Mini Review

Journal of Pharmaceutics and Therapeutics Plant-Derived Drugs in Malaria Treatment Hempelmann E*

Master of Science in biochemistry, University Tuebingen, Germany

*Correspondence: Ernst Hempelmann, Dorfhalde 14, D-88662, Überlingen, Germany, E-mail: [email protected]

Rec date: May 05, 2018; Acc date: June 04, 2018; Pub date: June 10, 2018 Introduction The First Recorded Use of the Term Mal aiere Every year 880,000 people are killed by malaria, most of them children in impoverished regions of the world In the 5th century, during the demise of the Western lacking adequate medical care. While many preventative Roman Empire, the mainland in northern Italy remained measures, such as mosquito nets have decreased the unsafe. At that time Torcello was one of the first islands to incidence of malaria, once the disease is contracted, be successfully settled in the Venetian Lagoon. Until the it must be treated. Many plasmodial species have 10th century Torcello remained the greatest commercial developed a frightening resistance to antimalarial agents, centre in the lagoon. As silt from rivers on the mainland making the search for new, effective antimalarial agents filled up the shallow waters around Torcello, trade an urgent priority of global importance. became more difficult and the foul-smelling waters of reduce salinity became perfect breeding places for Even now the World Health Organization estimates mosquitoes, turning the northern lagoon into dead water that 80% of the population in Africa and Asia relies (“laguna morta”). From the 12th century Torcello rapidly on plants and plant-derived products, rather than deteriorated and the inhabitants gradually made their way conventional medical therapies, to treat many different to nearby Venice. Buildings in Torcello were dismantled types of diseases. and Venetians recycled useful building materials.

Malaria, in particular, has a long history of plant- The fate of Torcello may still have been well derived anti-malarial therapy. Of the over 1200 plant remembered when in 1440 Venice itself was hit by a fever species reported to possess anti-malarial properties, outbreak, as documented by Marco Cornaro [3]. the development of plant-based antimalarial agents has focused primarily on two sources: Artemisia annua and ...Et cusi scorse le cose senza alcuna provision per fina Cinchona ledgerania, both of which are discussed in this al 1440, del qual anno el fu molte fievre in Venesia in paper [1]. modo chel se diceva che le aque dolce conduseva questo mal aiere... In light of the rising appearance of drug-resistant strains of Plasmodium falciparum, the World Health ... That’s how this went on without any protective Organization has issued a recommendation for the measures until 1440, a year in which there were many treatment of Plasmodium falciparum malarial infections cases of fever in Venice and the people meant that fresh showing resistance to monotherapies. In all regions in water was responsible for the mal aiere...(Translation which such resistance is common, combination therapies Paolo Arese, Turin) – preferably containing an artemisinin derivative - should be the first line of treatment [2]. The essay of Cornaro is written in old Venetian dialect.

J Pharm Sci Therap, 4(1):147-151 (2018) 147 “Mal aiere” is spelled in Toscanic dialect as “mala aria” by Acciajuoli in 1476 [4].

The term gained popularity in Britain in the 1800s, replacing words like ‘’ague’’ (from Latin: febris acuta), ‘’marsh fever’’ or ‘’intermittent fever’’ [4].

Artemisinin compounds

Artemisia annua is a two-meter high plant with aromatic leaves and tiny yellow flowers. A common weed in southern China, Artemisia is also a native plant in temperate regions across the globe, including Europe and North America. In Africa, where the need for antimalarial drugs is increasing, many current initiatives are in place to foster growth and production of this plant.

Chinese origins

A. annua is so named because it is the only member of the genus which has an annual growth cycle [5]. The Chinese name for A. annua is qinghao: Qing (Chinese for green) refers to the dark green uppermost leaves of the plant, which contain the highest concentration of drug Figure 1: Ge Hong (Emergency Prescription kept in when the plant is in flower, Hao refers to the tall stature one’s Sleeve, chapter 3.16) first recorded qing hao as an of the plant. antimalarial: “take a bunch of qing hao, soak in 2 sheng of water, wring out the liquid and drink.” Author’s note: A. annua was used by Chinese herbalists in ancient one sheng is equivalent to 0.2 liters. (Courtesy: Prof Ying times to treat fever and other diseases. The earliest Li, Shanghai Institut of Materia Medica, Chinese Academy known Chinese medicinal recipe book, entitled “The of Science, Shanghai, China) Prescription for fifty-two kinds of diseases” was unearthed in 1979 from a Han Tomb (Han dynasty 206 BC – 220 AD) In 343 Ge Hong died on Mt. Luofu at the age of sixty. at Mawangdui in the Hunan Province [6]. In this book, His treatment was later popularized by the legendary qinghao (A. annua) was prescribed as a treatment for Chinese pharmacist Li Shizhen (1518–1593) in his book hemorrhoids. entitled “Ben Cao Gang Mu” (“Compendium of Materia Medica”), published posthumously in 1596. In his book Li Ge Hong Shizhen describes in detail over 1,800 drugs. The book also Ge Hong (283–343 AD) was a prolific writer of describes the type, form, flavour, nature and therapeutic alchemical, medical and religious (Daoist) texts. He was application of 1,094 herbs and plants, among them, frequently offered positions by authorities but denied qinghao, which is mentioned as a cure for intermittent them all, believing that high and honourable positions fevers. Several new editions and numerous translations were bothersome and fleeting. of the Compendium have been made throughout the centuries. In modern times the herb qinghao has been In 331 Ge Hong retired to Mount Luofu where he wrote used as an antimalarial in the countryside of Southeast the book “Emergency Prescriptions Kept in One’s Sleeve”, China [8]. also known as “Handbook for Emergency Prescriptions.” In his book Ge Hong is the first in medical history to During the wars in neighbouring Cambodia and prescribe the use of qinghao for the treatment of what Vietnam in the late 1960s, the Chinese Government he terms “intermittent fevers”. His ingenious method began a systematic examination of plants used in consisted of soaking the fresh plant in water, wringing traditional Chinese medicine with the aim of finding a out the whole plant, and ingesting its juice in its entirety new antimalarial agent. In 1971, the pharmacologist Tu [7] (Figure 1). Youyou from the Institute of Chinese Materia Medica, J Pharm Sci Therap, 4(1):147-151 (2018) 148 China Academy of Traditional Chinese Medicine, the high forest (1500 – 2700 m) of the eastern slopes of extracted the active principle of qinghao. She used ether the Andes Mountains from Venezuela to Bolivia [12,13]. in her extraction and named the compound qinghaosu, The natives called the cinchona-bark quinquina (“the bark meaning “principle from qinghao” in Chinese. Qinghaosu of barks”), from which came the word quinine. The name is a stable and easily crystallizable compound with a Jesuits’ powder became synonymous with the bark since molecular weight of 282 Da and a molecular formula of the Jesuits had done so much to popularize it as a remedy

C15H22O5 [9]. for malaria. At the age of 46, Francisco de Goya (1746– 1828) suffered from a severe illness. An infectious disease Current use of Artemisinin such as meningitis, encephalitis, or malaria was the likely cause. After a few months he recuperated but was left To prevent the emergence of resistant Plasmodium stone-deaf forever. Toxicity associated with Quinine falciparum, Artemisinin is commonly used in combination treatment (cinchonism) may have complicated his illness. with other active antimalarial drugs. Artemisinin-based Quinine has a well known number of unpleasant side combination treatments (ACTs) are generally accepted effects such as bitter taste, tinnitus, nausea and vomiting as the best treatments for uncomplicated falciparum [14]. malaria [10]. Cost is a major obstacle to ensure adequate treatment in most malaria endemic countries. Only a Quinine has provided the basis for the development minority of the patients that need ACTs actually receive of synthetic counterparts such as chloroquine, them. One artemisinin-based combination therapy, amodiaquine and mefloquine [15]. Ironically, a synthetic artemether–lumefantrine (Coartem), is currently being quinine substitute, the skin-staining atebrin, developed produced by Novartis and has a wholesale price of US by Bayer (“Interessen-Gemeinschaft Farbenindustrie AG”, $2.40 per adult treatment (reportedly with little or no Elberfeld, Germany) in the 1930s proved instrumental to profit margin), as compared with US $0.10 retail for Allied success in the Second World War when the supply chloroquine [11], putting Coartem out of financial reach of quinine from countries in the South Pacific was cut for all but tourists, military forces and the urban elite. The off by Japanese military conquest. Malaria parasites are expense of artemisinin has already led to the production susceptible to quinine and other quinoline-containing of counterfeit drugs and black market distribution. drugs only when they degrade hemoglobin and produce pigment. The pigment forming pathway in P.falciparum Fortunately international support is being mobilized is a specialized parasite biocrystallization process with a to help provide ACTs to countries in need. During 2006 proven history as an exploitable therapeutic target [16]. In more than 62 million treatment courses of Coartem were the treatment of severe malaria, intravenous artesunate delivered to over 30 African countries, helping to save an is more rapidly acting than intravenous quinine in terms estimated 200,000 lives. of parasite clearance, is safer, and is simpler to administer. Quinoline-related Drugs Circulating malaria parasites catabolize hemoglobin Within a two day intraerythrocytic cycle P. falciparum as an important source of amino acids and to maintain digest more than two-thirds of the hemoglobin, the osmotic stability. Template mediated crystallization oxygen-carrying pigment of red blood cells. Protein free (“biocrystallization” for short) of toxic heme into inert hematin, the detergent-like component of hemoglobin, hemozoin is a vital defence mechanism that makes it is toxic when it is in a highly charged and soluble possible for Plasmodia to consume hemoglobin. The a-hematin state, but becomes insoluble and inert when main advantage of biocrystallization has been attributed bio crystallized to ß-hematin. The quinoline antimalarials to the fact that it is independent of energy consumption. appear to act by preventing biocrystallization of the Plasmodia are quite capable of mutating and have evolved toxic heme. Heme biocrystallization is highly specific to sophisticated mechanisms to inactivate drug targets. The the malarial parasite, and the drug target is outside the emergence and global spread of drug resistance is now genetic control of the parasite. threatening to undermine our ability to treat malaria. An exception is pigment biocrystallization because For hundreds of years quinine was the only drug used hemozoin biocrystallization in P.falciparum is a non- in the prevention and treatment of malaria. The drug is muta table target. Crystallization inhibitors will therefore found in the root, bark, and branches of cinchonas and remain a potential class of future antimalarial drugs. EM other trees, which are evergreen trees originally part of studies have shown the pigment formation as a carefully

J Pharm Sci Therap, 4(1):147-151 (2018) 149 controlled process involving many membranes and other cell components.

Figure 3: Labourers sorting out cinchona bark on the Cinchona estate Tjinjiroean, West-Java (1915- 1930) (Courtesy: Tropenmuseum, Amsterdam. Coll.nr. 10012685).

Conclusion Figure 2: Hermann Adolph Köhler 1887 plate 79 III Cinchona officinalis (Courtesy: Royal Botanic Gardens, The WHO recommended plant derived Anti Malaria Kew) compounds in combination with synthetic drugs to combat drug resistance. The choice of combination Hemoglobin Metabolism depends on efficacy, cost and resistance pattern. Drug resistance will spread and the next generation of drugs Camillo Golgi was the first to photograph the pigments are urgently needed. of malaria quartana in 1890 [17]. Since the report of Meckel in 1847 pigment was thought to be melanin References due to its similarity to the brownish colour of the skin pigment [18]. In 1911 Brown observed that all melanins 1. Willcox ML, Bodeker G. Traditional herbal medicines were bleaching rapidly with potassium permanganate, for malaria. BMJ. 2004; 329(7475):1156–9. PMID: while with this reagent malarial pigment manifests https://www.ncbi.nlm.nih.gov/pmc/articles/ not the slightest sign of a true bleach reaction [19]. His PMC527695/. spectroscopic examinations of a solution of malarial pigment proved conclusively that pigment is hematin 2. WHO Traditional Medicine Strategy 2002-2005 pdf and not melanin. The low solubility of malaria pigment Available from: http://www.wpro.who.int/health in mildly alkaline bicarbonate buffer was a long time technology/ puzzle which was solved in 1987 [20], hematin in malaria 3. Cornaro M (1440) Scritture sulla laguna In: PavanelloG pigment is in a ß-hematin form. ß-hematin lost charged (ed) Antichi scrittori d’idraulica veneta, Vol 1: groups by specific coordination linkage and can be either 81-82Venezia 1919. a linear polymer or a cyclic dimer [21]. Based on EM 4. Hempelmann E, Krafts K. Bad air, amulets and studies and electrophoretic separations Hempelmann mosquitoes: 2,000 years of changing perspectives on & Marques concluded that pigment is not produced by malaria. Malar J. 2013; 12:232. PMID: https://www. polymerisation but by biocrystallization [22]. ncbi.nlm.nih.gov/pubmed/23835014. J Pharm Sci Therap, 4(1):147-151 (2018) 150 5. Willcox M. Artemisia species: From traditional gov/pubmed/10541154. medicines to modern antimalarials--and back again. 15. Bray PG, Ward SA, O’Neill PM. Quinolines and J Altern Complement Med. 2009; 15(2):101–9. PMID: artemisinin: chemistry, biology and history. Curr Top https://www.ncbi.nlm.nih.gov/pubmed/19236169. Microbiol Immunol. 2005; 295:3–38. PMID: https:// 6. Li Y, Wu Y-L. An over four millennium story behind www.ncbi.nlm.nih.gov/pubmed/16265885. qinghaosu (artemisinin)--a fantastic antimalarial drug 16. Hempelmann E. Hemozoin biocrystallization in from a traditional chinese herb. Curr Med Chem. Plasmodium falciparum and the antimalarial activity 2003; 10(21):2197–230. PMID: https://www.ncbi.nlm. of crystallization inhibitors. Parasitol Res. 2007; nih.gov/pubmed/14529339 100(4):671–6. PMID: https://www.ncbi.nlm.nih.gov/ 7. Hsu E. The history of qing hao in the Chinese materia pubmed/17111179. medica. Trans R Soc Trop Med Hyg. 2006; 100(6):505– 17. Muscatello U. Golgi’s contribution to medicine. Brain 8. PMID: Res Rev. 2007; 55(1):3–7. PMID: https://www.ncbi. 1. https://www.ncbi.nlm.nih.gov/pubmed/16566952. nlm.nih.gov/pubmed/17462742. 8. Li Y, Wu YL. How Chinese scientists discovered 18. Frerichs FT. Klinik der Leberkrankheiten [Internet]. qinghaosu (artemisinin) and developed its derivatives? Braunschweig, Vieweg; 1858 [cited 2018 Jun 18]. What are the future perspectives? Med Trop (Mars). 442 p. Available from: http://archive.org/details/ 1998; 58(3 Suppl):9–12. PMID: klinikderleberk01frergoog 2. https://www.ncbi.nlm.nih.gov/pubmed/10212890. 19. Brown WH. MALARIAL PIGMENT (SO-CALLED 9. Liao F. Discovery of Artemisinin (Qinghaosu). MELANIN): ITS NATURE AND MODE OF PRODUCTION. Molecules. 2009; 14(12):5362–6. PMID: http://www. J Exp Med. 1911; 13(2):290–9. PMID: mdpi.com/1420-3049/14/12/5362. 3. https://www.ncbi.nlm.nih.gov/pmc/articles/ 10. Nosten F, White NJ. Artemisinin-based combination PMC2124860/ treatment of falciparum malaria. Am J Trop Med Hyg. 20. Fitch CD, Kanjananggulpan P. The state of 2007; 77(6 Suppl):181–92. PMID: https://www.ncbi. ferriprotoporphyrin IX in malaria pigment. J Biol nlm.nih.gov/pubmed/18165491. Chem. 1987; 262(32):15552–5. PMID: https://www. 11. Arrow KJ, Gelband H, Jamison DT. Making antimalarial ncbi.nlm.nih.gov/pubmed/3119578. agents available in Africa. N Engl J Med. 2005; 21. Lemberg R, Legge JW. Hematin compounds and 353(4):333–5. PMID: https://www.ncbi.nlm.nih.gov/ bile pigments; their constitution, metabolism, pubmed/16000348. and function, [Internet]. New York,: Interscience 12. Bruce-Chwatt LJ. Three hundred and fifty years of Publishers,; 1949. 784 p. Available from: https://www. the Peruvian fever bark. Br Med J (Clin Res Ed). 1988; biodiversitylibrary.org/item/28869 296(6635):1486–7. PMID: https://www.ncbi.nlm.nih. 22. Hempelmann E, Marques HM. Analysis of malaria gov/pubmed/3134079. pigment from Plasmodium falciparum. J Pharmacol 13. Kaufman TS, Rúveda EA. The quest for quinine: those Toxicol Methods. 1994; 32(1):25–30. PMID: https:// who won the battles and those who won the war. www.ncbi.nlm.nih.gov/pubmed/7833503. Angew Chem Int Ed Engl. 2005; 44(6):854–85. PMID: https://www.ncbi.nlm.nih.gov/pubmed/15669029. 14. Ravin JG, Ravin TB. What ailed Goya? Surv Ophthalmol. 1999; 44(2):163–70. PMID: https://www.ncbi.nlm.nih.

Copyright: © Hempelmann E. This is an Open Access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

J Pharm Sci Therap, 4(1):147-151 (2018) 151