Antimalarial Drugs

Mother Nature gave us the cinchona alkaloids and qinghaosu. World War II led to the introduction of chloroquine, chloroguanide (proguanil), and eventually amodiaquine and pyrimethamine. The war in Vietnam brought mefloquine and halofantrine. These drugs are all we have available now to treat malaria. It is difficult to see where the next generation of antimalarial drugs will come from….there is little pharmaceutical industry interest in developing new antimalarial drugs; the risks are great, but the returns on investment are low….If drug resistance in P. falciparum continues to increase at the current rate, malaria may become untreatable in parts of Southeast Asia by the beginning of the next millennium.

White NJ. The treatment of malaria. NEJM. 12.9.1996;335:11:800-806

The effectiveness of early diagnosis and prompt treatment as the principal technical components of the global strategy to control malaria is highly dependent on the efficacy, safety, availability, affordability and acceptability of antimalarial drugs. The effective antimalarial therapy not only reduces the mortality and morbidity of malaria, but also reduces the risk of resistance to antimalarial drugs. Therefore, antimalaria chemotherapy is the KEYSTONE of malaria control efforts. On the other hand, not many new drugs have been developed to tackle malaria (Nature, Oct 3, 2002; 419:426); of the 1223 new drugs registered between 1975 and 1996, only 3 were antimalarials! Hence the need for a rational antimalaria treatment policy.


Anti malarial drugs can be classified according to anti malarial activity and according to structure.

1. According to anti malarial activity:

  1. Tissue schizonticides for causal prophylaxis: These drugs act on the primary tissue forms of the plasmodia which after growth within the liver, initiate the erythrocytic stage. By blocking this stage, further development of the infection can be theoretically prevented. Pyrimethamine and Primaquine have this activity. However since it is impossible to predict the infection before clinical symptoms begin, this mode of therapy is more theoretical than practical.
  2. Tissue schizonticides for preventing relapse: These drugs act on the hypnozoites of P. vivax and P. ovale in the liver that cause relapse of symptoms on reactivation. Primaquine is the prototype drug; pyrimethamine also has such activity.
  3. Blood schizonticides: These drugs act on the blood forms of the parasite and thereby terminate clinical attacks of malaria. These are the most important drugs in anti malarial chemotherapy. These include chloroquine, quinine, mefloquine, halofantrine, pyrimethamine, sulfadoxine, sulfones, tetracyclines etc.
  4. Gametocytocides: These drugs destroy the sexual forms of the parasite in the blood and thereby prevent transmission of the infection to the mosquito. Chloroquine and quinine have gametocytocidal activity against P. vivax and P. malariae, but not against P. falciparum. Primaquine has gametocytocidal activity against all plasmodia, including P. falciparum.
  5. Sporontocides: These drugs prevent the development of oocysts in the mosquito and thus ablate the transmission. Primaquine and chloroguanide have this action.

Thus in effect, treatment of malaria would include a blood schizonticide, a gametocytocide and a tissue schizonticide (in case of P. vivax and P. ovale). A combination of chloroquine and primaquine is thus needed in ALL cases of malaria.

2. According to the structure:

  1. Aryl amino alcohols: Quinine, quinidine (cinchona alkaloids), mefloquine, halofantrine.
  2. 4-aminoquinolines: Chloroquine, amodiaquine.
  3. Folate synthesis inhibitors: Type 1 – competitive inhibitors of dihydropteroate synthase – sulphones, sulphonamides; Type 2 – inhibit dihydrofolate reductase – biguanides like proguanil and chloroproguanil; diaminopyrimidine like pyrimethamine
  4. 8-aminoquinolines: Primaquine, WR238, 605
  5. Antimicrobials: Tetracycline, doxycycline, clindamycin, azithromycin, fluoroquinolones
  6. Peroxides: Artemisinin (Qinghaosu) derivatives and analogues – artemether, arteether, artesunate, artelinic acid
  7. Naphthoquinones: Atovaquone
  8. Iron chelating agents: Desferrioxamine

The Artemisinin Derivatives

Artemisinin or Qinghaosu (“ching-how-soo”) is the active principal of the Chinese medicinal herb Artemisia annua. It has been used as treatment of fevers in China for more than 1000 years. The antimalarial value of Artemisia annua was first documented in Zhou Hou Bei Ji Fang (Handbook of prescriptions for emergency treatments) written as early as 340 AD by Ge Hong of the Eastern Jin Dynasty. The active antimalarial constituent of this plant was isolated in 1971 and it was named artemisinin. The WHO accorded high priority to the development of fast acting artemisinin derivatives for the treatment of cerebral malaria as well as for the control of multi-drug resistant P. falciparum malaria. A water soluble ester called artesunate and two oil soluble preparations called artemether and arteether (artemotil) have now been developed.

Anti malarial activity: They act by inhibiting a P falciparum-encoded sarcoplasmic-endoplasmic reticulum calcium ATPase, and not by inhibiting the haem metabolic pathway as previously supposed. Most clinically important artemisinins are metabolised to dihydroartemisinin (elimination half-life of about 45 min), in which form they have comparable antimalarial activity. However, their use in monotherapy is associated with high incidences of recrudescent infection, suggesting that combination with other antimalarials might be necessary for maximum efficacy.

It is the fastest acting anti malarial available. It inhibits the development of the trophozoites and thus prevents progression of the disease. Young circulating parasites are killed before they sequester in the deep microvasculature. These drugs starts acting within 12 hours. These properties of the drug are very useful in managing complicated P. falciparum malaria. These drugs are also effective against the chloroquine resistant strains of P. falciparum.

Artesunate and artemether have been shown to clear parasitaemias more effectively than chloroquine and sulfadoxine/pyrimethamine. Meta analysis of mortality in trials indicated that a patient treated with artemether had at least an equal chance of survival as a patient treated with quinine. It has also been reported that artemisinin drugs cleared parasites faster than quinine in patients with severe malaria but fever clearance was similar. Also, parenteral artemether and artesunate are easier to use than quinine and do not induce hypoglycaemia.

Gametocytocidal action: Artemisinin compounds have been reported to reduce gametocytogenesis, thus reducing transmission of malaria, this fact being specially significant in preventing the spread of resistant strains.

These drugs prevent the gametocyte development by their action on the ring stages and on the early (stage I-III) gametocytes.[2] In studies including over 5000 patients in Thailand, it was shown that gametocyte carriage was significantly less frequent after treatment with artemisinin derivatives than after treatment with mefloquine.

Absorption, fate and excretion: Artemisinin derivatives are absorbed well after intra muscular or oral administration. The drug is fully metabolised and the major metabolite is dihydroartemisinin, which also has anti parasite effects. It is rapidly cleared, predominantly through the bile.

Toxicity:[1] Toxic effects have been reported less frequently with the artemisinins than with other antimalarial agents. The most common toxic effects that have been identified are nausea, vomiting, anorexia, and dizziness; these are probably due, in many patients, to acute malaria rather than to the drugs. More serious toxic effects, including neutropenia, anemia, hemolysis, and elevated levels of liver enzymes, have been noted rarely. Two cases of severe allergic reactions to oral artesunate have been reported, with an estimated risk of approximately 1 reaction per 3000 treatments.

Neurotoxicity is the greatest concern regarding artemisinins, since the administration of high doses in laboratory animals has led to severe and irreversible changes in the brain. Extensive studies in many species showed that intramuscular dosing was more toxic than oral dosing and that, by any route, fat-soluble artemisinins were more toxic than artesunate. In humans, an episode of ataxia was reported after treatment with oral artesunate, and one case–control study showed hearing loss after the use of artemether–lumefantrine, but auditory toxic effects were not detected in another case–control study, and reported toxic effects may have been due to underlying malaria or other factors that were independent of artemisinin use. Multiple studies have shown that neurologic findings are fairly common with acute malaria, but there is no convincing evidence of neurotoxic effects resulting from standard oral or intravenous therapy with artemisinins.

Another concern about artemisinins is embryotoxic effects, which have been demonstrated in animals. Studies from Asia and Africa, including treatments during the first trimester, showed similar levels of congenital abnormalities, stillbirths, and abortions in patients who received and those who did not receive artesunate during pregnancy. Limited data are available on the use of intravenous artesunate for severe malaria during pregnancy.

Availability: Artemisinin is available as its derivatives, artemether, artesunate and arteether. The ether derivatives are more soluble in oil and are available as injections for intra muscular use. Artemether is available as injection of 80 mg in 1 ml. Artemether capsules containing 40 mg of the drug are also now available. Arteether is available as injection of 150 mg in 2 ml.

Artesunate is an ester derivative that is more soluble in water. The drug is available as a powder. It should be first dissolved in 1 ml of 5% sodium bicarbonate (usually provided with the vial) and shaken for 2-3 minutes. After it dissolves completely, it is diluted with 5% dextrose or saline (for intravenous use, dilute with 5 ml and for intramuscular use, dilute with 2 ml). Intravenous dose should be injected slowly at a rate of 3-4 ml/minute. It is also available as tablets, each containing 50 mg of the drug.


Artemether: Available as 80mg/ml Injection and 40mg per capsule

Injection: 3.2 mg/kg intra muscularly as a loading dose, followed by 1.6 mg/kg daily until oral therapy.

Oral: 4mg/kg on first day followed by 2mg/kg.

Arteether (Artemotil): Available as 150mg per 2 ml ampoule

Dose: 3 mg/kg once a day for 3 days, as deep intra muscular injection.

Artesunate: In India it is available as 50mg tablets and 60mg/ml injection. In China it is also available as 100mg suppository and in Switzerland is available as 200mg rectocap

Oral: 4 mg/kg.

Parenteral: Loading dose of 2.4 mg/kg followed by 2.4mg/kg after 12 hours, 24 hours and once daily thereafter.

Artesunate dosages need not be changed because of hepatic or renal failure or concomitant or previous therapy with other medications, including previous therapy with mefloquine, quinine, or quinidine. There are no known interactions between artesunate and other drugs.[1]

See Rectal artemisinins rapidly eliminate malarial parasites [Full text, Report, Report]

See Artemisinin based combinations

Resistance: The short half-lives of artemisinins limit the possibility of selection for resistance. Nonetheless, recent heavy use of artemisinins, including monotherapy, has created selective pressure.[1] Resistance to artesunate has been recently reported from Cambodia.[4] Some parasites isolated from French Guiana and Senegal recently showed diminished in vitro sensitivity to artemether, and the efficacies of artemisinin-based combination agents have apparently decreased along the Thailand–Cambodia border. However, at present, the likelihood of true artemisinin resistance in malaria parasites is low, and this concern should not prevent the use of intravenous artesunate to treat severe malaria.[1]


  1. Rosenthal PJ. Artesunate for the Treatment of Severe Falciparum Malaria. NEJM. 2008;358(17):1829-1836 Available at
  2. Mehra N, Bhasin VK. In vitro gametocytocidal activity of artemisinin and its derivatives on Plasmodium falciparum. Jpn J Med Sci Biol. 1993 Feb;46(1):37-43.
  3. Day N, Dondorp AM. The Management of Patients with Severe Malaria. Am. J. Trop. Med. Hyg. 2007;77(Suppl 6):29–35 Available at
  4. Fears of new malaria drug resistance. Available at


Chloroquine is the prototype anti malarial drug, most widely used to treat all types of malarial infections. It is also the cheapest, time tested and safe anti malarial agent.

Mechanism of action: The mechanism of action of chloroquine is unclear. Being alkaline, the drug reaches high concentration within the food vacuoles of the parasite and raises its pH. It is found to induce rapid clumping of the pigment. Chloroquine inhibits the parasitic enzyme heme polymerase that converts the toxic heme into non-toxic hemazoin, thereby resulting in the accumulation of toxic heme within the parasite. It may also interfere with the biosynthesis of nucleic acids. Other mechanisms suggested include formation of drug-heme complex, intercalation of the drug with the parasitic DNA etc.

Absorption, fate and excretion: 90% of the drug is absorbed from G.I.T and rapidly absorbed from intra muscular and subcutaneous sites. It has a large distribution volume due to extensive sequestration in tissues of liver, spleen, kidney, lung etc. Hence the need for a larger loading dose. Therapeutic blood levels persist for 6-10 days and elimination half-life is 1-2 months. Half of the drug is excreted unchanged by the kidneys, remaining is converted to active metabolites in the liver.

Anti malarial activity: It is highly effective against erythrocytic forms of P. vivax, P. ovale and P. malariae, sensitive strains of P. falciparum and gametocytes of P. vivax. It rapidly controls acute attack of malaria with most patients becoming afebrile within 24-48 hours. It is more effective and safer than quinine for sensitive cases.

Adverse effects: Chloroquine is a relatively safer anti malarial. At therapeutic doses, it can cause dizziness, headache, diplopia, disturbed visual accomodation, dysphagia, nausea, malaise, and pruritus of palms, soles and scalp. It can also cause visual hallucinations, confusion, and occasionally frank psychosis. These side effects do not warrant stoppage of treatment. It can exacerbate epilepsy. When used as prophylactic at 300 mg of the base/ week, it can cause retinal toxicity after 3-6 years (i.e. after 50-100 g of chloroquine). Intra muscular injections of chloroquine can cause hypotension and cardiac arrest, particularly in children.

Contra indications: Chloroquine should be used with caution in patients with hepatic disease, (even though it is not hepatotoxic per se, it is distributed widely in the liver and is converted to active metabolites there; hence the caution), severe gastro intestinal, neurological or blood disorders. The drug should be discontinued in the event of such problems during therapy.

It should not be co-administered with gold salts and phenyl butazone, because all the three can cause dermatitis.

Chloroquine may interfere with the antibody response to human diploid cell rabies vaccine.

Availability: Chloroquine is available as Chloroquine phosphate tablets; each 250-mg tablet contains 150 mg of the base. Chloroquine hydrochloride injection contains 40 mg of the base per ml.

Dose: Oral- 10mg/kg stat., then three doses of 5 mg/kg, over 36-48 hours.

Age in years Dose of chloroquine (as base)
(Each 250 mg tablet contains 150 mg base and each 5 ml of suspension contains 50 mg base)
1st dose 2nd dose 3rd dose 4th dose
0-1 75 mg 37.5 mg 37.5 mg 37.5 mg
1-5 150 mg 75 mg 75 mg 75 mg
5-9 300 mg 150 mg 150 mg 150 mg
9-14 450 mg 225 mg 225 mg 225 mg
>14 600 mg 300 mg 300 mg 300 mg

Dose of parenteral chloroquine:

Intra venous infusion 10 mg / kg (max.600mg) in isotonic fluid, over 8 hours; followed by 15 mg / kg (max.900mg) over 24 hours.
Intra muscular or sub cutaneous injections 3.5 mg of base/ kg (max.200 mg) every 6 hours or 2.5 mg of base/ kg (max.150mg) every 4 hours. (Intramuscular injection can cause fatal hypotension, especially in children).


Quinine is the chief alkaloid of cinchona bark (known as ‘Fever Bark’), a tree found in South America. It has a colourful history of more than 350 years. Calancha, an Augustinian monk of Lima, first wrote about the curative properties of cinchona powder in “fevers and tertians” as early as in 1633. By 1640, the bark had already found its way into Europe, thanks to the Jesuit fathers (hence the name ‘Jesuit’s bark’). Eminent philosopher Cardinal de Lugo popularised the bark in Rome (hence it is also called Cardinal’s bark). In 1820, Pelletier and Caventou isolated quinine and cinchonine from cinchona. Even today, quinine is obtained entirely from the natural sources due the difficulties in synthesising the complex molecule.

Mechanism of action: Quinine acts as a blood schizonticide although it also has gametocytocidal activity against P. vivax and P. malariae. Because it is a weak base, it is concentrated in the food vacuoles of P. falciparum. It is said to act by inhibiting heme polymerase, thereby allowing accumulation of its cytotoxic substrate, heme.

As a schizonticidal drug, it is less effective and more toxic than chloroquine. However, it has a special place in the management of severe falciparum malaria in areas with known resistance to chloroquine.

Absorption, fate and excretion: Quinine is readily absorbed when given orally or intramuscularly. Peak plasma concentrations are achieved within 1 – 3 hours after oral dose and plasma half-life is about 11 hours. In acute malaria, the volume of distribution of quinine contracts and clearance is reduced, and the elimination half-life increases in proportion to the severity of the illness. Therefore, maintenance dose of the drug may have to be reduced if the treatment is continued for more than 48 hours. The drug is extensively metabolised in the liver and only 10% is excreted unchanged in the urine. There is no cumulative toxicity on continued administration.

Adverse effects: Quinine is a potentially toxic drug. The typical syndrome of quinine side effects is called as cinchonism and it can be mild in usual therapeutic dosage or could be severe in larger doses. Mild cinchonism consists of ringing in the ears, headache, nausea and disturbed vision. Functional impairment of the eighth nerve results in tinnitus, decreased auditory acuity and vertigo. Visual symptoms consist of blurred vision, disturbed colour perception, photophobia, diplopia, night blindness, and rarely, even blindness. These changes are due to direct neurotoxicity, although vascular changes may contribute to the problem.

Gastrointestinal symptoms like nausea, vomiting, abdominal pain and diarrhoea may be seen. Rashes, sweating, angioedema can occur. Excitement, confusion, delirium are also seen in some patients. Coma, respiratory arrest, hypotension, and death can occur with over dosage. Quinine can also cause renal failure. Massive hemolysis and hemoglobinuria can occur, especially in pregnancy or on repeated use. Hypoprothrombinemia, agranulocytosis are also reported.

Quinine has little effect on the heart in therapeutic doses and hence regular cardiac monitoring is not needed. However it can cause hypotension in the event of overdose.

Quinine reduces the excitability of the motor end plate and thus antagonises the actions of physostigmine. It can cause respiratory distress and dysphagia in patients of myasthenia gravis.

Quinine stimulates insulin secretion and in therapeutic doses it can cause hypoglycemia. This can be more severe in patients with severe infection and in pregnancy. Hypoglycemia in malaria may go unnoticed and could even cause death. Therefore, it is advisable to monitor blood glucose levels at least once in 4-6 hours while quinine is administered, especially in severe infection and in pregnancy. Quinine induced hypoglycemia can recur even after administration of 25% or 50% dextrose. In such situations, maintenance with a 10% dextrose infusion is advisable. Resistant hypoglycemia due to quinine can be managed with Injection Octreotide, 50 microgram subcutaneously, every 6 to 8 hours.

Contraindications: Hypersensitivity in the form of rashes, angioedema, visual and auditory symptoms are indications for stopping the treatment. It is contraindicated in patients with tinnitus and optic neuritis. It should be used with caution in patients with atrial fibrillation. Hemolysis is indication for immediately stopping the drug. It is also contraindicated in patients suffering from myasthenia gravis.

Availability: It is available as tablets and capsules containing 300 or 600 mg of the base. It is also available as injections, containing 300mg /ml.


Oral: 10 mg/kg 8 hourly for 4 days and 5 mg/kg 8 hourly for 3 days.

Intra venous: 20 mg of salt/kg in 10 ml/kg isotonic saline or 5% dextrose over 4 hours, then 10 mg of salt/kg in saline or dextrose over 4 hours, every 8 hours until patient is able to take orally or for 5-7 days.

Intra muscular: 20 mg/kg stat, followed by 10 mg/kg 8 hourly by deep intra muscular injections for 5-7 days

Quinidine: The anti-arrhythmic drug related to quinine can also be used in the treatment of severe P. falciparum malaria. Dose is 10 mg of base / kg by infusion over 1-2 hours, followed by 0.02 mg/kg/min with ECG monitoring.

Chloroguanide (Proguanil)

More popularly known as proguanil, this drug was developed by British antimalarial research in 1945. It is a biguanide derivative that is converted to an active metabolite called cycloguanil pamoate. It exerts its antimalarial action by inhibiting parasitic dihydrofolate reductase enzyme. It has causal prophylactic and suppressive activity against P. falciparum and cures the acute infection. It is also effective in suppressing the clinical attacks of vivax malaria. However it is slower compared to 4-aminoquinolines.

Chloroguanide is slowly but adequately absorbed from the gastrointestinal tract. Peak plasma levels are attained within 5 hours and elimination half-time is about 16-20 hours.

Chloroguanide is available as tablets, each containing 100 mg of the drug. The dose for prophylaxis is 100-200 mg daily.

Chloroguanide along with chloroquine is used as prophylaxis effective against P. falciparum malaria.

At the prophylactic doses, it produces occasional nausea and diarrhoea. It is otherwise a safe drug and can be used in pregnancy.


Pyrimethamine and sulphadoxine are very useful adjuncts in the treatment of uncomplicated, chloroquine resistant, P. falciparum malaria. It is now used in combination with artesunate for the treatment of P. falciparum malaria. It is also used in intermittent treatment in pregnancy (IPTp)

Anti malarial activity: Pyrimethamine inhibits the dihydrofolate reductase of plasmodia and thereby blocks the biosynthesis of purines and pyrimidines, which are so essential for DNA synthesis and cell multiplication. This leads to failure of nuclear division at the time of schizont formation in erythrocytes and liver.

Sulfadoxine inhibits the utilisation of para-aminobenzoic acid in the synthesis of dihydropteroic acid. The combination of pyrimethamine and sulfa thus offers two step synergistic blockade of plasmodial division.

Absorption, fate and excretion: Pyrimethamine is slowly but completely absorbed after oral administration and is eliminated slowly with a plasma half-life of about 80-95 hours. Suppressive drug levels may be found in the plasma for up to 2 weeks. The drug is excreted in breast milk.

Sulfonamides are rapidly absorbed from the gut and are bound to plasma proteins. They are metabolised in the liver and are excreted in the urine. They pass through the placenta freely. Sulfadoxine is a long acting sulfonamide with a half-life of 7-9 days.

Toxicity and contraindications: Pyrimethamine can cause occasional skin rashes and depression of hematopoiesis. Excessive doses can produce megaloblastic anemia.

Sulfonamides can cause numerous adverse effects. Agranulocytosis; aplastic anemia; hypersensitivity reactions like rashes, fixed drug eruptions, erythema multiforme of the Steven Johnson type, exfoliative dermatitis, serum sickness; liver dysfunction; anorexia, vomiting and acute hemolytic anemia can also occur. The drug is contraindicated in patients with known hypersensitivity to sulfa, infants below 2 months of age, patients with advanced renal disease and first and last trimesters of pregnancy.

Availability: Pyrimethamine and sulphadoxine is no longer used as a single drug, but only in combination with artesunate.


Halofantrine was developed in the 1960s by the Walter Reed Army Institute of Research. It is a phenanthrene methanol structurally related to quinine. Its mechanism of action may be similar to that of chloroquine, quinine, and mefloquine; by forming toxic complexes with ferritoporphyrin IX that damage the membrane of the parasite. This synthetic anti malarial is effective against multi drug resistant (including mefloquine resistant) P. falciparum malaria.

Its bioavailability is low and variable (may be doubled if taken with a fatty meal). The peak plasma concentration is achieved in 4-8 hours after the oral dose. The elimination half-life is 1-3 days for the parent drug and 3-7 days for the active metabolite.

Halofantrine is no more used in the treatment of chloroquine resistant and multi-drug resistant, uncomplicated P. falciparum malaria.

Dose: For adults, three tablets of 500 mg each, 6 hours apart. For children, three doses of 8 mg/kg of the salt 6 hours apart. Treatment should be repeated after 7 days.

Side effects include abdominal pain, diarrhoea, prolongation of QTC interval and arrhythmias that could be fatal. It is contraindicated in patients with prolonged QTC interval (congenital, electrolyte disorders, myocardial disease). However, it appears less toxic than quinine and mefloquine. It is also contraindicated in pregnancy and lactation, infants, and patients who have received mefloquine in the preceding 3 weeks.


Mefloquine was born during the Vietnam war, as a result of research into newer anti malarials, to protect the American soldiers from the multi drug resistant falciparum malaria. Nothing much has happened after that and hence this ‘new’ drug should be restricted for use against multi drug resistant falciparum only.

Anti malarial activity: Mefloquine has been found to produce swelling of the P. falciparum food vacuoles. It may act by forming toxic complexes with free heme that damage membranes and interact with other plasmodial components. It is effective against the blood forms of falciparum malaria, including the chloroquine resistant types.

Absorption, fate and excretion: Mefloquine is available for oral administration only because parenteral preparations cause severe local reactions. It is absorbed rapidly and is extensively bound to plasma proteins. Elimination half-life is about 2-3 weeks. It is mainly excreted in the faeces.

Toxicity: It is generally well tolerated in therapeutic doses up to 1500 mg. Nausea, vomiting, abdominal pain and dizziness can occur in doses exceeding 1 g. Less frequently it can cause nightmares, sleeping disturbances, dizziness, ataxia, sinus bradycardia, sinus arrhythmia, postural hypotension, and an ‘acute brain syndrome’ consisting of fatigue, asthenia, seizures and psychosis. Mefloquine should be used with caution in patients with heart block, patients taking beta blockers, patients with history of epilepsy and psychiatric disease. It should be avoided in first trimester of pregnancy and pregnancy should be avoided within 3 months of taking the drug.

Contraindications: It should not be used for prophylaxis in pregnancy, particularly during the first trimester. It is contraindicated in patients with history of seizures, severe neuropsychiatric disturbances, or adverse reactions to quinoline antimalarials like chloroquine and quinine. It should not be used concomitantly with these drugs for increased risk of cardiotoxicity and risk of convulsions. Mefloquine is reported to increase the risk of seizures in patients taking valproate. It may compromise adequate immunisation by live typhoid vaccine. Patients taking mefloquine should refrain from driving or operating machinery.

Availability: It is available as 250 mg tablets and in combikits with artesunate.

Dose: 15 mg/kg in a single dose. If the dose exceeds 1000 mg, the second dose can be given after 4-8 hours to minimise gastric irritation. Total dose should not exceed 1500 mg.


A synthetic hydroxynaphthoquinone developed in the early 1980s, atovaquone has been found to be useful against the Plasmodia (as well as Toxoplasma and Pneumocystis carinii). It has a highly lipophilic molecule that supposedly interferes with the mitochondrial electron transport and thereby ATP and pyrimidine biosynthesis and in Plasmodia, it is found to target cytochrome bc1 complex and disrupt the membrane potential. Its bio-availability after oral administration is poor and may be increased by a fatty meal. It has a long half-life of 2-3 days and it undergoes entero-hepatic circulation. It is available as 750 mg tablets. It may cause rash, fever, vomiting, diarrhoea and head ache. Safety in pregnancy, lactation, children, and elderly is yet to be established.

Atovaquone plus Proguanil: A fixed dose combination of atovaquone and proguanil hydrochloride (Malarone™) is now approved for both treatment and prophylaxis of malaria. It is available as 250 mg atovaquone + 100 mg proguanil per tablet for adults and 62.5 mg atovaquone + 25 mg proguanil per tablet for children.

It has been shown to be highly efficacious in the treatment of uncomplicated malaria caused by Plasmodium falciparum, including malaria that has been acquired in areas with chloroquine-resistant or multidrug-resistant strains. The daily dose should be taken at the same time each day with food or milk.

For details:

Pyronaridine: Structurally, it resembles amodiaquine and has been found to be highly effective against chloroquine resistant strains in China.

Piperaquine: Its activity is similar to that of chloroquine. A combination with artimisinin is undergoing studies.

WR-288, 605: It is 7.4 times more active than primaquine as a tissue schizonticidal drug. It has lesser toxicity, good oral bio-availability and longer half-life.

Lumefantrine is an aryl alcohol related to quinine, mefloquine and halofantrine that is devoid of cardiac toxicity of halofantrine. It is being tried in combination with artemether.

Other Drugs with Antimalarial Activity:

Many drugs have been tested for their potential anti malarial effects. Research into newer anti malarials being scanty, such attempts might throw up one or two candidates for use in malaria, however, these drugs are yet to find a place in standard anti malarial regimen. Clindamycin, fluoroquinolones like ciprofloxacin and Norfloxacin, azithromycin etc. have been found to be effective against malarial parasites. Atovaquone; Desferrioxamine; Pyronaridine; Piperaquine; WR-288, 605; and 566C80 are drugs undergoing trials.


One among the first antibiotics to come into use in human beings, these drugs have stood the test of time and are continuing to be useful in treating a broad range of infections, including malaria.

Mechanism of action: Tetracyclines are bacteriostatic agents, supposedly acting by inhibiting protein synthesis by binding to the 30s ribosome subunit. They are effective against a wide range of organisms, including aerobic and anaerobic gram positive and gram negative bacteria, Rickettsia, Coxiella burnetii, Mycoplasma, Ureaplasma, Chlamydia, Legionella, Spirochaetes, Brucella, Helicobacter pylori, Yersinia, some atypical mycobacteria and Plasmodia.

Absorption, fate and excretion: These drugs are incompletely absorbed form the gut after oral administration and the absorption may be hampered by antacids containing aluminium hydroxide; calcium, magnesium and zinc salts and bismuth subsalicylate. They distribute widely in the tissues and accumulate in liver, spleen, bone marrow, bone, dentine and enamel of un-erupted teeth. The drug is mainly excreted through the kidney 9except minocycline) and that may be hampered in renal failure.

Adverse effects: Gastrointestinal irritation, nausea, vomiting, diarrhoea, photosensitivity, hepato-toxicity, aggravation of uremia, hypersensitivity reactions, staining of the teeth if used in young children and pregnant women etc.

Use in malaria: These anti microbials are useful in the treatment of drug resistant P. falciparum malaria. They act relatively slowly and hence should always be combined with a faster acting drug like quinine. They are contraindicated in children below the age of 8 years and in pregnant women because of their adverse effects on bones and teeth.

Both tetracycline and doxycycline are equally effective. Tetracycline is given at a dose of 250 mg every 6 hours for 7-10 days. Dose of doxycycline is 100 mg twice daily for 7-10 days.

Doxyxycline is also used for short term prophylaxis against P. falciparum malaria at 100mg once daily.

Clindamycin: It acts by inhibiting the protein synthesis by binding to the 50s subunit of ribosomes. It can be used for drug resistant malaria along with quinine at a dose of 10 mg/kg 8 hourly for 5 days. Adverse effects include pseudomembrane colitis and skin rashes. In one study, a cure rate of only 50% was observed. (Hall et al, P. falciparum malaria semiresistant to clindamycin. Br. Med. J., 1975, 2:12-14; Seaberg et al. Clindamycin activity against chloroquine resistant P. falciparum. Antimicrob. agents Chemothera., 1984, 150:904-911)

Fluoroquinolones: Both ciprofloxacin and norfloxacin have been found to have anti malarial activity both in vitro and in vivo. However, results are not consistent.

Azithromycin: Azithromycin is found to have anti malarial activity and has been found to be useful as a causal prophylactic agent. It was found to be effective at the dose of 300 mg stat, followed by 250 mg daily for 7 days as a prophylactic agent against chloroquine resistant P. falciparum infection.

Quick comparison between blood schizonticidal drugs

Onset of actionRapidSlowRapidRapidFastest
UsePrototype drug, first choice for all casesOnly for uncomplicated, resistant P. falciparumOnly for resistant P. falciparumOnly for uncomplicated, multi drug resistant P. falciparumReserved for drug resistant P. falciparum. However, it may be considered in life threatening complications of P. falciparum due to its rapid action
Use in severe P. falciparum malariaParenteral preparation can be used in areas with sensitive strainsNot useful in acute illness; can be co- prescribed with other parenteral antimalarialsDrug of choice for severe malaria; it was the only parenteral drug available for a long time until parenteral chloroquine and artemisinin arrivedNot to be used in acute illness; can be co-prescribed with artemisinin after acute phase is over.Useful in severe malaria; may be more effective and better tolerated than quinine.
Contra indicationsAlmost none, only advanced liver diseaseAllergy to sulphaPrior hypersensitive reactionsEpilepsy, psychosis, heart block, u00df blocker useNone
Use in pregnancyYesOnly in 2nd trimester if warrantedOnly if warranted, watch for hypoglycemiaNot in first trimesterYes, if the situation demands
The Salt-Base Table
Drug Salt Base
Chloroquine sulphate 136 mg 100 mg
Chloroquine diphosphate 250 mg 150 mg
Quinine sulphate 362 mg 300 mg
Quinine bisulphate 508 mg 300 mg
Quinine hydrochloride 405 mg 300 mg
Mefloquine hydrochloride 274 mg 250 mg
Primaquine 26.3 mg 15 mg

© ©BS Kakkilaya | Last Updated: Mar 10, 2015

Saga of Malaria Treatment

Fevers have always haunted mankind and several ingenious remedies were tried to combat the fevers. In the ancient times, limb blood-letting, emesis, amputation and skull operations were tried in the treatment of malarial fever. In England, opium from locally grown poppies and opium-laced beer were tried. Even the help of astrology was sought as the periodicity of malarial fevers suggested a connection with astronomical phenomena!



Claudius Galenus of Pergamum (131-201 AD), more popularly known as Galen, was an ancient Greek physician who worked in Rome from 162 AD. He suggested that the normal humoral balance should be restored by bleeding, purging, or both. Vomiting accompanying malaria was believed to be the body’s attempt to expel poisons. The bleeding supposedly rid the body of “corrupt humors.” These tenets were accepted without question for the next fifteen hundred years. Countless malaria patients were subjected to blood-letting and purgation with disastrous results: repeated bleedings only made the anemia of malaria much worse and the powerful purgatives on top of the debilitating effects of the disease itself often finished off most sufferers in a short time. The country folk and very poor who could not afford the help of the medical profession managed to survive!

Many turned to witchcraft. Allowing the insects to devour 77 small cakes made from a dough prepared by mixing flour and patient’s urine was one such suggested by the Dominican scholar Albertus Magnus. If this did not work, Albertus had another remedy: Let the matron of a noble family cut the ear of a cat, add three drops of its blood to brandy along with some pepper and administer it to the patient. Rubbing the patient’s body with chips from a gallows on which a criminal had been recently executed was yet another method.

Thus, until the early 17th century, European physicians had found no truly effective cure for malaria and their patients continued to die.

Artemisia annua

Artemisia annua

Artemisinin: The herb Artemisia annua (sweet wormwood) was known to the Chinese as qing-hao for more than 2000 years. The Mawanhgolui Han dynasty tombs, dating to 168 BC, mention it as a treatment for hemorrhoids. In 340 AD, the anti-fever properties of qinghao were first described by Ge Hong of the East Yin Dynasty.

An appeal for help from Ho Chi Minh to Zhou En Lai during the Vietnam War triggered the work on this herb and in 1967, the Chinese scientists set up Project 523. The active ingredient of qinghao was isolated by Chinese scientists in 1971. An ethyl ether extract of qinghao fed to mice infected with the rodent malaria strain, Plasmodium berghei, was found to be as effective as chloroquine and quinine at clearing the parasite. The human trails were published in the Chinese Medical Journal in 1979. Many active derivatives of artemisinin have since been synthesized and it is today a very potent and effective antimalarial drug, particularly against drug resistant malaria in many areas of southeast Asia. So far, clinically relevant genetic resistance to artemisinin has not been reported, although tolerance has been noted.

Cinchona Tree

Cinchona Tree

The history of cinchona bark, of more than 350 years, is full of intrigue and drama, greatly influencing that of pharmacy, botany, medicine, trade, theoretical and practical chemistry and tropical agriculture.

The origin of cinchona remains shrouded in mystery. Historians debate whether cinchona was an indigenous medicine or was discovered by Europeans. Evidence suggests that malaria did not exist in the New World before the arrival of the Spanish. It is said that the early Inca pharmacopoeias do not mention of cinchona, suggesting that its use followed the entry of the spaniards. However, even if malaria was not indigenous to South America, many years passed between the first arrival of the Spanish (and, presumably, malaria) and the earliest writings about cinchona by Europeans. Apparently during this interval, the native people would have developed a cure. Such a view is supported by the vast array of medicinal plants used by native healers and the large number of these plants transplanted to Europe from South and Central America at this time. Native plant remedies and treatment from native healers were more effective than the techniques of European physicians of the time.

One of the tales attributes the identification of cinchona bark to South American Indians. These natives supposedly noted that sick mountain lions chewed on the bark of certain trees. Malaria patients were given the bark and were helped.

Another holds that a member of a Peruvian Spanish garrison first discovered the bark. This soldier, overcome by malaria, was left behind to die by his comrades. Tortured by thirst, he crawled to a shallow pond, where he drank deeply and fell asleep. On awakening he found that his fever had disappeared, and then he remembered that the water had a bitter taste. A large tree trunk, split by lightning, had fallen into the pool; the bark from this tree, the soldier soon discovered, had both the bitter taste and the remarkable power to cure malaria.

history-treatment250It is widely accepted that the source of the bark was clearly identified by Jesuit priests. After Francisco Pizarro’s conquest of Peru in 1532, the Jesuit priests arrived there in 1568. Although the Jesuit doctrine forbid them from studying medicine, as it could detract from their primary focus of spiritual matters, they were allowed to study pharmacy and herbalism. In their studies of medical botany, the Jesuit priests undertook numerous field expeditions to describe and characterize the flora of remote forests in this newly discovered land. During an expedition between 1620 and 1630, to Loxa in the Southern district of Equador, bordering Peru, the Jesuit’s observed that the Incans, the indigenous people, were making teas out of the bark of certain trees to treat shivers from exposure to the cold. It is said that at Malacatos, 30 Km away from Loja, the Indian chief of the community, Pedro de Leiva provided tea made of this bark to a Jesuit priest who was sick with malaria and thereby cured him. Loxa (or Loja) being the natural habitat of this tree, the bark also came to be known as the Loja Bark.

The priest took samples of the bark to Lima, capital of Perú. The first written record of a malaria cure with cinchona bark dates back to 1630, mentioning that Juan López de Cañizares, Spanish governor of Loja (Ecuador), sent the same bark to Lima to cure the wife of the Count of Cinchón who was also sick with malaria fever, and this name also stuck to the bark.

Cinchona Bark

Cinchona Bark

It is not very clear as to who brought the cinchona bark to Europe. Sebastiano Bado, an Italian, gives this honor to the Countess of Chinchón, in an account published in 1663. The fourth Count of Chinchón, Don Luis Gerónimo Fernández de Cabrera de Bobadilla Cerda y Mendoza, was appointed by Philip IV to rule the vast Spanish South American Empire. The count and his wife, Señora Ana de Osorio, arrived in Lima in 1629. Shortly thereafter, according to Bado, the countess became severely ill with tertian fever, and news of her suffering soon spread throughout the colony. The governor of Loxa wrote the count, recommending that some of the same medicine by which he had been recently cured be given to Señora Ana. Don Juan was summoned to Lima, the remedy given, and the countess cured. Soon the natives were swarming around the palace, both to express their joy at the recovery and to learn the secret of the remedy. Upon hearing the people’s pleas, the generous Señora Ana ordered a large quantity of the bark and gave it personally to the sick. The grateful sufferers, all of whom were cured, named the new remedy los polvos de la condeça, “the countess’ powder.” In 1639, according to Bado, the countess returned to Spain, bringing a large quantity of bark with her. She distributed her remedy among the peons on the Chinchón estate, and also sent some to an ailing theology professor at the University of Alcalá de Henares. At the same time, Juan de Vega, Señora Ana’s physician, who had also returned to Spain with a supply of bark, sold part in Seville at an exorbitant price, one hundred reals per pound. This unscrupulous practice was to be repeated by many men in many places before the precious bark became readily available.

But the official diary of the Count of Chinchón, written by his secretary Don Antonio Suardo, was discovered in 1930. This contradicts many of the claims made by Bodo. The diary states that Ana de Osorio, the first Countess of Chinchón, died in Spain at least three years before Philip IV appointed the count viceroy of Peru. The second countess, Francisca Henríquez de Ribera, accompanied her husband to South America. And while Doña Francisca continued to enjoy excellent health, the count had several episodes of fever, none of which was treated with bark. Don Antonio also records that even the second countess never returned to Spain; instead, she died in the port of Cartagena, Colombia, during the trip home. Juan de Vega, her supposed physician, who, according to Bado, extorted enormous prices in Seville for the bark, never in fact left Peru because of an appointment as professor of medicine at the University of Lima. The count himself did return to Spain in 1641, and though he probably brought some bark with him, none reached the professor at the University of Alcalde de Henares, for this theologian had already been cured of his fever two years earlier.

In light of the evidence in Don Antonio’s diary, historians have been forced to conclude that cinchona bark appeared in Europe entirely by accident.

The first Europeans to appreciate the true value of cinchona were the Jesuits. As they cared for the natives throughout the Spanish New World Empire, Jesuit priests ascertained the medicinal properties of the Peruvian bark. Jesuit Barnabé de Cobo (1582-1657), who explored Mexico and Peru, is credited with taking Cinchona bark to Europe (hence called the Cobæa plant). He brought the bark from Lima to Spain, and afterwards to Rome and other parts of Italy, in 1632. The properties of the bark of the cinchona tree in the treatment of malaria were first written around 1633 by an Augustinian monk, Father Antanio de la Calancha, who lived in Peru. He wrote thus in a work on the Augustinian Order: “A tree grows which they call ‘the fever tree’ in the country of Loxa, whose bark, of the color of cinnamon, made into powder amounting to the weight of two small silver coins and given as a beverage, cures the fevers and tertiana; it has produced miraculous results in Lima.” Another Jesuit Bartolomé Tafur, came to Spain in 1643 and proceeded through France and took it to Italy as far as Rome.

Juan Lugo

Juan Lugo

The celebrated Jesuit theologian Juan de Lugo heard of the cinchona from Tafur. In 1640, Juan de Lugo first employed the tincture of the cinchona bark for treating malaria. Juan de Lugo (made cardinal in 1643) was entrusted by Pope Innocent X to learn more about the bark. De Lugo had the bark analysed by the pope’s physician, Gabriele Fonseca, who reported on it very favourably. In the late 1640s, directions for the use of the bark were published as the Schedula Romana. While on a visit to Paris in 1649 the cardinal even used some of his cinchona to treat the young Louis XIV. After the king’s recovery, the French eagerly embraced the new remedy. Juan de Lugo remained a faithful advocate, zealous defender, and generous, disinterested dispenser of the bark in Italy and the rest of Europe until his death in 1660. He was honoured at many places and several portraits of him were painted.

The Jesuit priests got natives to harvest the bark and the workers were made to replant five trees, arranged in the shape of a cross, for every tree they cut down. The bark was harvested around what is now the Peruvian and Ecuadorian border. From there it was carried to Paita on the coast and transferred onto ships bound for Panama. Once in Panama, it was carried north across the isthmus to Portobelo during the dry season, or taken via the Chagres River during the rainy season. At Portobelo the bark was once again loaded onto ships and sent to Spain via Havana. Occasionally, smuggling also took place, but rather than transport the bark via the western seaboard, smugglers carried it eastward, across most of the continent, following the course of rivers to the Atlantic. Once in Europe, the bark was distributed by a variety of means. Jesuits often gave it away, merchants sold it, and the nobility sometimes used it as gifts.

Pietro Paolo Pucciarini of Rome, Honoré Fabri, a French Jesuit and others helped in spreading the use of the bark across Europe and the “Jesuit Bark” also reached England. By 1657, it reached India. Under the pseudonym of Antimus Conygius, Fabri wrote in 1655 the first paper on cinchona published in Italy. The first prescription of cinchona  in England is attributed to Robert Brady, a Professor of Physic in Cambridge, who in 1658 began prescribing the powder of the ‘Jesuits’ bark’ to treat an outbreak of malaria. Thomas Sydenham, an eminent English physician, published a book called Method for Curing the Fever (Methodus curandi febres) in 1666. A firm believer in the remedies of Hippocrates and Galen, Sydenham staunchly adhered to the old humoral theory of malaria. Grudgingly, though, he admitted that cinchona might be of some benefit if given after the fever had declined. Physician Bado declared that this bark had proved more precious to mankind than all the gold and silver which the Spaniards obtained from South America. The Italian professor of medicine Ramazzini said that the introduction of Peruvian bark would be of the same importance to medicine that the discovery of gunpowder was to the art of war.

Despite positive results and the backing of the Vatican, the use of cinchona was not universally adopted in 17th century Europe; many orthodox physicians in Protestant England in particular were prejudiced against its use. Many factors contributed to the delay in acceptance. First, the bark often did not work. Cinchona could not cure all fevers except those of malaria. Furthermore, unscrupulous dealers might have sold inferior bark or the bark of some other tree, and after the long journey from New Spain to Europe the bark sometimes arrived too rotten to use. The use of cinchona had not been mentioned in and even contradicted the teachings of the ancient author Galen, according to whom, a patient with malaria needed to release humors, making bleeding, purging, and the use of emetics the preferred treatments. The use of a hot, bitter drink seemed to conflict with both Galenic medicine and common sense. Lack of a reliable prescription also distanced physicians from prescribing it. The support of the Vatican for the drug and the fact that its export from Peru and Bolivia was in the hands of Catholics also worked against its acceptance in some regions, particularly in England. The close association of the drug with Catholicism made many Protestants fear it was part of a “Popish plot” against them. Oliver Cromwell, who had ordered the execution of Charles I, steadfastly refused cinchona during a severe attack of malaria in 1658, and died as a result (and that supposedly changed the history of England!).

In other countries that initially accepted cinchona the drug was sometimes used improperly. For example, the Austrian governor general of the Netherlands, Archduke Leopold William, was given cinchona with excellent results by Chifflet, his physician. But when the malaria recurred a month later, the archduke blamed the cinchona and foolishly refused to take more. His subsequent demise gave the medicine a bad name throughout Europe, and even Chifflet somehow came to believe that cinchona “fixed the humors” while reducing the fever, making recurrence certain and death likely.

It took an untrained “quack” to popularize cinchona in England in a highly unorthodox manner. Robert Talbor was born in Cambridge in 1642. He entered St. John’s College but dropped out at the age of twenty-one, becoming apprenticed to a Cambridge apothecary from whom he first learned of cinchona. He abandoned his apprenticeship and moved to Essex and then to London. He used the prevalent fears and confusion about the Jesuits’ Bark to make his name as a “feverologist” by treating malaria patients with what he called a ‘secret remedy’. He developed a safe dosage and an effective treatment regimen: “I planted myself in Essex near the sea side, in a place where agues are the epidemical diseases, where you will find but few persons but either are, or have been afflicted with a tedious quartan.” After several years of study and testing, he developed a secret formulation that was essentially an infusion of cinchona powder, skillfully disguising the bitter taste of the cinchona with opium and wine. His secret remedy cured many sufferers in the Fens and Essex marshes. In 1672, Talbor wrote a small book titled “Pyretologia: A Rational Account of the Cause and Cure of Agues”. But all along, Talbor avoided mention of actually having used ‘Jesuit’s bark’ himself and to protect his secret, he made careful slurs against the Jesuit’s bark. He solemnly warned his patients and the public to “Beware of all palliative Cures and especially of that known by the name of Jesuits powder….. for I have seen most dangerous effects following the taking of that medicine,” thus cornering himself a lucrative monopoly of both the patients and the remedy. Thanks to this book, his reputation grew. The success of his treatments became widely known and brought him rapid fame and fortune. Charles II appointed him Physician Royal in 1672 and he was knighted in 1678. The Royal College of Physicians was furious at Talbor’s doings and advocated his prosecution for practicing medicine without a license. But the king would not hear of such a thing; in an angry, threatening letter, he warned the College members that any interference with Talbor would be certain to arouse the royal displeasure. When the dauphin, last living son of Louis XIV, became ill with fever, Charles II sent Talbor to the French court as a gesture of goodwill. Louis had sheltered the English monarch in his period of exile during the Protectorate of Cromwell. Now the favor was returned. Sir Robert cured the stricken dauphin. With the additional title of Chevalier Talbot, he became famous throughout Europe, curing Louisa Maria, Queen of Spain, Prince de Condé, the Duc de Roche-foucauld, and hundreds of other royal and aristocratic persons. But this again met with hostility from physicians in Paris and Madrid. Forbidden to employ the new remedy, the jealous French physicians tried vainly to humiliate this foreign upstart. “What is fever?” they asked. “I do not know,” replied the wily Talbor. “You gentlemen may explain the nature of fever; but I can cure it, which you cannot.”


The English Remedy: Talbor’s Wonderful Secret for Curing of Agues and Feavers (1682) [Source]

In 1679, King Charles II fell ill with tertian fever and was cured by Talbor’s ‘remedy’. Louis XIV of France, in recognition of the life of his son being saved, paid 3000 gold crowns, a large pension and a title and sought to know the ‘secret’ of his ‘remedy’. Talbor agreed on the condition that the formula would not be revealed during his lifetime. After returning to England, Talbor, now rich, tried to become even richer. Covertly he cornered the cinchona market by buying all the bark he could find. But he did not live long enough to enjoy his wealth. He died in 1681 at the age of thirty-nine, and was interred in Cambridge’s Holy Trinity Church. Fearing that in death his enemies in the medical profession would defame his memory, Talbor included a bit of professional advertising in his epitaph: “most honourable Robert Talbor, Knight and Singular Physician, unique in curing Fevers of which he had delivered Charles II King of England, Louis XIV King of France, the Most Serene Dauphin, Princes, many a Duke and a large number of lesser personages.”

In the same church, another imposing tablet hailed him even more eloquently as “Febrium Malleus,” smasher of fevers. In 1682, King Louis arranged for a small volume to be published that year. Nicholas de Blegny, physician-in-ordinary to the king, thereupon wrote a small book which was quickly translated into English: The English Remedy: Or Talbor’s Wonderful Secret for the Curing of Agues and Fevers–Sold by the Author, Sir Robert Talbor to the Most Christian King and since his Death ordered by His Majesty to be published in French, for the Benefit of his Subjects. The formula contained rose leaves, lemon juice, wine and a strong infusion of Peruvian bark! These revelations and a subsequent book, in 1712, on the therapeutic properties of the bark, by Fransesco Torti, professor of medicine at Modena, helped to popuarize the use of the treatment.



For a hundred years after it had been brought to Europe the bark remained difficult to obtain and Peru was its only source. Attempts to remove cinchona plants from the country were not successful. Charles de la Condamine, a French naturalist and explorer, was one of the first to make such an attempt in 1735. Condamine was determined to bring the trees back to France and grow rich selling the bark. He collected a large number of seedlings, planted them in boxes of earth, and then braved swamps, jungles, hostile natives, dangerous animals, and wild river rapids to reach the coast. After a perilous eight-month journey, within sight of the ship for Paris, his small boat was swamped by a wave and his plants washed away. However, with the help of the specimens of the bark that Condamine had obtained, Carolus Linnaeus, a Swedish botanist, classified the family of the Peruvian bark in 1742. He named the tree cinchona after the Countess, apparently accepting Sebastiano Bado’s account. Linnaeus misspelled the name, or rather he spelled it as had Bado, who had partially Italianized the count’s name, since c before i in Italian is pronounced like the Spanish (and English) ch. After Linnaeus’s death the error was discovered, much too late to change.

One member of Condamine’s expedition, Joseph de Jussieu, remained in the South American jungles for seventeen years to study cinchona. When he decided to return to France in 1761, he carried with him cinchona seeds packed into a wooden strongbox. But on the day of departure from Buenos Aires, a “trusted servant” made off with the box in the mistaken belief that it was filled with money. Jussieu returned to France ten years later, hopelessly insane. A Jesuit expedition was able to transport cinchona seedlings to Algeria, but the plants died in their new home. Success in this regard had to wait for another century.

At the beginning of the eighteenth century, as the use of cinchona spread throughout Europe, apothecaries and chemists attempted to extract the active ingredient of the bark so as to standardise the treatment. The first attempt to isolate the active principle in cinchona was made by Count Claude de la Garaye, a French pharmacist. In 1745 Garaye announced that he had successfully extracted the “essential salt,” but this was soon found to be not effective against malaria. Another French chemist, Antoine François Fourcroy in 1790 extracted a resinous substance with the characteristic color of the bark but that was not effective in treatment of malaria. Armand Seguin, Fourcroy’s student, came to the absurd conclusion that the active principle in cinchona was gelatin and published his findings despite inadequate experimental data. For years thereafter, many physicians reading Seguin’s paper adopted clarified glue to treat their malaria patients.

The first partially successful separation of the active principle from cinchona was achieved in 1811 by a Portuguese naval surgeon named Bernadino A. Gomez. He extracted the gray bark of poor variety with dilute acid and then neutralized it with alkali and managed to obtain a few crystals which he named cinchonin (later, to be known as cinchonine).



French pharmacists, Joseph Pelletier and Joseph Bienaimé Caventou, appointed a full professor of toxicology at the École de Pharmacie in Paris at age 22, isolated a medicinally worthless quinine poor powder, from the gray bark in 1817. In 1819, Friedlieb Runge isolated a base from cinchona, which he named “China base” – which was different from cinchonine. Later, in 1820, Pelletier and Caventou isolated from the yellow bark a sticky, pale yellow gum that could not be induced to crystallize. The gum was soluble in acid, alcohol, and ether and highly effective against malaria. The properties of the gum were seen to be identical to “China” base; but Runge`s prior discovery was overlooked. The two men named the new chemical quinine after quinquina, the name given by Peruvian Indians to the bark, meaning medicine of medicines or bark of barks. Pelletier and Caventou refused any profit from their discovery. Instead of patenting the extraction process, they published all the details so that anyone could manufacture quinine. They received many honors, the most lucrative of which was the Prix Monthyon of ten thousand francs awarded by the French Institute of Science. A monument was erected in Paris commemorating this achievement of Pelletier and Caventou.


Paris monument of Pelletier and Caventou [1,2]

More than 30 alkaloids are known from the bark of this genus. Formerly, the bark in different forms was used as a drug, but later natural harvesting formed the base of the production of cinchona alkaloids. This industry was carried on principally in Germany, and the Dutch and English cinchona plantations in Java, Ceylon and India were the chief sources whence the raw material was supplied. Its main active principle, quinine is now chemically synthesized. In 1823, Dr. John Sappington of Philadelphia acquired several pounds of quinine and issued “Dr. Sappington’s Fever Pills.” He persuaded ministers in the Mississippi River Valley to ring the church bells every evening to alert people to take the pills, and through that enterprise, Sappington became a very wealthy man.

By the mid-19th century the Dutch and English began claiming that the South American supply of cinchona was threatened by the non-sustainable cutting practices of the indigenous harvesters. In 1839, William Dawson Hooker, son of the renowned botanist William Jackson Hooker, wrote his dissertation on cinchona. He claimed that completely cutting the trees, rather than harvesting pieces of bark, was a better method, because insects would attack cinchona plants that had simply been debarked. On completely cut plants, new growth quickly appeared, and could be harvested again in 6 years. Years later it was also discovered that cut and regrown cinchona had higher levels of the effective alkaloids in its bark, and this method of harvesting became common on many plantations.

Attempts were continued to grow cinchona in other parts of the world. Seeds carried to Paris and Java by French and Dutch expeditions failed to germinate. In 1860 an English government clerk, Clements Robert Markham, carried seedlings to England; shortly thereafter, a distinguished botanist, Dr. Richard Spruce, did the same. These plants supplied the London market for only six years before being destroyed by insects.

In the meantime, to protect their monopoly, Peruvian authorities had barred foreigners from the cinchona forests. But in 1865 Charles Ledger, an Englishman living in Peru, obtained sixteen pounds of seed from a loyal native servant Manuel Incra Mamani for a fee of about 20 dollars. Mamani was jailed, beaten, and eventually starved to death for his act. A pound of this seed was sold to the Dutch in Java, and though apparently decayed on arrival, it germinated readily, giving birth to an enormous Dutch cinchona industry, destroying the South American monopoly on quinine and establishing a new Dutch monopoly. By grafting what was eventually named C. ledgeriana onto the hardier C. succirubra, the Dutch soon dominated cinchona cultivation, eventually producing 80 percent of the world’s quinine on the Indonesian island of Java. The high price of quinine was driven down and the drug was made available to large numbers of impoverished malaria sufferers.

The widespread use of cinchona came about because of the colonizing efforts of Europeans, and the drug, in turn, aided Europe in expanding its colonization even further. However, the world supply of cultivated quinine trees in Asia (especially in Indonesia and Java) was captured by Japan in 1942 during World War II and Germany captured the quinine reserves in Amsterdam, so Allied forces had to use emergency measures during World War II. Before the fall of the Philippines, the U.S. managed to escape with four million seeds, which were germinated back in Maryland and then transplanted in Costa Rica and other Latin American countries. Meanwhile, a Smithsonian botanist named Raymond Fosberg was able to secure millions of pounds ofCinchona bark in 1943 and 1944 for the Allies from forests and plantations in northern South America.

Even today quinine remains an important and effective treatment for malaria in most parts of the world, although resistance has been reported sporadically in 1844 and 1910.

Chloroquine: Many drugs were developed to protect the troops from malaria, particularly during World War II. Chloroquine, Primaquine, Proguanil, amodiaquine and Sulfadoxine/Pyrimethamine were all developed during this time.

During World War I, Java and its valuable quinine stores fell into Japanese forces. As a result, the German troops in East Africa suffered heavy casualties from malaria. In a bid to have their own antimalarial drugs, the German government initiated research into quinine substitutes and entrusted it to Bayer Dye Works. Most of the work was done at Bayer Farbenindustrie A.G. laboratories in Eberfeld, Germany. Several thousands of compounds were tested and some were found to be useful. Plasmochin naphthoate (Pamaquine) in 1926 and quinacrine, mepacrine (Atabrine) in 1932 were the first to be found. Plasmochin, an 8 amino quinoline, was quickly abandoned due to toxicity, although its close structural analog primaquine is now used to treat latent liver parasites of P. vivax and P. ovale. Atabrine, although found superior and persisting in the blood for at least a week, had to be abandoned due to side effects like yellowing of the skin and psychotic reactions. The breakthrough came in 1934 with the synthesis of Resochin (chloroquine) by Hans Andersag, followed by Sontochin or Sontoquine (3 methyl chloroquine). These compounds belonged to a new class of antimalarials known as 4 amino quinolines. But Farben scientists overestimated the compounds’ toxicity and failed to explore them further. Moreover, they passed the formula for Resochin to Winthrop Stearns, Farben’s U.S. sister company, in the late 1930s. Resochin was then forgotten until the outbreak of World War II.

With the German invasion of Holland and the Japanese occupation of Java, the Allied forces were cut off from quinine. This stimulated a renewed search for other antimalarials both in the United Kingdom and in the United States. After the Allied occupation of North Africa, the French soldiers raided a supply of German manufactured Sontochin in Tunis and handed it over to the Americans. Winthrop researchers made slight adjustments to the captured drug and this new formulation was called chloroquine. Later, it was found to be identical to the older and supposedly toxic Resochin. However it was not available for the troops until the end of the War. But following World War II, chloroquine and DDT became the two principal weapons in the global malaria control campaign.

However, after only about ten to twelve years of use, chloroquine resistance appeared in P. falciparum. Two initial foci of resistance developed simultaneously in Colombia and on the Cambodia-Thailand border. From these loci, resistance spread throughout South America and southern Asia. By the late 1970s chloroquine resistance had reached Africa and has since spread across sub-Saharan Africa.

Other antimalaria drugs: The formula of Atabrine (mepacrine, a 9-amino-acridine), was also soon solved by Allied chemists and it was produced in large scale in the U.S. It immediately gained widespread acceptance as an excellent therapeutic agent. After the experiments of Brigadier N. Hamilton Fairley in Australia in l943, it was also found to be useful as a prophylactic agent, protecting the troops in malarious areas. It is no longer used in view of many undesirable side effects.

The success of chloroquine led to the exploration of many (nearly 15000) compounds in the United States and another 4-aminoquinoline Camoquin (amodiaquin) was discovered. Studies on 8-aminoquinolines led to the discovery of Primaquine by Elderfield in 1950. Meanwhile, British investigators at ICI also carried out extensive studies on malaria drugs and Curd, Davey and Rose synthesised antifolate drugs proguanil or Paludrine (chlorguanide hydrochloride) in 1944 and Daraprim or Malocide (pyrimethamine) was developed in 1952. However, resistance to proguanil was observed within a year of introduction in Malaya in 1947. P. falciparum strains resistant to pyrimethamine, and cross-resistant to proguanil emerged in 1953 in Muheza, Tanzania. Sulfadoxine-pyrimethamine combination was introduced in Thailand in 1967. Resistance to this was first reported in Thailand later that year and spread quickly throughout Southeast Asia and recently appeared in Africa.

Mefloquine was jointly developed by the U.S. Army Medical Research and Development Command, the World Health Organization (WHO/TDR), and Hoffman-La Roche, Inc. After World War II, about 120 compounds were produced at the Walter Reed Army Institute of Research and WR142490 (mefloquine), a 4-quinoline methanol was developed. Its efficacy in preventing and treating resistant P. falciparum was proved in 1974-75 and was useful for the US Army in Southeast Asia and South America. By the time the drug became widely available in 1985, evidence of resistance to mefloquine also began to appear in Asia.

Malarone: In 1998 a new drug combination was released in Australia called Malarone. This is a combination of proguanil and atovaquone. Atovaquone became available 1992 and was used with success for the treatment of Pneumocystis carrinii. The synergistic combination with proguanil is found to be an effective antimalarial treatment.

It is thus clear that the plant-derived drugs have outlived many of the synthetic drugs, to which resistance has developed!


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