products and some other foods should therefore be avoided. Nephrotoxicity may be exacerbated with diuretics, methoxyflurane or other potentially nephrotoxic drugs. Potentially hepatotoxic drugs should be avoided. Tetracyclines produce increased concentrations of digoxin, lithium and theophylline, and decrease plasma atovaquone concentrations and also the effectiveness of oral contraceptives. They may antagonize the actions of penicillins so should not be given concomitantly.

A3.15 Doxycycline

(See also tetracycline) Molecular weight: 444.4

Doxycycline is a tetracycline derivative with uses similar to those of tetracycline. It may be preferred to \tetracycline because of its longer half-life, more reliable absorption and better safety profile in patients with renal insufficiency, where it may be used with caution. It is relatively water insoluble but very lipid soluble. It may be given orally or intravenously. It is available as the hydro-chloride salt or phosphate complex, or as a complex prepared from the hydrochloride and calcium chloride.


• Capsules and tablets containing 100 mg of doxycycline salt as hydrochloride.


Doxycycline is readily and almost completely absorbed from the gastrointestinal tract and absorption is not affected significantly by the presence of food. Peak plasma concentrations occur 2 h after administration. Some 80-95% is protein- bound and half-life is 10-24 h (78). It is widely distributed in body tissues and fluids. In patients with normal renal function, 40% of doxycycline is excreted in the urine, although more if the urine is alkalinized. It may accumulate in renal failure. However, the majority of the dose is excreted in the faeces.


As for tetracycline. Gastrointestinal effects are fewer than with tetracycline, although oesophageal ulceration can still be a problem if insufficient water is taken with tablets or capsules. There is less accumulation in patients with renal impairment. Doxycycline should not be given to pregnant or lactating women, or children aged up to 8 years.

Drug interactions

Doxycycline has a lower affinity for binding with calcium than other tetracyclines, so may be taken with food or milk. However, antacids and iron may still affect absorption. Metabolism may be accelerated by drugs that induce hepatic enzymes, such as carbamazepine, phenytoin, phenobarbital and rifampicin, and by chronic alcohol use.

A3.16 Clindamycin

Molecular weight: 425.0

Clindamycin is a lincosamide antibiotic, i.e. a chlorinated derivative of lincomycin. It is very soluble in water. It inhibits the early stages of protein synthesis by a mechanism similar to that of the macrolides. It may be administered by mouth as capsules containing the hydrochloride or as oral liquid preparations containing the palmitate hydrochloride. Clindamycin is given parenterally as the phosphate either by the intramuscular or the intravenous route. It is used for the treatment of anaerobic and Gram-positive bacterial infections, babesiosis, toxoplasmosis and Pneumocystis carinii pneumonia.


• Capsules containing 75 mg, 150 mg or 300 mg of clindamycin base as hydrochloride.


About 90% of a dose is absorbed following oral administration. Food does not impede absorption but may delay it. Clindamycin phosphate and palmitate hydrochloride are rapidly hydrolysed to form the free drug. Peak concentrations may be reached within 1 h in children and 3 h in adults. It is widely distributed, although not into the cerebrospinal fluid. It crosses the placenta and appears in breast milk. It is 90% bound to plasma proteins and accumulates in leukocytes, macrophages and bile. The half-life is 2-3 h but this may be prolonged in neonates and patients with renal impairment. Clindamycin undergoes metabolism to the active N-demethyl and sulfoxide metabolites, and also some inactive metabolites. About 10% of a dose is excreted in the urine as active drug or metabolites and about 4% in the faeces. The remainder is excreted as inactive metabolites. Excretion is slow and takes place over many days. Clindamycin is not effectively removed from the body by dialysis.


Diarrhoea occurs in 2-20% of patients. In some, pseudomembranous colitis may develop during or after treatment, which can be fatal. Other reported gastrointestinal effects include nausea, vomiting, abdominal pain and an unpleasant taste in the mouth. Around 10% of patients develop a hypersensitivity reaction. This may take the form of skin rash, urticaria or anaphylaxis. Other adverse effects include leukopenia, agranulocytosis, eosinophilia, thrombocytopenia, erythema multiforme, polyarthritis, jaundice and hepatic damage. Some parenteral formulations contain benzyl alcohol, which may cause fatal "gasping syndrome" in neonates.

Drug interactions

Clindamycin may enhance the effects of drugs with neuromuscular blocking activity and there is a potential danger of respiratory depression. Additive respiratory depressant effects may also occur with opioids. Clindamycin may antagonize the activity of parasympathomimetics.

A3.17 Pharmacology of antimalarials in special groups and conditions

A3.17.1 Safety and tolerability of antimalarials in infants

Infants under 12 months of age constitute a significant proportion of patients in malaria endemic countries. Yet few studies focus specifically on this age range, partly because of ethical dilemmas and also owing to technical difficulties with sampling. Very young children cannot report adverse effects themselves, so detection of these is dependent upon parents and health professionals making observations. In addition, pre-marketing clinical trials for new drugs are not represented by important subpopulations including infants (79), yet there are potentially important pharmacokinetic differences in infants compared to older children and adults (80).

Drug absorption

The gastric pH at birth is usually 6-8 but within a few hours falls to 2 and then rises again until virtual achlorhydria occurs for several days. As the gastric mucosa develops, the acidity increases again until 3 years of age when adult values are attained. The gastric emptying time is prolonged (up to 8 h) in neonates and approaches adult values only after 6 months. Intramuscular injections can also be problematic in young children. Infants with acute or severe malaria may become extremely "shut down" whereby visceral, muscle and skin blood flow is reduced. This may result in slow, erratic or incomplete drug absorption and the consequent delay in achieving therapeutic drug levels at a time when speed and adequacy of drug delivery are crucial.


Relatively large total and extracellular body water compartments in infancy lead to larger apparent volumes of distribution. Total body lipids rise steadily after birth for the first 9 months of life but then decrease until adolescence. These changes in body composition can modulate volume of distribution and clearance. Liver mass per body weight is higher in infants than adults and the liver undergoes rapid growth during the first 2 years. The brain is disproportionately large in young children, and the blood brain barrier relatively immature, making a further contribution to volume of distribution. Finally drug distribution is also affected by lower protein binding in infancy with more free drug and thus increased clearance. The former might also lead to a greater risk of toxicity.

Drug metabolism

The cytochrome P450 mixed function oxidase system is the most important biotransformation system incorporating many enzymes and isoenzymes. In general, these enzyme systems are immature at birth. There is therefore relatively slow clearance of most metabolized drugs in the first 2-3 months of life. Between 2 and 6 months clearance is more rapid than in adults and even more so for most drugs from 6 months to 2 years (elimination half-life for metabolized drugs in infants aged 6 months to 2 years is 0.6 times that in adults).

Renal clearance

Glomerular filtration rate only reaches surface-area-adjusted adult levels at around 6 months of age. Thus for drugs that rely on renal elimination, elimination half-lives in very young infants may be up to 2-3 times longer than in adults. After 2 months, half-lives are shorter (0.35-0.5 times adult values) until about 2 years of age.

A3.17.2 Malnutrition and antimalarials

Malaria and malnutrition frequently coexist. The relationship between malaria and nutritional status is complex and has been the subject of debate for many years (81). Given that a significant proportion of the world's malnourished children live in malaria endemic countries (82) it is important to understand how antimalarial drug disposition may be affected when malnutrition is severe. This section outlines the physiological changes that occur in malnourished patients and discusses how these may influence the pharmacokinetic properties of antimalarials, drawing on the few studies of antimalarial drug disposition in malnutrition that are available

Note: in reviewing the literature it was apparent that many studies were conducted in populations and settings where some degree of malnutrition would have been expected. However, this was only rarely mentioned as a possible confounder for drug efficacy, although there was an occasional comment that obviously malnourished patients appeared to respond differently to treatment than did other patients (83). Several ongoing studies are planning to look specifically at treatment outcomes in this group of patients.


There are different ways of classifying malnutrition. Earlier studies employ the Wellcome classification: where body weight is given as a percentage of standard weight (50th percentile of the Harvard value): underweight 80-60%; marasmus 60%; kwashiorkor 80-60% + oedema; marasmic kwashiorkor 60% + oedema. Other studies refer to low weight-for-height (wasting); low weight- for-age (underweight); or low height-for-age (stunting) and use anthropometric indicators and reference standards. Protein-energy malnutrition is defined as a range of pathological conditions arising from coincident lack, in varying proportions, of protein and calories, occurring most frequently in infants and young children and commonly associated with infections (84).



Anorexia, diarrhoea and vomiting are common. Anorexia will affect the absorption of drugs requiring concomitant administration of fatty foods, and oral bioavailability will be reduced in vomiting patients or those with a rapid transit time. Atrophy of the bowel mucosa, which occurs in severe protein-energy malnutrition, will also hinder absorption.

Children with oedematous lower limbs may be expected to have altered absorption from intramuscular injections. Patients with protein-energy malnutrition frequently have poor peripheral perfusion due to circulatory insufficiency associated with bradycardia, hypotension and a reduced cardiac output. Thus absorption of intramuscular and possibly intrarectal drugs may be expected to be slower than in patients without protein-energy malnutrition. Diminished muscle mass may make repeated intramuscular injections difficult.


Total body water increases in proportion to the degree of malnutrition, mainly owing to an expansion of the extracellular fluid (most obvious in oedematous patients). Thus the volume of distribution of some drugs can be expected to be larger and plasma concentrations lower. Albumin is the most important plasma protein for binding of many drugs, but in protein-energy malnutrition hypoalbuminaemia results from decreased synthesis as dietary deficiency occurs. With highly bound drugs this could in theory lead to an increase in the amount of unbound drug, which may increase both the elimination, since more drug is available for metabolism, and potential toxicity. There are other plasma proteins less severely affected by decreased synthesis, and if these are able to bind some free drug, then the increase in free fraction might not be as great as anticipated.


Fatty infiltration occurs but jaundice is uncommon unless septicaemia is present. Liver function tests may be abnormal and urea cycle enzymes are decreased. Children with kwashiorkor excreted a higher proportion of unchanged chloroquine before therapy than in the recovery phase (85). This suggests that hepatic function was inadequate during the acute phase of kwashiorkor. Animal studies have demonstrated that some enzyme systems, such as cytochrome P450, have decreased activity in the presence of significant malnutrition.


Owing to the reduction in cardiac output, the kidneys receive less than the usual 25% of renal blood flow. Glomerular filtration rate, renal blood flow and tubular function have all been shown to be inadequate, and compounded by concomitant dehydration. Drugs dependent on renal excretion might be expected to have elevated plasma concentrations under such circumstances. Abnormal excretion of drugs into bile has also been described in severe protein-energy malnutrition.

Antimalarials and protein-energy malnutrition


Few data are available for chloroquine kinetics in malnourished patients. Children with kwashiorkor excreted a higher ratio of chloroquine to its metabolites before nutritional rehabilitation (85). Presumably the metabolism of chloroquine by the liver was affected adversely in protein-energy malnutrition. In a study of chloroquine pharmacokinetics in five children with kwashiorkor (but without malaria), peak plasma concentrations of the drug were approximately one-third of the values for healthy controls (mean 40 + 30 ng/ml compared to 134 + 99 ng/ml), but the times to peak levels and the elimination half-lives were not significantly different, indicating reduced absorption. There was also reduced metabolism of chloroquine to its metabolite, desethyl-chloroquine, which suggested some impairment of drug metabolism. However, the study did not consider plasma protein binding or drug distribution. Currently there are no recommendations for dose alterations in patients with protein-energy malnutrition (86).


Three studies examining the kinetics of quinine in malnourished patients have been published. The first from Nigeria compared the pharmacokinetics of an oral dose of quinine 10 mg/kg in six children with kwashiorkor and seven normal controls who were attending a malaria follow-up clinic (87). The children were aged 1-3 years. Values for total plasma proteins and albumin for children with kwashiorkor were 74% and 67% of those for control children. Absorption of quinine was slower in the kwashiorkor group than in the controls (mean time to maximum concentration (tmax) 2.5 ± 0.3 h compared to 1.5 ± 0.6 h); maximum plasma concentration (Cmax) was also lower (1.7 ± 0.5 µmol/l compared to 2.4+ 0.3 µmol/l). Rate of clearance of quinine in kwashiorkor was less than one-third of the value for well-nourished patients (31.5 ± 8.5 mg/min compared to 108.5 ± 34.8 mg/min) and the elimination half-life was also longer (15.0 ± 4.4 h compared to 8.0 ± 1.3 h). The authors concluded that the combination of malabsorption, reduced plasma protein binding and reduced metabolism in the liver was responsible for the differences observed. No dose alterations were suggested.

The second study, in Gabon, compared eight children with non-kwashiorkor global malnutrition (defined as having a ratio of left mid-arm circumference:head circumference < 0.279) with seven children with normal nutritional status (88). The children were aged 9-60 months. Only two were subsequently confirmed to have malaria, although all had been febrile at presentation. Mean serum albumin levels in the two groups were 28.7 and 31.0 respectively. Each child received a loading dose of 16 mg/kg quinine base (25 mg/kg quinine resorcine hydrochloride; Quinimax) by deep intramuscular injection followed by 8 mg/kg at 12 h. The tmax was significantly shorter in malnourished children (1.1 ± 0.4 h compared to 2.2 ± 1.2 h). No difference was observed for Cmax, volume of distribution or protein binding. Clearance was significantly faster for malnourished children (4.4 ± 3.6 ml/min/kg compared to 2.3 ± 1.4 ml/min/kg), and half-life shorter (6.3 ± 1.8 h compared to 10.1 ± 3.4 h). Concentration at 12 h was lower in malnourished children (3.3 ± 1.6 mg/ml compared to 5.3 ± 1.6 mg/l). There was a significant correlation between elimination half-life and left mid-arm:head circumference. The ratio between the area under the curve for hydroxyquinine, the main metabolite of quinine, and that for quinine was significantly higher in the malnourished group and significantly correlated with left mid-arm:head circumference ratio, indicating increased metabolism of quinine in malnourished patients. The authors suggest that the administration interval should be reduced to 8 h in malnourished children in order to obtain plasma concentrations of quinine similar to those found in children with normal nutrition.

In the third study, from Niger, 40 children were divided into four groups: normally nourished children with or without cerebral malaria, and malnourished children (>2 SD below the median value for at least two of the following: weight-for-height, weight-for-age and height-for-age) with or without cerebral malaria (89). The age range studied was 24-72 months. Patients with kwashiorkor were excluded. All patients received 4.7 mg/kg quinine base (as 8 mg/kg Quinimax) by intravenous infusion over 4 h. Infusions were repeated every 8 h for children with cerebral malaria. Cmax was highest in malnourished children, and was higher in those without malaria than with malaria (8.5 ± 4.7 mg/l compared to 7.7 ± 2.0 mg/l); it was lowest in the control groups without and with malaria (3.0 ± 2.1 mg/l and 6.6 ± 3.0 mg/l). There were no differences between the area under the curve for 0-8 h and elimination half-life for the two malnutrition groups and controls with malaria, but all were higher than for controls without malaria. Conversely plasma clearance of quinine and volume of distribution were smaller in these three groups than in controls without malaria. Alpha 1-glycoprotein plasma concentrations and protein-bound fraction of the drug were increased in the three groups. Malnourished children had slower parasite clearance but the difference was not significant. The authors concluded that severe global malnutrition and cerebral malaria have a similar effect on quinine pharmacokinetics in children and that cerebral malaria-mediated modifications of quinine disposition are not potentiated. They recommend that current dosing schedules should not be altered for children with malnutrition.


No studies exist of sulfadoxine-pyrimethamine kinetics in malnourished patients. However, observational data from Rwandan refugee children showed that malnourished children (defined as weight-for-height <80% of the reference median with or without oedema) were more likely to have treatment failure than children without malnutrition (86% compared to 58% (83). Higher initial parasite counts and host immunity, as well as pharmacokinetic differences, may also have contributed to this finding.


A number of small studies have been conducted on tetracycline kinetics in malnourished adults from India. One study compared the kinetics of intravenous and oral tetracycline in malnourished and normal adult males (90). Compared to the control group, malnourished patients had lower protein binding, shorter elimination half-life and reduced volume of distribution. The authors suggest that in order to keep levels of tetracycline above the minimum inhibitory concentration, the dose interval should be reduced. A similar conclusion was reached by another study that also found more rapid distribution of tetracycline and faster clearance in the malnourished group (91). The same author, in a separate study, also looked at absorption of oral compared with intravenous tetracycline in various types of malnutrition. Oral absorption was slower in patients with protein-energy-malnutrition and pellagra than in patients with anaemia or vitamin B complex deficiency patients and healthy controls. In a third study, patients with nutritional oedema were found to have increased Cmax and area under the curve values, and reduced clearance and volume of distribution compared with healthy controls (i.e. some differences with non-oedema malnutrition patients) (92).


There is a single study examining the kinetics of doxycycline given orally to adult patients in India (93). Area under the curve, elimination half-life and plasma protein binding were reduced, and clearance increased in the malnourished group. Renal clearance was similar in controls and malnourished patients. The authors surmised that increased total body clearance of doxy-cycline might be due to higher metabolism in malnourished patients. Steady state plasma Cmin levels were lower than in healthy patients but still within the therapeutic range. A change in dose recommendation does not seem necessary given these findings.

Other antimalarials

There are no studies of the kinetics of clindamycin, amodiaquine, artemisinin derivatives (dihydroartemisinin), artemether-lumefantrine, mefloquine or primaquine kinetics in malnourished patients.


There are many reasons why pharmacokinetics may be different in malnourished patients compared to those who are well nourished. However, with the possible exception of quinine, there are insufficient data available for specific dosing changes to be recommended.

A3.18 References24

24 Further information on the chemistry and pharmacology of antimalarials can be obtained from the web site of the United States National Library of Medicines, Specialized Information Services, ChemIDplus Advanced:

1. Krugliak M, Ginsburg H. Studies on the antimalarial mode of action of quinoline-containing drugs: time-dependence and irreversibility of drug action, and interactions with compounds that alter the function of the parasite's food vacuole. Life Sciences, 1991, 49:1213-1219.

2. Bray PG et al. Access to hematin: the basis of chloroquine resistance. Molecular Pharmacology, 1998, 54:170-179.

3. Gustafsson LL et al. Disposition of chloroquine in man after single intravenous and oral doses. British Journal of Clinical Pharmacology, 1983, 15:471-479.

4. Walker O et al. Plasma chloroquine and desethylchloroquine concentrations in children during and after chloroquine treatment for malaria. British Journal of Clinical Pharmacology, 1983:16:701-705.

5. White NJ et al. Chloroquine treatment of severe malaria in children. Pharmacokinetics, toxicity, and new dosage recommendations. New England Journal of Medicine, 1988, 319:1493-1500.

6. Mnyika KS, Kihamia CM. Chloroquine-induced pruritus: its impact on chloroquine utilization in malaria control in Dar es Salaam. Journal of Tropical Medicine and Hygiene, 1991, 94:27-31.

7. Taylor WR, White NJ. Antimalarial drug toxicity: a review. Drug Safety, 2004, 27:25-61.

8. Riou B et al. Treatment of severe chloroquine poisoning. New England Journal of Medicine, 1988, 318:1-6.

9. Clemessy JL et al. Treatment of acute chloroquine poisoning: a 5-year experience. Critical Care Medicine, 1996, 24:1189-1195.

10. Winstanley PA et al. The disposition of amodiaquine in Zambians and Nigerians with malaria. British Journal of Clinical Pharmacology, 1990, 29:695-701.

11. Hatton CS et al. Frequency of severe neutropenia associated with amodiaquine prophylaxis against malaria. Lancet, 1986, 1:411-414.

12. Miller KD et al. Severe cutaneous reactions among American travelers using pyrimethamine-sulfadoxine (Fansidar) for malaria prophylaxis. American Journal of Tropical Medicine and Hygiene, 1986, 35:451-458.

13. Bjorkman A, Phillips-Howard PA. Adverse reactions to sulfa drugs: implications for malaria chemotherapy. Bulletin of the World Health Organization, 1991, 69:297-304.

14. Winstanley PA et al. The disposition of oral and intramuscular pyrimethamine/sulphadoxine in Kenyan children with high parasitaemia but clinically non-severe falciparum malaria. British Journal of Clinical Pharmacology, 1992, 33:143-148.

15. Price R et al. Pharmacokinetics of mefloquine combined with artesunate in children with acute falciparum malaria. Antimicrobial Agents and Chemotherapy, 1999, 43:341-346.

16. Krishna S, White NJ. Pharmacokinetics of quinine, chloroquine and amodiaquine. Clinical implications. Clinical Pharmacokinetics, 1996, 30:263-299

17. Simpson JA et al. Population pharmacokinetics of mefloquine in patients with acute falciparum malaria. Clinical Pharmacology and Therapeutics, 1999, 66:472-484.

18. Slutsker LM et al. Mefloquine therapy for Plasmodium falciparum malaria in children under 5 years of age in Malawi: in vivo/in vitro efficacy and correlation of drug concentration with parasitological outcome. Bulletin of the World Health Organization, 1990, 68:53-59.

19. Karbwang J et al. Pharmacokinetics and pharmacodynamics of mefloquine in Thai patients with acute falciparum malaria. Bulletin of the World Health Organization, 1991, 69:207-212.

20. Nosten F et al. Mefloquine pharmacokinetics and resistance in children with acute falciparum malaria. British Journal of Clinical Pharmacology, 1991, 31:556-559.

21. Svensson US et al. Population pharmacokinetic and pharmacodynamic modelling of artemisinin and mefloquine enantiomers in patients with falciparum malaria. European Journal of Clinical Pharmacology, 2002, 58:339-351.

22. Gimenez F et al. Stereoselective pharmacokinetics of mefloquine in healthy Caucasians after multiple doses. Journal of Pharmaceutical Sciences, 1994, 83:824-827.

23. Bourahla A et al. Stereoselective pharmacokinetics of mefloquine in young children. European Journal of Clinical Pharmacology, 1996, 50:241-244.

24. Bem JL, Kerr L, Stuerchler D. Mefloquine prophylaxis: an overview of spontaneous reports of severe psychiatric reactions and convulsions. Journal of Tropical Medicine and Hygiene, 1992, 95:167-179.

25. ter Kuile FO et al. Mefloquine treatment of acute falciparum malaria: a prospective study of non-serious adverse effects in 3673 patients. Bulletin of the World Health Organization, 1995, 73:631-642.

26. Phillips-Howard PA, ter Kuile FO. CNS adverse events associated with antimalarial agents. Fact or fiction? Drug Safety, 1995, 12:370-383.

27. Mai NTH et al. Post-malaria neurological syndrome. Lancet, 1996, 348:917-921.

28. Supanaranond W et al. Lack of a significant adverse cardiovascular effect of combined quinine and mefloquine therapy for uncomplicated malaria. Transactions of the Royal Society of Tropical Medicine and Hygiene, 1997, 91:694-696.

29. Eckstein-Ludwig U et al. Artemisinins target the SERCA of Plasmodium falciparum. Nature, 2003, 424:957-961.

30. Navaratnam V et al. Pharmacokinetics of artemisinin-type compounds. Clinical Pharmacokinetics, 2000, 39:255-270.

31. Ashton M, Nguyen DS, Nguyen VH, et al. Artemisinin kinetics and dynamics during oral and rectal treatment of uncomplicated malaria. Clinical Pharmacology and Therapeutics, 1998, 63:482-493.

32. Ribeiro IR, Olliaro P. Safety of artemisinin and its derivatives. A review of published and unpublished clinical trials. Medicine Tropical (Mars), 1998, 58(3 Suppl.):50-53.

33. Price R et al. Adverse effects in patients with acute falciparum malaria treated with artemisinin derivatives. American Journal of Tropical Medicine and Hygiene, 1999, 60:547-555.

34. Leonardi E et al. Severe allergic reactions to oral artesunate: a report of two cases. Transactions of the Royal Society of Tropical Medicine and Hygiene, 2001, 95:182-183.

35. van Vugt M et al. A case-control auditory evaluation of patients treated with artemisinin derivatives for multidrug-resistant Plasmodium falciparum malaria. American Journal of Tropical Medicine and Hygiene, 2000, 62:65-69.

36. Kissinger E et al. Clinical and neurophysiological study of the effects of multiple doses of artemisinin on brain-stem function in Vietnamese patients. American Journal of Tropical Medicine and Hygiene, 2000, 63:48-55.

37. Hien TT et al. Neuropathological assessment of artemether-treated severe malaria. Lancet, 2003, 362:295-296.

37aAssessment of the safety of artemisinin compounds in pregnancy. Geneva, World Health Organization, 2003 (document WHO/CDS/MAL/2003.1094).

38. Ezzet F, Mull R, Karbwang J. Population pharmacokinetics and therapeutic response of CGP 56697 (artemether + benflumetol) in malaria patients. British Journal of Clinical Pharmacology, 1998, 46:553-561.

39. Murphy SA et al. The disposition of intramuscular artemether in children with cerebral malaria; a preliminary study. Transactions of the Royal Society of Tropical Medicine and Hygiene, 1997, 91:331-334.

40. Hien TT et al. Comparative pharmacokinetics of intramuscular artesunate and artemether in patients with severe falciparum malaria. Antimicrobial Agents and Chemotherapy, 2004, 48:4234-4239.

41. Mithwani S et al. Population pharmacokinetics of artemether and dihydro-artemisinin following single intramuscular dosing of artemether in African children with severe falciparum malaria. British Journal of Clinical Pharmacology, 2004, 57:146-152.

42. Brewer TG et al. Neurotoxicity in animals due to arteether and artemether. Transactions of the Royal Society of Tropical Medicine and Hygiene, 1994, 88 (Suppl. 1):S33-36.

43. Bethell DB et al. Pharmacokinetics of oral artesunate in children with moderately severe Plasmodium falciparum malaria. Transactions of the Royal Society of Tropical Medicine and Hygiene, 1997, 91:195-198.

44. Batty KT et al. A pharmacokinetic and pharmacodynamic study of intravenous vs oral artesunate in uncomplicated falciparum malaria. British Journal of Clinical Pharmacology, 1998, 45:123-129.

45. Newton PN et al. Antimalarial bioavailability and disposition of artesunate in acute falciparum malaria. Antimicrobial Agents and Chemotherapy, 2000, 44:972-997.

46. Krishna S et al. Bioavailability and preliminary clinical efficacy of intrarectal artesunate in Ghanaian children with moderate malaria. Antimicrobial Agents and Chemotherapy, 2001, 45:509-516.

47. Ilett KF et al. The pharmacokinetic properties of intramuscular artesunate and rectal dihydroartemisinin in uncomplicated falciparum malaria. British Journal of Clinical Pharmacology, 2002, 53:23-30.

48. Newton PN et al. Comparison of oral artesunate and dihydroartemisinin antimalarial bioavailabilities in acute falciparum malaria. Antimicrobial Agents and Chemotherapy, 2002, 46:1125-1127.

49. White NJ, van Vugt M, Ezzet F. Clinical pharmacokinetics and pharmacodynamics of artemether-lumefantrine. Clinical Pharmacokinetics, 1999, 37:105-125.

50. van Vugt M et al. No evidence of cardiotoxicity during antimalarial treatment with artemether-lumefantrine. American Journal of Tropical Medicine and Hygiene, 1999, 61:964-967.

51. Mihaly GW et al. Pharmacokinetics of primaquine in man: identification of the carboxylic acid derivative as a major plasma metabolite. British Journal of Clinical Pharmacology, 1984, 17:441-446.

52. Chan TK, Todd D, Tso SC. Drug-induced haemolysis in glucose-6-phosphate dehydrogenase deficiency. British Medical Journal, 1976, 2:1227-1229.

53. McGready R et al. The pharmacokinetics of atovaquone and proguanil in pregnant women with acute falciparum malaria. European Journal of Clinical Pharmacology, 2003, 59:545-552.

54. Sabchareon A et al. Efficacy and pharmacokinetics of atovaquone and proguanil in children with multidrug-resistant Plasmodium falciparum malaria. Transactions of the Royal Society of Tropical Medicine and Hygiene, 1998, 92:201-206.

55. Helsby NA et al. The pharmacokinetics and activation of proguanil in man: consequences of variability in drug metabolism. British Journal of Clinical Pharmacology, 1990, 30:593-598.

56. Kaneko A et al. Proguanil disposition and toxicity in malaria patients from Vanuatu with high frequencies of CYP2C19 mutations. Pharmacogenetics, 1999, 9:317-326.

57. Wattanagoon Y et al. Single dose pharmacokinetics of proguanil and its metabolites in healthy subjects. British Journal of Clinical Pharmacology, 1987, 24:775-780.

58. Hussein Z et al. Population pharmacokinetics of proguanil in patients with acute P. falciparum malaria after combined therapy with atovaquone. British Journal of Clinical Pharmacology, 1996, 42:589-597.

59. Wangboonskul J et al. Single dose pharmacokinetics of proguanil and its metabolites in pregnancy. European Journal of Clinical Pharmacology, 1993, 44:247-251.

60. McGready R et al. Pregnancy and use of oral contraceptives reduces the biotransformation of proguanil to cycloguanil. European Journal of Clinical Pharmacology, 2003, 59:553-557.

61. Veenendaal JR, Edstein MD, Rieckmann KH. Pharmacokinetics of chlorproguanil in man after a single oral dose of Lapudrine. Chemotherapy, 1988, 34:275-283.

62. White NJ et al. Quinine pharmacokinetics and toxicity in cerebral and uncomplicated falciparum malaria. American Journal of Medicine, 1982, 73:564-572.

63. van Hensbroek MB et al. Quinine pharmacokinetics in young children with severe malaria. American Journal of Tropical Medicine and Hygiene, 1996, 54:237-242.

64. Supanaranond W et al. Disposition of oral quinine in acute falciparum malaria. European Journal of Clinical Pharmacology, 1991, 40:49-52.

65. Waller D et al. The pharmacokinetic properties of intramuscular quinine in Gambian children with severe falciparum malaria. Transactions of the Royal Society of Tropical Medicine and Hygiene, 1990. 84:488-491.

66. White NJ. Optimal regimens of parenteral quinine. Transactions of the Royal Society of Tropical Medicine and Hygiene, 1995, 89:462-464.

67. Silamut K et al. Binding of quinine to plasma proteins in falciparum malaria. American Journal of Tropical Medicine and Hygiene, 1985, 34:681-686.

68. Silamut K et al. Alpha 1-acid glycoprotein (orosomucoid) and plasma protein binding of quinine in falciparum malaria. British Journal of Clinical Pharmacology, 1991, 32:311-315.

69. Mansor SM et al. Effect of Plasmodium falciparum malaria infection on the plasma concentration of alpha 1-acid glycoprotein and the binding of quinine in Malawian children. British Journal of Clinical Pharmacology, 1991, 32:317-321.

70. Phillips RE et al. Quinine pharmacokinetics and toxicity in pregnant and lactating women with falciparum malaria. British Journal of Clinical Pharmacology, 1986, 21:677-683.

71. Hall AP et al. Human plasma and urine quinine levels following tablets, capsules, and intravenous infusion. Clinical Pharmacology and Therapeutics, 1973, 14:580-585.

72. Pukrittayakamee S et al. A study of the factors affecting the metabolic clearance of quinine in malaria. European Journal of Clinical Pharmacology, 1997, 52:487-493.

73. Newton PN et al. Pharmacokinetics of quinine and 3-hydroxyquinine in severe falciparum malaria with acute renal failure. Transactions of the Royal Society of Tropical Medicine and Hygiene, 1999, 93:69-72.

74. Bruce-Chwatt LJ. Quinine and the mystery of blackwater fever. Acta Leidensia, 1987, 55:181-196.

75. White NJ, Looareesuwan S, Warrell DA. Quinine and quinidine: a comparison of EKG effects during the treatment of malaria. Journal of Cardiovascular Pharmacology, 1983, 5:173-175.

76. Boland ME, Roper SM, Henry JA. Complications of quinine poisoning. Lancet, 1985, 1:384-385.

77. Pukrittayakamee S et al. Adverse effect of rifampicin on quinine efficacy in uncomplicated falciparum malaria. Antimicrobial Agents and Chemotherapy, 2003, 47:1509-1513.

78. Newton PN et al. The Pharmacokinetics of oral doxycycline during combination treatment of severe falciparum malaria. Antimicrobial Agents and Chemotherapy, 2005, 49:1622-1625.

79. Atuah KN, Hughes D, Pirmohamed M. Clinical pharmacology: special safety considerations in drug development and pharmacovigilance. Drug Safety, 2004, 27:535-554.

80. Ginsberg G et al. Pediatric pharmacokinetic data: implications for environmental risk assessment for children. Pediatrics, 2004, 113(4 Suppl.):973-983.

81. Shankar AH. Nutritional modulation of malaria morbidity and mortality. Journal of Infectious Diseases, 2000, 182(Suppl. 1):S37-S53.

82. de Onis M et al. The worldwide magnitude of protein-energy malnutrition: an overview from the WHO Global Database on Child Growth. Bulletin of the World Health Organization, 1993, 71:703-712.

83. Wolday D et al. Sensitivity of Plasmodium falciparum in vivo to chloroquine and pyrimethamine-sulfadoxine in Rwandan patients in a refugee camp in Zaire. Transactions of the Royal Society of Tropical Medicine and Hygiene, 1995, 89:654-656.

84. Wellcome Trust Working Party. Classification of infantile malnutrition. Lancet, 1970, 2:302-303.

85. Wharton BA, McChesney EW. Chloroquine metabolism in kwashiorkor. Journal of Tropical Pediatrics, 1970, 16:130-132.

86. Walker O et al. Single dose disposition of chloroquine in kwashiorkor and normal children - evidence for decreased absorption in kwashiorkor. British Journal of Clinical Pharmacology, 1987, 23:467-472.

87. Salako LA, Sowunmi A, Akinbami FO. Pharmacokinetics of quinine in African children suffering from kwashiorkor. British Journal of Clinical Pharmacology, 1989, 28:197-201.

88. Treluyer JM et al. Metabolism of quinine in children with global malnutrition. Pediatric Research, 1996, 40:558-563.

89. Pussard E et al. Quinine disposition in globally malnourished children with cerebral malaria. Clinical Pharmacology and Therapeutics, 1999, 65:500-510.

90. Shastri RA, Krishnaswamy K. Undernutrition and tetracycline half life. Clinica Chimica Acta, 1976 66:157-164.

91. Raghuram TC, Krishnaswamy K. Tetracycline kinetics in undernourished subjects. International Journal of Clinical Pharmacology, Therapy, and Toxicology, 1981, 19:409-413.

92. Raghuram TC, Krishnaswamy K. Tetracycline absorption in malnutrition. Drug-Nutrition Interactions, 1981, 1:23-29.

93. Raghuram TC, Krishnaswamy K. Pharmacokinetics and plasma steady state levels of doxycycline in undernutrition. British Journal of Clinical Pharmacology, 1982, 14:785-789.

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