The Journal of the Royal Institute of Thailand Volume III

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The Journal of the Royal Institute of Thailand

Volume III - 2011

150

Quinine and Quin-Ghao, NatureûsTwo Most Important Anti-malarial Drugs

Quinine and Quin-Ghao, Natureûs Two Most

Important Anti-malarial Drugs

Sasithon Pukrittayakamee1,2

and Arjen Dondorp3

1Department of Clinical Tropical Medicine, Faculty of Tropical Medicine, Mahidol University2Associate Fellow of the Royal Institute of Thailand.

3Mahidol Oxford Tropical Medicine Research Unit (MORU), Faculty of Tropical Medicine,Mahidol University

Abstract

Quinine and Quin-Ghao (artemisinins) both have a centuries old medicalhistory as effective anti-ague remedies and remain natureûs two most importantanti-malarial drugs. From ancient records of early discovery, it took less than adecade for quinine to be widely used in Europe in the 17th century. In contrast, ittook over a thousand years until the 20th century for Quin Ghao (artemisinin) tobecome known and accepted outside China. These divergent timelines of the twodrugs, partly reflect differences in the scientific heritage between the two civilizationsi.e general publication in the West versus confidential ownership in the East.Quinine, but especially artemisinin derivatives, still play an important role inmalaria control and treatment as witnessed in the WHO malaria treatment guidelines.Recent evidence shows that artesunate is superior to quinine in preventing deathfrom severe falciparum malaria. Quinine is more wildly available and has remainedthe first line anti-malarial regimen for first trimester pregnant women.

Key words: malaria, quinine, Quin-Ghao, artesunate

Introduction

Plasmodium, the malaria parasite, is a single cell organism in the class ofblood protozoa. Its origin predates humanity and is estimated to be over half abillion years old (Kakkilaya, 2006). A large variety of Plasmodium species haveevolved, all characterized by alternate cycles in mammals including humans and

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151Sasithon Pukrittayakamee, Arjen Dondorp

the blood-feeding female Anopheles mosquito hosts. The earliest documentedmosquito fossil is dated some 30-65 million years ago, but it is thought that theirorigin goes even further back to the Jurassic era 135 million years ago. Records ofmalaria-like infection in humans is as old as the earliest known scriptures about6,000 years ago. Sumerian and Egyptian texts dating from 3,500 to 4,000 yearsago mention about fevers and splenomegaly suggestive of malaria and splenomegalyin Egyptian mummies is believed to have been caused by malaria.

After having caused millennia of devastation, the first global malariaeradication campaign began after the Second World War. In 1957 AD morethan 130 countries underwrote the call by the World Health Organization (WHO)to eradicate malaria infection from the Earth. The effort was supported by a potentnew insecticidal dichlorodiphenyltrichloroethane (DDT) developed in 1939 AD,which was tested with great success during World War II to control malariaand typhus among civilians and military troops. After important initial successes,the global malaria eradication campaign eventually failed and was officially endedin 1969. Development of DDT resistance in mosquito species and chloroquineresistance in P. falciparum, the most fatal human malaria parasite, are consideredimportant contributors to this failure. Recently in 2007 a renewed malaria eradicationplan was promoted by the Bill and Melinda Gates Foundation.

The Malaria Burden

At present, malaria remains as the most important parasitic infection ofmankind. Each year, 300-500 million of the worldûs populations are infected andaround one million people die from malaria infection. The last decade has seensome success in reducing the burden of malaria is both Southeast Asia andSub-Saharan Africa, mainly through widespread deployment of insecticide treatedbed nets and artemisinin-based combination therapy (Charunwatthana& Pukrittayakamee, 2010). But the development of drug resistance in falciparumand vivax malaria, the two most important species infecting humans, is alwayslingering and threatens to annihilate these recent achievements to reducethe massive burden of morbidity and mortality from malaria (Figure 1,WHO, 2010). The malaria parasite has proven an evolutionally very successfulsurvivor in the worldûs biological history.

The prevention and treatment of malaria have been investigated for overa thousand years. Despite their long history of discovery and development, antimalarial

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drugs are still considered ùorphan drugsû, because of their limited commercialvalue, since malaria confines to poor and underprivileged tropical regions.At present less than 10 different antimalarial drugs are commercially available,many of which are not yet generally accessible. Of the current antimalarial drugs,quinine and Quin-Ghao are the two most important natural drugs. As evidencedfrom early treatment efficacy records, it took less than 10 years for quinine to beadopted for use in Europe in the 17th century. In contrast, it took over a thousandyears until the 20th century for Quin-Ghao to become known and accepted outsideChina. These divergent timelines of both drugs, quinine from the West andQuing-Ghao from the East, partly reflects differences in the scientific heritagebetween these two civilizations i.e. encouragement of general publication of knowledgein the West versus a culture of confidentiality and personal ownership in the East.

The Discovery of Quinine

Quinine is an alkaloid found in the bark of the cinchona tree and has beenused for more than 350 years to treat ùrecurrent feverû (malaria) (Kakkilaya 2006;Table 1). Legends suggest the earliest use of the bark by the native PeruvianIndian population. It was referred to as çJesuitûs bark,é çcardinalûs bark,é andçsacred barké after Jesuit missionariesû working in the Andes mountains in westernSouth America around 1630. Its first introduction to Europe in 1638 (Pukrittayakamee& Looareesuwan, 2003) is said to be linked to the Countess of Chinchon(Figure 2), who had visited Peru and was there cured from malaria by the Peruvianbark (Schreiber & Mathys, 1987). After 1950s, cinchona became widely known inEurope following successful treatment for malaria of several royals including,Louis XIV of France and Charles II of England. The first scientific publication oncinchona was by the French jezuite Honoré Fabri, under the pseudonum ofAntimus Conygius in 1655 in Italy. In 1742 Swedish botanist Carol Linnaeus(1707-1778) called the tree çCinchona“ bark in honor of the Countess of Chinchon.At the end of the 17th Century, the use of cinchona spread throughout Europe andgained wide acceptance in the medical community. In 1820 French chemistPierre-Joseph Pelletier (1788-1842) and Joseph-Bienaime Caventou (1795-1877)isolated quinine from cinchona bark. The drugs became widely known to the worldin the 18th-19th century. Quinine was also used as the main ingredient in severalearly tonic drinks and is was included in army medical kits during the Second

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World War (Figure 3). At present quinine remains an important and effectivetreatment for malaria in most parts of the world, although resistance has beenreported sporadically. Intravenous quinine is used as an alternative regimento artesunate for treatment of severe malaria. Artesunate has proven to be superiorin preventing death from severe malaria, but is not yet generally available throughoutthe tropical world. Quinine remains at present the first line anti-malarial regimenfor first trimester pregnant patients.

The Discovery of Artemisinin

The discovery of Quin-Ghao was part of a series of complex historicalprocesses in Chinese medicine (Table 2). The blue-green herb has been used byChinese herbalists for more than a thousand years for treatment of a varietyof illnesses (Willcox et al, 2004). The earliest record of Quin-Ghao dates back to200 BC, in the çFifty-two Prescriptionsé unearthed from the Mawangdui HanDynasty Tombs. In 340 AD, the anti-fever properties of Quin-Ghao were firstdescribed by Ge Hong (284-363) in the East Yin Dynasty (Figure. 4). Related toChinaûs cultural heritage which did not promote scientific progress duringthe centuries to follow, it took another 1.6 thousand years for the rediscovery ofQuin-Ghao in the early 1970s. The drug remained largely unknown to the rest ofthe world for the following decade The early results of human trials were publishedin a local Chinese language journal, the Chinese Medical Journal, in 1979.The first international publication on artimisinin as an effective anti-malarial drugwas published in Lancet 1982 (Jiang et al, 1982). Pharmaceutical productionof marketable drugs began in 1986. Many active derivatives of artemisinin havesince been synthesized and it is today the most potent and effective knownantimalarial drug, particularly against drug resistant malaria in many areas ofSoutheast Asia (Hien & White, 1993). The World Health Organization (WHO)started to investigate artemisinin and its derivatives in the early 1990s and haspromoted them on a large scale since 2004. Although it has taken Quin-Ghao33 years to gain full WHO recognition, it is now the treatment of choice in the2006 and 2011 WHO treatment guideline for both uncomplicated falciparummalaria (as ACT) and severe malaria. The rediscovery of artemisinin derivativeis an astounding success for both modern and traditional medical science.

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Quinine or Artesunate for the treatment of severe malaria.

In the last decade of the last century it was recognized that the Quin-Ghaoderived antimalarial drugs had very potent antimalarial action and a broad stagespeficity, that is killing young parasites in the red blood cells. Malaria parasites inthe red blood cells mature during a 48 hour life cycle. During maturation, parasitederived proteins are transported to the red cell membrane, making the red bloodcell sticky and adherent to the endothelial vessel wall of the microcirculation.This blocks the normal blood flow to vital organs, and is thought to be the pivotalmechanism in severe malaria pathophysiology. Quinine has a slower antimalarialaction, and does not kill the ring form parasites. As a consequence, clinicaltrials were designed to compare quinine with the Qinghaosu derivatives for thetreatment of severe malaria. The initial trial, though, were conducted with thefat-soluble derivative artemether, produced outside of China. Several large trialsin both Africa and Southeast Asia were conducted, but a meta-analysis in 1919patients could not show a significant life-saving effect of artemether over quinine.It took many years before it was shown that the erratic absorption of artemetherfrom its intramuscular injection site was the likely explanation for this lack ofsuperiority. Especially in very sick patients, with a high chance to die, plasmaconcentrations of artemether were found to remain dangerously low in individualcases. Water-soluble artesunate does not have these pharmacokinetic disadvantages,and provides very reliable blood concentrations after both intravenous andintramuscular administration. After a promising pilot trial in adults patientswith severe falciparum malaria in Northwestern Thailand, two large trials comparingartesunate with quinine were conducted (Figure 5). The first trial with the acronymùSEAQUAMATû, included 1461 mainly adult patients with severe malaria in4 Asian countries in India, Bangladesh, Myanmar and Papua Indonesia (Dondorpet al, 2005). The study was stopped prematurely by the ùdata safety monitoringboardû because of the superiority ùbeyond doubtû of artesunate over quinine insaving lives from severe malaria. Mortality was 35% lower in patients treated withartesunate, and this was not at the expense of an increase in neurological sequelaein the survivors. Side-effects like hypoglycaemia, were higher in patientstreated with quinine. This important finding resulted in an adaptation of theWHO-treatment guidelines for severe malaria in adults. However, it did not lead toa change in policy for the treatment of paediatric severe malaria in Africa, wherethe majority of cases occur. For this reason a large trial was organized in

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Sub-Saharan Africa, in 11 study sites over 9 countries (Dondorp et al, 2010).The study included 5,425 children with severe falciparum malaria, and the overallmortality was around 10%. However, mortality in children treated with intravenousor intrauscular artesunate was 22.5% lower than with quinine, a highly significantdifference. The trial was published end of 2010. Simultaneously, the Chineseartesunate product obtained ùWHO-prequalificationû, which is a quality assurancecertificate issued by the WHO. This was early 2011 followed by another changein the WHO guidelines for the treatment of severe malaria, now recommendingartesunate for all patients with severe malaria, irrespective of age or endemicsetting. The next step will have to be a wide deployment of parenteral artesunatein all countries of the world with important malaria mortality. General use ofartesunate over quinine for the treatment of severe falciparum malaria has thepotential to safe hundreds of thousands of precious lives each year.

Table 1. Timeline for Quinine Discovery1620-1630 The first written record of a malaria cure with cinchona bark in Peru1629 Use to treat Countess of Chinchon in Lima1633 The cinchona bark was brought to Spain1640s Directions for the use of the bark were published (Juan de Lugo)1649 Cinchona to treat the young Louis XIV1655 Antimus Conygius, Fabri wrote in the first paper on cinchona.1658 Prescription of cinchona (ùJesuitsû barkû) in England by Robert Brady1666 Thomas Sydenham, an eminent English physician, published a book

called Method for Curing the Fever (Methodus curandi febres)1670s Robert Talbor develops an infusion of cinchona powder in white

wine and uses it as a ùsecret remedyû to cure of agues1679 King Charles II was treated with Talborûs remedy1742 Linnaeus, a Swedish botonist, classifies the Peruvian bark and names

the tree cinchona after the Countess1817 Joseph Pelletier and Jean Biename Caventou isolated quinine1900s Widespread use of cinchona came about because of the colonizing1844/1910 Sporadic resistance to quinine reported1980 Quinine as a first line drug for treatment of severe malaria WHO2006/2011 Quinine as alternative to artesunate for severe malaria in adults and

children

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Table 2. Time Line for Quin-Ghao Discovery

200 BC The earliest record in the çFifty-two Prescriptionsé unearthed fromthe Mawangdui Han Dynasty Tombs.

340 AD Anti-fever properties of Quin-Ghao first described by Ge Hong(284-363) in China

1960-1971 The systematic screening of the Chinese materia medica led to thefirst demonstration of the antimalarial effects of an extract of QuinGhao

1970s Artemisinin, qinghaosu, was extracted from the traditional Chinesemedical drug Quin-Ghao (the blue-green herb)

1979 The human trails were published in the Chinese Medical Journal1982 The first international publication on artimisinin1986 Pharmaceutical production of marketable drugs began1990-2004 WHO started to investigate artemisinin and its derivatives2006 WHO guideline as first line drug for severe malaria in adult2011 WHO guideline as first line drug for severe malaria in all age groups

Figure legends.

Figure 1. World Malaria Situation (WHO, 2009)

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Figure 2. A fresco art work in Rome depicting the 1st use of quinine to treatmalaria in the 1630s. The Countess of Chinchon , the wife of the Spanish Viceroyto Peru, is receiving a drink made from the bark of a tropical tree traditionally usedby the native inhabitants to cure malaria. The peruvian Indian is holding some ofthe bark in his hand. (Rome, Ospedale di Santo Spirito)

Figure 3. Quinine was also used as the main ingredient in several early tonicdrinks (left) and was included in army medical kits during the War (right).(http://www.chemheritage.org/EducationalServices/pharm)

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Figure 4. The treatment of malaria with qinghao was first recorded in Handbookof Prescriptions for Emergency Treatment by Ge Hong (281-340 AD)(http://www.cultural-china.com/)

Figure 5. Clinical trial sites of severe malaria comparing intravenous quinine andartesunate (Dondorp et al, 2005, 2010)

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