(Carapichea Ipecacuanha (Brot.) L. Andersson): Plants for Medicinal Use from the 16Th Century to the Present

Home , Carapichea, Carapichea ipecacuanha, Charles Ledger, Scirus, Syrup of ipecac

journal of herbal medicine 2 (2012) 103–112

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Review Use and importance of quina (Cinchona spp.) and ipeca (Carapichea ipecacuanha (Brot.) L. Andersson): Plants for medicinal use from the 16th century to the present

Washington Soares Ferreira Júnior ∗, Margarita Paloma Cruz, Lucilene Lima dos Santos, Maria Franco Trindade Medeiros

Laboratory of Applied Ethnobotany, Department of Biology, Federal Rural University of Pernambuco, Av. Dom Manoel de Medeiros, s/n, Dois Irmãos, CEP: 52171-900, Recife, PE, Brazil article info abstract

Article history: Observations in prescriptions of the monasteries’ apothecaries of São Bento from Rio de Received 1 February 2012 Janeiro (Rio de Janeiro) and Olinda (Pernambuco) dating from the nineteenth century, Received in revised form prescribed quina (Cinchona spp., Rubiaceae) and ipeca (Carapichea ipecacuanha [Brot.] L. Ander- 30 May 2012 sson, Rubiaceae) for antidiarrheal/febrifuge and emetic/expectorant uses. In addition to Accepted 30 July 2012 these observations, pharmacological and anthropological literature indicate a great impor- Available online 4 October 2012 tance of using these plants for treating human diseases since ancient times. From this information, the present work conducts a literature review to investigate the history of dis- Keywords: covery and use of these species, recovering information about past and current uses of quina Historical ethnobotany and ipeca, seeking also to record possible changes in usage over time. Rubiaceae © 2012 Elsevier GmbH. All rights reserved. Past pharmacopoeias

Contents

1. Introduction ...... 104 2. Methodology ...... 104 3. The genus Cinchona ...... 104 3.1. Taxonomic aspects and geographical distribution ...... 104 3.2. Historical remarks ...... 106 3.2.1. How indigenous people and Europeans knew about the uses and applications of quina ...... 106 3.2.2. Records prior to the seventeenth century on Cinchona use...... 106 3.2.3. The role of naturalists in the description of the genus and species of Cinchona ...... 106 3.2.4. Plantations and commercial activity ...... 107 3.2.5. Use of Cinchona from the twentieth century ...... 107 4. The case of Carapichea ipecacuanha (Brot.) L. Andersson ...... 108

∗ Corresponding author. E-mail address: [email protected] (W.S. Ferreira Júnior). 2210-8033/$ – see front matter © 2012 Elsevier GmbH. All rights reserved. http://dx.doi.org/10.1016/j.hermed.2012.07.003 104 journal of herbal medicine 2 (2012) 103–112

4.1. Taxonomic aspects and geographical distribution of the species ...... 108 4.2. Historical Remarks ...... 110 4.2.1. How Europeans came to use ipeca ...... 110 4.2.2. Past and present use of C. ipecacuanha ...... 110 5. Final considerations: linking information on the historical use of Cinchona spp. and Carapichea ipecacuanha ...... 110 Acknowledgment ...... 111 References ...... 111

1. Introduction 2. Methodology

The use of plants for disease treatment in tropical regions is This study was conducted through a comprehensive, sys- widespread, and the use of these plants has been documented tematic literature search regarding the use of plants of the from the times that people in the old world met the indige- genus Cinchona and C. ipecacuanha for medicinal purposes. nous American people (Ortiz Crespo, 1994). In South America, Empirical searches were conducted via the databases JSTOR there is an interest in the use of the Rubiaceae species, popu- (http://www.jstor.org), Scopus (http://www.scopus.com) and larly known as quina or cinchona (Cinchona spp.) (Kurian and Scirus (http://www.scirus.com) as well as periodicals using the Sankar, 2007) and ipeca or ipecacuanha (Carapichea ipecacuanha following four keyword combinations: Cinchona and medic- (Brot.) L. Andersson) (De Boer and Thulin, 2005). These plants inal; Cinchona and ethnobotany; Ipecacuanha and medicinal are extremely important in history, and have been used by and Ipecacuanha and ethnobotany. Publications were consid- many groups of people, both natives and settlers (Möller et al., ered up to the end of 2010. Information on the history of the 2007). For example, authors from several regions throughout knowledge and use of these plants was also recorded after history have reported the importance of Cinchona spp. and consulting the collections from the following Brazilian insti- Carapichea ipecacuanha for disease treatment (Sandwith et al., tutions: the National Library of Rio de Janeiro; the National 1914; Kurian and Sankar, 2007; Alencar et al., 2010; Medeiros Museum Library; the Federal University of Rio de Janeiro and et al., 2010). the Library of the Institute of Botany of the Rio de Janeiro According to Medeiros et al. (2010) and Medeiros and Botanical Garden. All of the information regarding the plants; Albuquerque (2012), nineteenth-century prescriptions from their past and present therapeutic uses; the part of the plant chemists and pharmacies in the monasteries of São Bento that was used and data about planting and marketing was from Rio de Janeiro (State of Rio de Janeiro, Brazil) and taken directly from the selected papers. Both in vitro and Olinda (Pernambuco, Brazil) described quina as an anti- in vivo pharmacological studies in humans and animals for diarrheal and febrifuge and ipecac as an emetic and each plant species were considered. expectorant. Historically, these plants were initially used Data regarding the botanical aspects and geographical dis- by indigenous populations, and have since been used in tribution of the plants was also extracted. Europe and other parts of the world (Sandwith et al., The taxonomic update was performed by consulting an 1914; Ortiz Crespo, 1994); therefore, there has been sub- expert botanist, Regina Helena Potsch Andreta, Santa Ursula stantial overuse of these species throughout time (Assis University, Brazil and the Missouri Botanical Garden database and Giulietti, 1999) from pharmaceutical companies (Brandão (http://www.tropicos.org/). To describe the quina and ipeca et al., 2008). plants, illustrations from a reference work entitled “Flora Despite the fact that quina and ipecac have been used do Brasil” were also included (Argoviensis and Schumann, as medicinal plants throughout history, there is a lack of 1889a,b). information on these species and a detailed analysis that The results in this paper are divided into two sections, one describes their use over time. Thus, the purpose of this for Cinchona and one for C. ipecacuanha. For each plant general paper is to provide a detailed historical documentation of the information about the species, historical considerations about use of these two plants based on the observations made by their medicinal use since the sixteenth and seventeenth cen- Medeiros et al. (2010) and Medeiros and Albuquerque (2012) turies, data from the initial written records of their use, as well related to their important participation in the nineteenth- as the present pharmacological properties of the species are century Brazilian pharmacopoeia, particularly from 1837 to reported. 1839, the 1840s, 1860s and 1880s, which is the time when the Rio de Janeiro monastery source was written, and the period from 1823 to 1829, when the Olinda monastery source 3. The genus Cinchona was written. This work seeks to conduct a literature review to document the history of the discovery and use of these 3.1. Taxonomic aspects and geographical distribution plants by accessing their ancient as well as their contempo- rary uses and to understand the reasons why these plants The genus Cinchona (Fig. 1) is composed of a shrub or small tree were and still are considered important for disease treat- species, reaching up to 20 m high with a diameter between 15 ment. and 20 cm. It has a natural distribution, extending from the journal of herbal medicine 2 (2012) 103–112 105

Fig. 1 – Board representing the species Cinchona carabayensis Wedd. in Flora Brasiliensis (1840–1906). Source: Flora Brasiliensis Online: http://ﬂorabrasiliensis.cria.org.br.

mountains of Southern Costa Rica and Northern Panama, to According to Kirkbride (1982), Carl F. Linnaeus established the Andean mountains of Colombia, Venezuela, Ecuador and the genus Cinchona in the second edition of his work entitled Peru, to Bolivia (Andersson, 1998). The genus has also been “Genera Plantarum” (1742), which was based on the mem- found in the Amazon, as was the case for Cinchona amazonica oir of Charles Marie de La Condamine, a French geographer Standl. in the town of Acre (Pollito and Tornazello-Filho, 2006), and mathematician, presented in the “Annales de l’Academie even though the genus Cinchona is not listed as Brazilian flora Royale des Sciences” of Paris in 1738. In the first edition in the Lista de Espécies da Flora do Brasil (see Forzza et al., 2010). of “Species Plantarum” written in 1753, Linnaeus published The taxonomy of the genus is hampered by poor collection a species, Cinchona officinalis. In 1764, José Celestino Mutis, and an increase in the trend of interspecific crossing, espe- a Spanish naturalist from Nuevo Reino de Granada, sent a cially in growing areas, leading to a large number of hybrids branch of the Peruvian bark prepared by Don Miguel de San- (Prendergast and Dolley, 2001). tisteban in the province of Loja, Peru to Linnaeus. Based on 106 journal of herbal medicine 2 (2012) 103–112

the branch deposited in the Linnean Herbarium, London, Lin- not believe it due to a lack of evidence and inconsistencies naeus presented a more detailed description of the species in within the reports (Taylor, 1943; Triunfol, 2002). For example, “Systema Naturae”, which was published in 1767. This concep- according to Ortiz Crespo (1994), several authors argue that tual change corresponded more closely to C. cordifolia, named this episode could not have occurred because the first Count’s by Mutis in 1793 (Kirkbride, 1982). Thus, over time, several wife would have died before he was appointed Peru’s Viceroy names were introduced for different species within the genus, and traveled to America. The second wife would have died and a few revisions were made to systematize them, which on American soil without returning to Europe, so it would be caused some confusion among researchers (Andersson, 1998). unlikely that she had transported quina and made it available From reviews performed, Andersson (1998) stands out as hav- for use on this continent. ing recognized 23 species within the genus. According to the present data, it is still not known how the use of quina was discovered and transferred to Europe. 3.2. Historical remarks Although reports have historical relevance, many have not been proven or clarified, which still does not explain the ori- 3.2.1. How indigenous people and Europeans knew about gin or history of Cinchona use in the treatment of fevers. It is the uses and applications of quina also unclear how Conquistadors came to effectively use quina There are two reports on how the indigenous people possibly to treat malaria (Urdang, 1945), although some authors claim came to know about the medicinal properties of Cinchona. One that this plant had likely been used in America for malaria report tells the story of an Indian who got lost and sick in a treatment (Patino,˜ 1963; Tene et al., 2007). However, it has not Peruvian jungle with a fever. Unable to walk, he laid near a been possible to determine whether the indigenous people small pond from which he drank some water and fell asleep. first started using quina to treat this disease, or whether the When he awoke the next day, he found that his fever was conquerors discovered the plants’ effectiveness because of the gone, an improvement that was apparently attributed to a Cin- similarity in symptoms between common fevers and fevers chona tree that was submerged in the pond (Thompson, 1928; caused by malaria. Urdang, 1945). The second version of the story reports that Indians found out about the febrifugal properties of Cinchona 3.2.2. Records prior to the seventeenth century on after observing other animals consume the Cinchona tree bark Cinchona use to cure their fevers (Urdang, 1945). A study carried out by Ortiz Crespo (1994) shows that in There are also reports detailing how the knowledge of this 1571–1572, the Spanish authors Nicolás Monardes and Juan plant travelled from the South American indigenes, mainly Fragoso reported the use of these plants to combat fevers and the Malacotas, an Ecuadorian indigenous group, to Europeans. dysentery. These records are older than the story of the Jesuit According to the chronicle of Joseph de Jussieu, who visited missionary that was treated by a Malacota healer; therefore, Loja in 1739 in around 1600, a Jesuit missionary suffered from this would be the first record of transferring the knowledge intermittent fevers and was cured after a Malacota leader of this plant from a native to a European. However, accord- administered the quina bark (Thompson, 1928). The Jesuits ing to Ortiz Crespo (1994), Monardes and Fragoso do not make played an important role in spreading the knowledge of quina explicit mention of the cinchona or quina plant, but by the throughout Europe by using the powder extracted from its bark taxonomic descriptions of the plants as well as descriptions to prepare drugs to fight the tertian fever. For this reason, quina of the uses, all seems to indicate that this could be the same also received the name of “Jesuit’s powder” or “Jesuit’s bark” plant. (Thompson, 1928). Other authors also mention that the American popula- The introduction of quina into Europe is attributed to the tion had little knowledge about the use of this plant species wife of Count Chinchon, who in around 1630 was appointed (Thompson, 1928; Urdang, 1945). According to Thompson the viceroy of Peru. According to this report (Thompson, 1928), (1928), the Malacotas had knowledge of the use of this plant, once they were established in South America in late 1630, the while the Incas did not make any reference to this plant Count’s wife suffered strong episodes of fevers that could only in their pharmacopoeia (Taylor, 1943). Humboldt, quoted by be treated with the cinchona bark. Don Lopez de Canizares, the Thompson (1928), indicated that at that time, Indians did not Loja Spanish magistrate, may have communicated the proper- want to use quina to treat diseases, because they only knew ties of this plant to the Countess’ doctor in 1628. The Spanish it as a dye for clothes, and considered its consumption to be magistrate, in turn, would have been aware of this information dangerous. by having also been cured by this plant. However, it remains unknown how the magistrate came to know about the thera- 3.2.3. The role of naturalists in the description of the peutic properties of the cinchona bark (Thompson, 1928; BMJ genus and species of Cinchona Publishing Group, 1930). In 1753, Linnaeus described the genus Cinchona and species Once the countess was cured, she could have traveled to Cinchona officinalis, honoring the Countess of Chinchón with Europe with the powdered cinchona bark, thereby disclos- this name (BMJ Publishing Group, 1930; Gurib-Fakim, 2006), ing its efficacy for treatment of tertian fever. It was then though he committed an error and omitted the letter “H” in that Europeans began to know about this product as the the name, possibly because of incorrect information (Triunfol, “Chinchón powder,” in honor of the Countess that would have 2002; Honigsbaum and Willcox, 2004). By the late eighteenth reported this knowledge (Thompson, 1928; BMJ Publishing and early nineteenth centuries, José Celestino Mutis, who was Group, 1930). Although some authors believe this story to be sent by Spanish royalty to serve as physician to the viceroy true (Thompson, 1928; BMJ Publishing Group, 1930), others do of Nuevo Reino de Granada (comprising Colombia, and parts journal of herbal medicine 2 (2012) 103–112 107

of Ecuador, Peru and Venezuela), became interested in the Charles Ledger had in the correct selection of seeds that were study of quina. Because of this interest, he was the first to find suitable for cultivation. records of quina use in the northern hemisphere (Kirkbride, Conversely, in America during the nineteenth century, 1982; Appel, 1994). However, due to a delay in releasing this though there were naturally occurring populations of several information, and because he had trusted the Panamanian Cinchona species, quinine production could no longer meet the doctor Sebastián López Ruiz with his find, it was Ruiz who increasing demand; thus, it had to be purchased from Holland reported this finding and gained a honorary position driving (Fosberg, 1947). However, this situation changed in 1934 when quina trade between Madrid and Bogota (Appel, 1994). Merck & Co. began financing and promoting quina crops in Mutis, however, dismissed Lopez de Ruiz and began to the New World. To accomplish this, seeds were taken from devote more time to the study of quina; he sent plant mate- the varieties whose levels of quinine in the bark were proven rial to Spain in 1787, which was rejected for not having the to be sufficiently high to allow for its commercial extraction, ascribed medicinal properties. Rather than being discouraged which promoted quina planting in territories of Central Amer- he resolutely continued his research on this group of plants. ica where coffee used to be planted. The Second World War Thus, considering the wide variability within Cinchona,itwas caused a temporary loss of Dutch colonies in the East, and necessary to do a meticulous study to determine the exist- provided Americans with the impetus needed to achieve suc- ing species of this genus and from which species quinine, the cess with their crops (Fosberg, 1947). The wild populations of active ingredient of Cinchona that is important for its therapeu- Cinchona would not be sufficient to meet the increased demand tic value, could be extracted (Appel, 1994). In 1802, Francisco for quinine; thus, it was necessary to establish quina crops. José de Caldas, a follower of Mutis, traveled to Loja to look According to Taylor (1943), quina extraction was only possi- for information about quina that would allow him to establish ble through destruction of the trees. The main bark collections the existing species number and their geographical distribu- are obtained 15–20 years after planting the tree. Commercial tion and to determine where the species that are suitable for extraction of quinine is only possible if the bark has 6% or more extraction of quinine can be found (Appel, 1994). quinine, but most wild Cinchona in South America contains as little as 2.5–3% quinine in its bark. Because of the difficulties highlighted above, it was necessary to synthesize molecules 3.2.4. Plantations and commercial activity with similar effects in the laboratory for malaria treatment Since the discovery that Cinchona is effective for the treat- (Taylor, 1943). ment of malaria, its demand keeps increasing, especially in countries that had colonies in tropical regions, where there were alarming increases in the reported cases of malaria. 3.2.5. Use of Cinchona from the twentieth century Due to the increased demand for quinine, and the highly It was found by analysis of 19th century prescriptions from destructive techniques that are necessary for extraction of this pharmacies of the Benedictine monasteries in Rio de Janeiro alkaloid from the bark of quina, it was necessary to establish and Olinda, Brazil that quina (Cinchona spp.) was used dur- crop fields of this plant. It is for these reasons that England ing this time period (see Medeiros et al., 2010; Medeiros and Holland started planting quina in their tropical colonies, and Albuquerque, 2012) for treatment of diarrhea and fever India and Java, respectively (Taylor, 1943). (Medeiros and Albuquerque, 2012). Charles Ledger (1818–1905) noted for his work in con- The use of Cinchona was and still is suitable as an anti- nection with quinine was a very important figure in the malarial, because malaria infects approximately 500 million search for and selection of appropriate plant material to start and kills approximately two million people a year, and has plantations, along with the native Manuel Incra Mamai, the historically been a disease that threatens human populations indigenous person who collected and indicated the appro- (Kinsley-Scott and Norton, 2003). priate material for obtaining individual plants that had high There are thirty different alkaloids present in Cinchona enough levels of quinine in the bark to allow its extraction bark (Hodge, 1948). Some of these compounds are qui- (Thompson, 1928; Taylor, 1943; Triunfol, 2002). Thus, Ledger nine, dihydroquinine, cinchonidine, epiquinine, quinidine, managed to send large amounts of seeds that were collected dihydroquinidine, cinchonine and epiquinidine (Karle and in Bolivia to his brother, who was in charge of selling them to Bhattacharjee, 1999), which are divided into two groups: crys- the British and Dutch governments. The British were not very talline and amorphous alkaloids (BMJ Publishing Group, 1924). successful in establishing their plantations, while the Dutch The alkaloids responsible for the antimalarial activity of Cin- managed to establish large plantations in the late nineteenth chona are crystalline compounds found in the bark of the and early twentieth centuries after overcoming cultivation plant’s stem, and these compounds are divided into two types: difficulties relating to climate and the maintenance of pure natural alkaloids and hydroalkaloids (Acton, 1922). According lineages. Because the plants of this genus hybridize very easily, to the same author, natural alkaloids are the main compounds it was virtually impossible to obtain large populations with the present in the bark. Quinine, a widely recognized antimalarial desired characteristics without carefully managing the indi- that has been used for 300 or 400 years, is also found in the vidual plants and their reproduction. The Dutch performed bark (Bruce-Chwatt, 1986; Muthaura et al., 2011). The hydroal- much research on how to plant and appropriately care for kaloids are found in small quantities in the bark of the Cinchona these crops (Taylor, 1943). For a long time, these plantations stem and are mostly prepared in the laboratory (Acton, 1922). produced the large amounts of quinine that were in demand Quinidine, a stereoisomer of quinine, is a crystalline alkaloid worldwide. The species that was planted in Java was named drug that has been used in its sulfate or gluconate form mostly Cinchona ledgeriana, which highlighted the important role that to treat irregular cardiac rhythms since the twentieth century, 108 journal of herbal medicine 2 (2012) 103–112

and similar to quinine, it was used to treat malaria (Roden, Notwithstanding the evidence of efficacy of these com- 1996; Menezes et al., 2001). pounds in the laboratory, the authors suggest searching for There are several types of bark: red (Cinchona succirubra), new active antimalarial compounds because of the increasing gray (C. micrantha and C. nitida), yellow (C. calisaya), Colombian resistance of Plasmodium falciparum to chloroquine since the (C. lancifolia) or colorless (C. officinalis)(BMJ Publishing Group, 1960s, especially in Africa, Asia and Oceania (Bruce-Chwatt, 1924), each of which has a stable ratio of alkaloids. Plants 1986; Gurib-Fakim, 2006; Botsaris, 2007). In 1971, the discov- with the yellow bark seem to be richer in quinine than those ery of artemisinin as a potent antimalarial compound and the that have red or gray bark, the latter having the lowest com- production of its analogues generated important new avenues pound concentration (BMJ Publishing Group, 1924). Therefore, for the treatment of malaria, because chloroquine treatment an important factor in choosing which bark types to plant was no longer effective given the resistance of the parasite to and market for antimalarial use is the nature of the alka- the drug (Wright, 2005). Even with artemisinin, data show that loid, because the value of the barks for febrifuge treatment the mortality rate due to malaria has increased over the last 25 is related to the concentration of these substances (Fletcher, years (Wright, 2005). Given this situation, efforts to find new 1926). alternatives should be employed (Kumar et al., 2009; Rukunga Plants with yellow bark (C. calisaya) contain the highest qui- et al., 2009). Some alternatives have been created such as nine concentration; this species was widely used within the the drug Quinimax®, which is formed by combining quinine, pharmaceutical trade to treat malaria in the time of Fletcher quinidine and cinchonine, the naturally occurring alkaloids (1926). In 1924 when BMJ Publishing Group published their from Cinchona stem bark. Quinimax® has been shown to be article on the cinchona bark and its alkaloids, quinine was more effective than chloroquine, which is the standard malar- the only compound used against malaria and was the main ial treatment regimen of the World Health Organization (see compound separated from the Cinchona bark. Because the Deloron et al., 1990; Sowunmi et al., 1990). In addition, quinine plants with yellow bark were being used most often, there was is still regarded as an effective treatment for severe malaria in a shortage and a risk of decreased production. To decrease Africa (Wright, 2005) and French Guiana (Legrand et al., 2008). quinine use, the BMJ Publishing Group encouraged the use Quinine, in addition to its importance for malarial treat- of other crystallized alkaloids because they also had consid- ment, has also been used on a smaller scale as a treatment erable antimalarial activity, suggesting the need for further for goiter, Meniere’s disease (an inner ear disorder), and vari- studies on the subject (BMJ Publishing Group, 1924). The anti- cose veins, and in obstetrics for its action on uterine muscles malarial potential of other crystalline alkaloids was further (Taylor, 1943). Currently, the high demand for products con- supported by Fletcher (1926), who showed that four crystal- taining quinine from Cinchona spp. is not only because of its lized alkaloids were effective in a 10-g dose administered twice extensive use in treatment of malaria but also because it can daily. be used to enhance digestion, as an anti-amoebic medica- According to the British Medical Journal (1924), amorphous tion, to treat colds, coughs, influenza and other fevers, as an alkaloids have faster physiological activity, although several insect repellent and an insecticide, and in lotions for the treat- authors have shown that these compounds cause adverse ment of burns (Weiss, 2002; Kurian and Sankar, 2007). Some effects, and often do not provide antimalarial activity. For studies have found additional uses for Cinchona alkaloids in example, Eden (1880) observed irritation in patients after using the laboratory. For example, Solomon and Lee (2009) found pure Cinchona spp. due to the amorphous compounds, and that chloroquine and its analogues may play an important Fletcher (1926) stated that amorphous alkaloids caused toxic- role in cancer therapy. Moreover, research by Turker and Usta ity, vomiting and diarrhea in patients and also did not provide (2006) demonstrated the efficacy of Cinchona as an antimicro- effective malaria treatment. bial by observing the activity of aqueous Cinchona succirubra There were no studies describing quinine synthesis in the Paon extracts against both Gram-positive and Gram-negative laboratory until 1943 (Taylor, 1943). However, the first formal bacteria. synthesis was performed in 1944 by the American chemists R.B. Woodward and W.E. Doering, followed by others (Kumar et al., 2009). However, quinine synthesis was not able to com- 4. The case of Carapichea ipecacuanha (Brot.) pete economically with the isolation of alkaloids from natural L. Andersson or synthetic resources (Cuyubamba et al., 2009; Kumar et al., 2009), although quinine was considered expensive. 4.1. Taxonomic aspects and geographical distribution Since the late twentieth century, compounds that are sim- of the species ilar to quinine, such as chloroquine and mefloquine, were developed, which also provided effective malaria treatment The origin of the term ipecacuanha comes from the Brazil- (Kumar et al., 2009) and replaced the chemical compound ian Indians (Sandwith et al., 1914), whose etymology comes extracted directly from quina plants. At the end of the twen- from the Indian words ipê (bark), caa (plant), cua (fragrant), tieth century, studies sought to investigate the mechanism of nha (grooved), i.e., “bark of fragrant and striated plant” (Saint- action of Cinchona compounds in the treatment of malaria. For Hilaire, 2009). Currently, there are several popular names for example, Olliaro and Goldberg (1995) note that the mecha- Psychotria ipecacuanha (Brot.) Stokes in Brazil, such as ipeca, nism of action of quinine may be related to modification of ipecacuanha, poaia, poalha (Skorupa and Assis, 1998) and pepa- the activity of the parasite’s digestive vacuoles. Chloroquine, conha (Albuquerque et al., 2007). for example, inhibits lysosome enzyme activity, thus causing Similar to many popular names are the six synonyms for changes in cellular chemical signals (Hostetler et al., 1985). P. ipecacuanha (Assis and Giulietti, 1999). Currently, the main journal of herbal medicine 2 (2012) 103–112 109

synonym of P. ipecacuanha is Cephaelis ipecacuanha (Assis and Nomura et al., 2008) and occurs in the sub-forest of tropical Giulietti, 1999; Oliveira and Martins, 2002; Möller et al., 2007). forests (Assis and Giulietti, 1999)(Fig. 2). According to Assis However, Assis and Giulietti (1999), who studied ipecauanha and Giulietti (1999), it has a disjunctive distribution in the populations between Central and South America, consider rainforests of Central (Nicaragua, Costa Rica and Panama) and Psychotria ipecacuanha (Brot.) Stokes to be the correct name for South America (Colombia and Brazil). In Brazil, it is found in the different populations. In 2005, De Boer and Thulin made the Amazon Forest in the states of Amazonas, Para, Maranhão, the most recent revision to the name Carapichea ipecacuanha Rondônia and Mato Grosso, along the Atlantic Forest in the (Brot.) L. Andersson, which is actually accepted for the species. northeastern states of Pernambuco and Bahia, in the South- Thus, this is the species name that will be used throughout east in Espírito Santo, Minas Gerais, Rio de Janeiro and São this work. Paulo, and in the South in Paraná State (Flückiger and Hanbury, Carapichea ipecacuanha is native to the hot and humid 1878; Baillon, 1884; Chernoviz, 1908; Cruz, 1965; Rizzini and forests of South and Central America (Skorupa and Assis, 1998; Mors, 1995; Assis and Giulietti, 1999; Lorenzi and Matos, 2002).

Fig. 2 – Board of Psycotria ipecacuanha (Brot.) Stokes in Flora Brasiliensis (1840–1906). Source: Flora Brasiliensis Online: http://ﬂorabrasiliensis.cria.org.br. 110 journal of herbal medicine 2 (2012) 103–112

4.2. Historical Remarks Some studies have tested the pharmacological activity of ipecac root in the laboratory. For example, Boxer et al. (1969) 4.2.1. How Europeans came to use ipeca observed that the effect of ipecac-induced emesis was more Indigenous people who inhabited the Brazilian territory prior effective for removal of excess salicylate than gastric lavage. to the discovery of America by the Europeans already used Further studies have shown expectorant, emetic and amebic ipecacuanha as medicine and knew the emetic properties of activities of the species (Garcia et al., 2005; Brandão et al., the plant (Sandwith et al., 1914; Lorenzi and Matos, 2002). This 2008). The alkaloids emetine and cephaline have proven phar- knowledge was in turn passed to the first European colonizers macological activity as emetics, anti-amebics and for the (Garcia et al., 2005), who used ipeca for decades as an emetic treatment of diarrhea (Assis and Giulietti, 1999; Brandão et al., for patients who had ingested poison, and for children who 2008). had ingested a toxic substance (Möller et al., 2007). According The records of using ipecac to induce vomiting in patients to Brandão et al. (2008), historic uses of the plant were as an who ingested poison peaked in the mid-1980s, and decreased emetic in patients with diarrhea. thereafter (Manoguerra and Cobaugh, 2005). Currently the use The first written source about ipecacuanha is dated 1601; of ipecac is not recommended for use after poisoning (Möller its author was a Portuguese Jesuit who recorded aspects of et al., 2007) due to ipecac abuse from easily accessible over- Brazilian history and mentioned a drug named igpecaya or the- counter products (Silber, 2005) causing high levels of tox- pigaya (Flückiger and Hanbury, 1878; Lorenzi and Matos, 2002). icity (Tietze and Rackelmann, 2004). Csuka and Antoni (1984) In 1648, Piso and Marcgrave described two plants that were and Salako (1970) observed inhibition of the immune response also named igpecaya. However, based on the information in mice and muscle contraction in rats, respectively, by eme- from Sandwith et al. (1914), it is known that one of these is tine. Thus, the inappropriate use of ipecac can cause serious ipecacuanha. damage to the body. Even with these problems, syrup of ipecac The introduction of ipecacuanha in Europe occurred in is sold in several countries such as Brazil, France, Japan and approximately 1672, when the doctor Le Oras arrived in Paris the United States, where it induces emesis in humans after from South America bringing some of the plant root with poisoning (Garcia et al., 2005). him (Flückiger and Hanbury, 1878). However, knowledge of its Additional uses of ipecac have been found in recent stud- virtues did not expand across the European continent until ies, including the treatment of dysentery, bronchitis, worms, 1686, when the French herbalist Grenier took large amounts blood disorders, leukemia, teething children, cancer, induc- of ipecacuanha roots from Brazil. The roots were used by his tion of vomiting, expectoration and as an anti-amebic (see partner, the Dutch physician Helvetius (1625–1709), who cured Vieira, 1999; Garcia et al., 2005; Manoguerra and Cobaugh, numerous cases of dysentery, and was even granted the priv- 2005; Möller et al., 2007; Albuquerque et al., 2007). ilege to use his secret remedy exclusively by King Louis XIV of France, making him a great fortune (Flückiger and Hanbury, 1878; Sandwith et al., 1914; Lee, 2008). Feeling aggrieved, Gre- nier made public that ipecacuanha roots were the secret of 5. Final considerations: linking information Helvetius’s cure (Caminhoá, 1884). on the historical use of Cinchona spp. and Carapichea ipecacuanha 4.2.2. Past and present use of C. ipecacuanha During the 19th century, ipecacuanha was registered as an The discussion presented herein shows the importance of emetic and an expectorant in the pharmacies of the Benedic- studies investigating the historical use of plants to understand tine monasteries of Rio de Janeiro and Olinda, Brazil (Medeiros the use of these plants throughout history. The studies on et al., 2010; Medeiros and Albuquerque, 2012). At this time, Cinchona spp. and C. ipecacuanha illustrate several points. the therapeutic uses of this plant were known in traditional, First, according to the historical reports obtained, two academic, and official medicine (Gomes, 1876). These major species were originally used by native Indians from Central uses have allowed ipecac to remain in use in India and and South America and were later found and sent to Europe Europe, although the plant was also used to treat dysentery by European settlers, Jesuits or travellers in a short time period (Sandwith et al., 1914; Saint-Hilaire, 2009). However, according during the seventeenth century. While the history of these to Sandwith et al. (1914), the emetic and muscle depressant species is relatively similar, the medicinal uses of these plants effects when the root is administered in high doses eventually are very different. Historically, Cinchona has been used primar- limited the use of the plant for the treatment of dysentery. ily for the treatment of malaria and C. ipecacuanha has been According to Sandwith et al. (1914), in 1817, the investiga- used as an emetic and an expectorant, although other uses tor Pelletier and colleagues separated the “emetic principle” have been discovered over time. These pharmacological prop- of ipecacuanha they called emetine. In 1894 and 1895, Paul erties have been proven by the discovery of compounds that and Cownley showed that this “active principle” was formed have biological activity for the alleged purposes. by several different bases. Compounds that have a non- The need for the export of these plants and their success crystalline base but form crystalline salts continued to be in new continents can be explained by the effectiveness in called emetine, the second base that formed crystalline salts treating diseases that were common in other continents such was called cephalin, which earned the name ipecacuanha as as Europe and Africa. However, Europeans who came to the Cephaelis ipecacuanha. In addition to these, a third alkaloid was Americas may also have been affected by diseases for which also identified, which was called psycotrin (Sandwith et al., they had no proper treatment. In this case, the search for spe- 1914). cific plant remedies could also be justified. journal of herbal medicine 2 (2012) 103–112 111

Knowledge and memories of the past may change over BMJ Publishing Group. The cinchona bark and its alkaloids. time. However, some types of knowledge or memories can be British Medical Journal 1924;3:1023–4. perpetuated in a given culture. The knowledge and use of the BMJ Publishing Group. Cinchona febrifuge. The British Medical Journal 1930;2:969–70. plants discussed here was not altered by human civilization Botsaris AS. Plants used traditionally to treat malaria in Brazil: during history. This knowledge has persevered over several the archives of Flora Medicinal. Journal of Ethnobiology and centuries, as evidenced by written records revealing the his- Ethnomedicine 2007;3:18, torical process by which it was passed down. It is interesting http://dx.doi.org/10.1186/1746-4269-3-18. that the use of quina and ipecac persisted in different regions. Boxer L, Anderson FP, Rowe DS. 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