Quina) in Brazilian Traditional Medicine

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Journal of Ethnopharmacology 149 (2013) 790–796

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Journal of Ethnopharmacology

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Bitter plants used as substitute of Cinchona spp. (quina) in Brazilian traditional medicine

Gustavo P. Cosenza a,b, Nádia S. Somavilla c, Christopher W. Fagg d, Maria G.L. Brandão a,b,n

a DATAPLAMT, Museu de História Natural e Jardim Botânico, Universidade Federal de Minas Gerais, Brazil b Faculdade de Farmácia, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil c Depto de Botânica, Universidade Federal de Juiz de Fora, Juiz de Fora, Brazil d Faculdade de Ceilândia and Departamento de Botânica, Universidade de Brasília, DF, Brazil

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Article history: Ethnopharmacological relevance: Bitter tasting plant species are used as tonics and have been previously Received 21 April 2013 used to treat intermittent fevers in Brazil, the principal symptom of malaria. Many of these species were Received in revised form named quina and were used as substitutes of Cinchona spp., the source of quinine. 25 July 2013 Aim of the study: To present data on these bitter species named quina and to discuss their potential as Accepted 3 August 2013 sources of bioactive substances. Available online 9 August 2013 Materials and methods: Data about the plants were obtained from a survey of the literature and Keywords: documents written by early naturalists and clinical doctors living in the 18th and 19th centuries in Brazil. Bitter plants Correlated pharmacological studies were obtained from different scientiﬁc databases. Quinas Results: A total of 29 species were recorded. The largest number of species belonged to the Rubiaceae Cinchona spp. family (14), being Remijia ferruginea (A. St.-Hil) DC. the most representative. Strychnos pseudoquina A. St.- Historical records Antimalarials Hil. (Loganiaceae), Hortia brasiliana Vand. ex DC. (Rutaceae) and Solanum pseudoquina A. St.-Hil. Tonics (Solanaceae) were also frequently mentioned in the historical bibliography. Pharmacological studies have shown the presence of bitter bioactive substances useful to treat digestive disorders and/or with antimalarial activities, in all of the recorded botanic families. Conclusion: This study shows that several bitter species named quina were used in the past as substitute of Cinchona spp. and studying these plants can lead to the development of new products. & 2013 Elsevier Ireland Ltd. All rights reserved.

1. Introduction orientations, our research group is focused on acquiring information and samples from plant remedies that were historically used in Since 2002, the World Health Organization (WHO) has been Brazilian traditional medicine. Data and images of the plants are encouraging studies with old remedies used in traditional medi- constantly recovered from historical bibliography and documents cine, because their secular use could confirm their efficacy as prepared by naturalists, researchers and clinical doctors that lived medicine (Bagla, 2011; WHO, 2011). The Brazilian flora represents in Brazil in the 18th and 19th centuries. These informations are one important source of such plants, due to its biodiversity, used important because, at that time, the Brazilian vegetation was by the Amerindians. Currently, however, despite medicinal plants conserved and native species were predominantly used in tradi- being widely used in Brazil by both rural and urban populations, tional medicine (Brandão et al., 2008, 2012; Oliveira et al., 2012; the mainly known and used species are native from other Breitbach et al., 2013). continents, and were introduced here since the beginning of the Among the useful Brazilian plants recorded in the historical European colonization. This phenomenon is related to the mixture literature, several species possess a bitter taste and were used as of cultures, but is also, and mainly, a result of the continuous substitute of Cinchona spp, known as quinas (or china). The bitter destruction of the rich Brazilian ecosystems. Following the WHO taste of the bark of Cinchona spp. was one of most important characteristics to consider its use as a tonic. Quinine, alkaloid present predominantly in the barks of Cinchona calisaya Wedd. n Corresponding author at: Universidade Federal de Minas Gerais, DATAPLAMT, and Cinchona succirubra Pav. ex Klotzsch is very bitter, and is Museu de História Natural e Jardim Botânico, Av. Antônio Carlos, 6627, Campus da responsible for the antimalarial activity of the quina barks. Pampulha, 31270-901 Belo Horizonte, MG, Brazil. Tel.: +55 31 33396970; Currently, besides being used for production of antimalarials, fax: +55 31 34096935. E-mail addresses: [email protected], quinine is commercially explored as ingredient of the beverage [email protected] (M.G.L. Brandão). known as tonic water. Other important Amerindian bitter specie is

Quassia amara (Simarubaceae). In the 19th century tonic-cups, 2.2. Survey on other bibliography and databases prepared using the wood of this species, were very popular in North America and Canada (Odonne et al., 2007). This plant also Other data about the recorded species were searched in the shows strong antimalarial activity, both in vitro and in vivo, and following documents: A Monografia das falsas-quinas brasileiras this activity is attributed to the presence of the quassinoids, very (Monograph on Brazilian false-quine), written in 1916 by the bitter substances (Bertani et al., 2005; Cachet et al., 2009). researcher W. Peckolt (marked as 1 in Table 1); the first edition Other species, from different botanical families, were named of the Brazilian Official Pharmacopoeia (1929) (Brandão et al., quina and used as substitutes of Cinchona spp., as tonic and 2009), marked as 2 in Table 1; data on the use of the plants to febrifuge, in the Brazilian traditional medicine. In this study, we prepare medicine by Brazilian Pharmaceutical Laboratories, present data on these species and discuss their potential as source marked as 3 in Table 1. Data on the actual use of the recorded of bioactive substances. plants was obtained from ethnobotanical studies performed specifically on antimalarial plants (Brandão et al., 1992; Milliken, 1997a, 1997b; Oliveira et al., 2003, marked as 4 in Table 1). 2. Materials and methods Results on pharmacological studies correlated with the plants used as tonic and febrifuge were verified using the scientific 2.1. Ethnopharmacological historical literature survey databases Pubmed and Scopus. The actual botanical names of each species were checked using the websites www.theplantlist. Data about the use of the bitter species named quina were org and www.mobot.org. The status of each species as a native obtained from books and other documents (manuscripts) written Brazilian plant was verified using an official Brazilian species list, by naturalists and clinical doctors who lived in Brazil in the 18th Lista de Espécies da Flora do Brasil (http://floradobrasil.jbrj.gov.br). and 19th centuries. The book Quinographia portugueza, ou coleção de várias memórias de 22 espécies de quinas tendentes ao seu descobrimento nos vários domínios do Brazil (Quinographia Portu- 3. Results guese, or collection of several memories of 22 species of quina aiming to their discovery in the various fields of Brazil), was The survey of the historical documents showed the occurrence written in 1799 by the Brazilian naturalist Frei M.C. Vellozo. Data of 29 bitter plants named quina, which were used as substitutes were also found in books (travel diaries) from European naturalists for Cinchona species in Brazil in 18th and 19th centuries. The who traveled throughout Brazil in the 19th century. The diaries of species and their families are listed in Table 1, which also includes the Austrian Pohl (1976), the Germans G.H. von Langsdorff (Silva, their popular names (correlated with the name quina), the authors 1997) and Spix and von Martius (1981), the Englishmen Mawe who cited them and results of pharmacological studies. (1978), Bunbury (1981) and Burton (1976, 1977), and the French Among the naturalists, Von Martius (1843) described most of Saint-Hilaire, 1975a, 1975b, 1975c, 1975d) were studied (www. the species: 22 were registered in his book Systema de Materia dataplamt.org.br). The books specifically written about Brazilian Medica being seven in a special chapter about bitter remedies: useful plants, Systema Materiae Medicae Vegetabilis Brasiliensis Baccharis genistelloides sbsp. crispa (Spreng.) Joch. Müll., Strychnos (Von Martius, 1843), Plantes Usuelles des Brasiliens (Saint-Hilaire, pseudoquina A. St.-Hil., Esenbeckia febrifuga (A. St.-Hil.) A. Juss. Ex 1842a, 1842b) and Histoire des plantes les plus remarquables du Mart., Hortia brasiliana Vand. Ex DC., Discaria febrifuga Mart., Brésil et du Paraguay (Saint-Hilaire, 1842a, 1842b) were carefully Cestrum euanthes Schldl. and Solanum pseudoquina. Vellozo studied. Data were also obtained from the travel notebook (manu- described organoleptic and morphological characteristics of the scripts) of Saint-Hilaire [manuscript, 1816–1822] (Brandão et al., bark of 19 Cinchona species occurring in Peru, the Caribbean and 2012), as well as a manuscript from John Miers, (deposited in the other parts of northern South America. However, the search of the Natural History Museum of London). online official Brazilian species list (www.floradobrasil.org.br) Other studied books were written by clinical doctors who revealed that five of these Cinchona species (Cinchona lutescens, worked in Brazil during the 19th century and incorporated the Cinchona fusca, Cinchona bergeniana, Cinchona lambertiana and native medicinal species into their practices. Chernoviz (1842) Cinchona cujabensis) are native to Brazil and, actually, belong to was born in Poland, studied medicine in Montpellier, France, other genera of Rubiaceae (Table 1). Vellozo also described and came to Brazil in 1837. He wrote one of the most important Solanum sp. (quina-do-Piauhy), Portlandia hexandra (Coutarea books, Dicionário e Guia Médico (Dictionary and Medical Guide). hexandra, quina de Pernambuco) and Coutinia illustris (Aspidos- This book was widely used by Doctors and Pharmacists in perma illustris (Vell.) Kuhlm & Pirajá, quina-de-camamu). Saint- Brazil, until the publication of Brazilian Official Pharmacopoeia, Hilaire recorded the use of 11 species, and was responsible for the in 1929. The Danish T. Langgaard (1813–1883) came to Brazil in botanical description of eight of them: Strychnos pseudoquina A. 1842 and wrote the book Dicionário de Medicina Popular e St.-Hil., Polyouratea hexasperma A. St.-Hil., Remijia ferruginea A. St.- Doméstica (Dictionary of Domestic and Popular Medicine) Hil., Remijia vellozii (A. St.-Hil.) DC., Bathysa australe A. St.-Hil., (Langgaard, 1865). M.A. Câmara was born in Pernambuco, Brazil, Bathysa cuspidatum A. St.-Hil., Esenbeckia febrifuga A. St.-Hil. and studied medicine in Montpellier. The book Dicionário de (Rutaceae) and Solanum pseudoquina A. St.-Hil. All of these species Botânica ou Compêndio dos Vegetais do Brasil, tanto indígenas were published in his book Plantes usuelles des Brasiliens (Saint- quanto aclimatados (Dictionary of Botany or Compendium on Hilaire, 1842a, 1842b). The use of Galipea jasminiflora (A. St.-Hil.) plants of Brazil, indigenous and acclimatized) was organized by Engl. (¼Ticorea febrifuga A. St.-Hil.) as a substitute for quina, was Pinto (1873), but most of the data about the plants were described mentioned by Saint-Hilaire several times in his travel notebook by Câmara. J.M. Caminhoá was born in Bahia, Brazil, and was a (Brandão et al., 2012). The manuscript of John Miers described professor of medical botany at the Medicine School in Rio de eight species of quina, and the use of Cheiloclinium cognatum Janeiro. His book, Elementos de Botânica Geral e Médica (Elements (Miers) A.C.Sm (Celastraceae) and Quiina guianensis Aubl. (Ochna- of General and Medical Botany) was published in 1877, and also ceae) was registered only by this author. contains data on several native plants. Among the clinical doctors, Langgaard (1865) described more It is important to emphasize that several species are described species (13), followed by Câmara (Pinto, 1873), who mentioned the in the literature as being bitter and useful as tonic and febrifuge, use of 12 species. Notably, Langaaard distributed the species in his but in the present study, only those named quina were recorded. book into three categories: (i) those belonging to genus Cinchona, 792 G.P. Cosenza et al. / Journal of Ethnopharmacology 149 (2013) 790–796

Table 1 Bitter species used as substitutes of the quinas (Cinchona spp.) and the results of correlated pharmacological studies.

Families/species Popular names (correlated with quina) Authors from 18–19th centuries Correlated studies

Apocynaceae Aspidospema illustris (Vell.) Kuhlm & quina-de-camamú Langgaard, Martius, Pinto (A. Câmara), None Pirajá (Coutinia illustris Velloso; Vellozo Dipladenia ilustris Müll. Arg.)1 Geissospermum laeve (Vell.) Miers quina-amargosa, quina-de-pobre Burton, Mawe Antimalarial (Muñoz et al., 2000; (Geissospermum vellosii Alemão)1,3a,4b Vigneron et al., 2005; Mbeunkui et al., 2012) Geissospermum sericeum Miers3a,4b,c quina, quinarana Chernoviz Not studied

Asteraceae Baccharis genistelloides subsp. crispa quina-de-condamine Martius, Saint-Hilairea, Vellozo Digestive disorders (Biondo et al., 2011); (Spreng.) Joch. Müll. (Baccharis trimera presence of ﬂavonoids with (Less.) DC.)4b antihepatotoxic activities (Soicke and Leng-Peschlow, 1987)

Celastraceae Cheiloclinium cognatum (Miers) A.C.Sm. quina-do-matto Miers None (Kippistia cognata Miers)

Loganiaceae Strychnos pseudoquina A. St.-Hil.1,2,3b 4b quina-do-campo,quina-de-vellozo, quina- Bunbury, Caminhoá, Chernoviz, Antiulcer (Silva et al., 2005; Bonamin falsa, quina-do-cerrado, quina de Langgaard, Martius, Miers, Pinto (A. et al., 2011); antimalarial (Andrade-Neto Mendanha Câmara), Pohl, Saint-Hilairea,a,b,c,d et al., 2003)

Ochnaceae Polyouratea hexasperma (A. St-Hil.) Tiegh. Quina Saint-Hilairec None (Gomphia hexasperma A. St.-Hil.) Quiina guianensis Aubl. Quiina Miers None

Rhamnaceae Discaria febrifuga Mart.1 quina-do-campo, quina-do-brasil, quina- Langgaard, Pinto (A. Câmara), Martius None do-rio-grande

Rubiaceae Bathysa australis (A. St.-Hil.) K. Schum. quina-de-santa-catarina, quina-do- Chernoviz, Langgaard, Martius, Pinto None (Exostema australe A. St.-Hil.)1 paraná (A. Câmara), Saint-Hilaireb Bathysa cuspidata (A. St.-Hil.) Hook. F. ex quina-do-mato, quina-do-piauí Caminhoá, Chernoviz, Langgaard, Hepatoprotective (Gonçalves et al., 2012) K.Schum. (Exostema cuspidatum A. St.- Martius, Miers, Pinto (A. Câmara), Hil., Schoenleinia cuspidata (A. St.-Hil.) Saint-Hilairea,c, Spix Klotz.)1 Chiococca alba (L.) Hitsch. (Chiococca Quina-preta Martius None anguifuga Mart.)1 Coutarea hexandra (Jacq.) K. Schum. quina-quina, quina-do-pará, quina-de- Langgaard, Martius, Miers, Pinto (A. None (Chiococca speciosa Aublet., Exostema dom-diogo, quina-do-brasil,quina-do- Câmara), Pohl, Spix, Vellozo souzanum Mart., Portandia hexandra mato, quina-de-pernambuco, quina-de- Jacq.)1,3a,4b,c cabo-frio Ladenbergia cujabensis Klotzsch quina de Cuiabá, quina-do-Mato-Grosso Langgaard, Martius, Pinto (A. Câmara) None (Cinchona cujabensis Silva Manso ex Klotzsch) 1 Ladenbergia hexandra Klotzsch (Buena quina-vermelha, quina-de-folha-larga, Chernoviz, Langgaard, Martius, Pohl, None hexandra Pohl., Cascarilla riedeliana quina-quina, quina-do-rio-de-janeiro Spix (Casar) Wedd.)1 Ladenbergia lambertiana (A.Br. ex Mart.) Quina Langgaard, Martius, Vellozo None Klotzsch (Chiococca lambertiana A. BraunexMart.) 1 Ladenbergia oblongifolia (Humb. ex quina-amarela Vellozo Presence of cinchonidine-like alkaloids Mutis) L.Andersson (Cinchona lutescens (Okunade et al., 2001) Vell.) Macrocnemum roseum (Ruiz & Pav.) quina-parda Vellozo, Martius None Wedd. (Cinchona fusca Vell.) Remijia ferruginea (A. St.-Hil.) DC. quina-mineira, quina-de-remijo, quina- Bunbury, Burton, Caminhoá, Antimalarial in vivo (Andrade-Neto et al., (Cinchona ferruginea A. St.-Hil)1,2,3c rosa, quina-da-serra, quina-do-campo, Chernoviz, Langgaard, Martius, Miers, 2003) quina-de-velloso Pinto (A. Câmara), Pohl, Saint-Hilairea, b,c,d, Spix Remijia ﬁrmula (Mart.) Wedd. (Cinchona quina-do-Amazonas Langgaard, Martius, Vellozo None bergeniana Mart., Cinchona ﬁrmula Mart.)1 Remijia macrocnemia (Mart.) Wedd. quina-do-norte Martius None (Cinchona macrocnemia Mart.)1 Remijia vellozii (A. St.-Hil.) DC. (Cinchona quinquina de vellozo Saint-Hilairec vellosii A. St.-Hil.) Rustia formosa (Cham. & Schltdl.) quina-do-rio-de-janeiro, quina-do-sul Martius None Klotzsch (Exostema formosum Cham. & Schltdl.)1 G.P. Cosenza et al. / Journal of Ethnopharmacology 149 (2013) 790–796 793

Table 1 (continued )

Families/species Popular names (correlated with quina) Authors from 18–19th centuries Correlated studies

Rutaceae Esenbeckia febrifuga (A. St.-Hil.) A. Juss. quina-laranjeira, quina-do-mato, quiina, Martius, Miers, Saint-Hilaireb,c, Antimalarial (Dolabela et al., 2012; ex Mart. (Evodia febrifuga A. St.- quina-molle Langgaard Carvalho et al., 1991) Hil.)1,3a,4b Galipea jasminiﬂora (A. St.-Hil.) Engl. quina-das-três-folhas, quina-quina Martius, Saint-Hilairea,b,c,d None (Galipea multiﬂora Schult., Ticorea febrifuga A. St.-Hil.)1, 3a Hortia brasiliana Vand. ex DC.1,4b quina-do-campo Langgaard, Martius, Miers, Pinto (A. None Câmara), Saint-Hilairea,b

Solanaceae Cestrum euanthes Schltdl. (Cestrum quina-do-Pará., quina-do-mato, quina-da- Langgaard, Martius, Pinto (A. Câmara) None pseudo-quina Mart.)1 terra, quina-de-porto-alegre, quina-da- mata, quina-branca Solanum pseudoquina A. St.-Hil.1,4b quina-de-São-Paulo, quina-branca, quina- Caminhoá, Chernoviz, Langgaard, None de-Curitiba, quina-de-Surrogat Martius, Pinto (A. Câmara), Saint- Hilairea,b,c,d

Authors of 19th century (and year of the first edition): Bunbury [18xx](1981), Burton [1869](1976–1977), Caminhoá (1877), Chernoviz [1842](1996), Von Martius (1843), Langgaard (1865), Miers (manuscript 1832–1838), Saint-Hilaire (a¼manuscript 1816–1822, b¼travel diaries 1830, c¼Plantes Usuelles des Brasiliens 1824a, d¼Histoire de plants plus remarcables du Brésil et Paraguay 1824b), Pinto (1873)¼Arruda Câmara), Pohl [1832](1976), Spix [1823] Spix and Martius (1981) (¼Spix and von Martius, 1981), Vellozo (1799). Other data in: (1) Monograph about the Brazilian false-quina (Peckolt, 1916); (2) 1st edition of Brazilian Official Pharmacopoeia (1929) (Brandão et al., 2009); (3) used in preparing medicine by Pharmaceutical Laboratories: 3a¼Flora Medicinal (Botsaris, 2007)); 3b= Araújo and Lucas (1930);3c¼other (Brandão et al., 2010); (4) more recent ethnobotanical studies specifically about the antimalarial effects: 4a¼Brandão et al. (1992),4b¼Milliken (1997a, 1997b),4c¼Oliveira et al. (2003).

such as Cinchona bergeniana Mart. and Cinchona lambertiana A. medicines. A survey on ethnobotanical studies performed in the Braun ex Mart; (ii) other species of Rubiaceae such as Bathysa 20th century, searching specifically for antimalarial plants australis (A. St.-Hil) K. Schum, Bathysa cuspidata (A. St.-Hil.) Hook. (Brandão et al., 1992; Milliken, 1997a, 1997b; Oliveira et al., F. ex K. Schum, Coutarea hexandra (Jacq.) K. Schum., Ladenbergia 2003) showed that Geissospermum leave, Geissospermum sericeum, hexandra (Pohl.) Klotzsch and Remijia ferruginea (A. St.-Hil.) DC.; Baccharis genistelloides, Strychnos pseudoquina, Coutarea hexandra, and (iii) species from other botanical families. Peckolt (1916) Esenbeckia febrifuga, Hortia brasiliana and Solanum pseudoquina included data of several quina species, being twenty also cited were cited as quina and are used to treat fevers and malaria by the studied authors (marked with “1” in Table 1). The other (marked with “4a” to “4c”). species are Hortia arborea Engler (Rutaceae), Colletia cruciata Gill & Hook (Rhamnaceae), Strychnos triplinervia Mart. (Loganiaceae), Tachia guianensis Aubl. and Deianira erubescens Cham & Schlcht. (Gentianaceae), Plumeria lancifolia Müll. Arg., Aspidosperma peroba 4. Discussion Saldanha, Sickingia rubra (Mart.) K.Schum., Macrocnemum grand- iflorum Weddel (Rubiaceae), Alseis floribunda Schott. and Basana- When the Europeans arrived for the first time in South cantha annae Schum. (Rubiaceae). America, the Amerindians were affected by only a few diseases, The plants listed in Table 1 are distributed throughout nine such as diarrhea and some skin problems. Malaria was already a families, with Rubiaceae being the most representative, with 14 devastating disease in Europe and was introduced in Brazil, when species. Of these, four are Ladenbergia spp. and Remijia spp., and the land began to be colonized by the Portuguese in 1500. In the two Bathysa spp. The other families are Rutaceae (4 species), 18th and 19th centuries, the period studied in this work, inter- Apocynaceae (3), Ochnaceae and Solanaceae (2) and Asteraceae, mittent fever, a typical symptom of malaria, was one of the most Celastraceae, Loganiaceae, Rhamnaceae and Simaroubaceae (1). feared diseases, and it was already widespread in the central part With the exception of Aspidosperma illustris (Vell.) Kuhlm & Pirajá, of the Brazilian territory. Baccharis genistelloides subsp. crispa (Spreng.) Joch. Müll. and The cure for malaria originated from Amerindian knowledge when Chiococca alba (L.) Hitsch., all of the mentioned species are shrubs the Spaniards learned to use the bark of the plant named quina (or and trees, and their barks are used for the preparation of remedies. china) in the 17th century. Quina are species of the Rubiaceae family, The most frequently mentioned species was Remijia ferruginea especially Cinchona succirubra Pav. ex Klotzsch and Cinchona calisaya (A. St. Hil.) DC., described by 11 of the 13 studied authors. The Wedd, which produce quinine. The bark of these plants was intro- second most cited species was Strychnos pseudoquina A. St.-Hil., duced to Europe in 1640 by the Jesuits, and until the mid 1800s, the mentioned by nine of them. Bathysa cuspidata (A. St.-Hil.) Hook. F. powder prepared from quina bark (Jesuit′spowder)wasthemost ex K. Schum was cited by eight authors and Coutarea hexandra important remedy for the treatment of malaria. In 1812, the Portu- (Jacq.) K. Schum. by seven, followed by Solanum pseudoquina A. St.- guese Bernardino A. Gomes purified the alkaloid cinchonina and, in Hil., that was recorded by six. The Hortia brasiliana Vand. Ex DC. 1820, quinine was first isolated by the French Pelletier and Caventou and Galipea jasminiflora (A. St.-Hil.) Engl. were recorded by five (Soldán, 1941; Claus and Tyler, 1965). authors, and the use of the Baccharis genistelloides subsp. crispa Until the 18th century, the Spanish had a monopoly on the (Spreng.) Joch. Müll. was recorded by three authors. All other commerce of Cinchona plants, and the Portuguese promoted its species were recorded by only one or two authors. cultivation in their colony. In 1864, the first plants were sent to Only two species (Remijia ferruginea and Strychnos pseudoquina, Africa (Gomes, 1864; Von Martius, 1868; Ferrão, 2005). Despite the marked with “2” in Table 1) were included in the Brazilian Official incentive to cultivate Cinchona species in Brazil, the search for Pharmacopoeia, and eight species (marked with “3a” to “3c”)were substitutes for the Peruvian bark at the native vegetation was used by Brazilian Pharmaceutical Laboratories to prepare incentivized. In 1723, for example, an award was offered to those 794 G.P. Cosenza et al. / Journal of Ethnopharmacology 149 (2013) 790–796 who discovered a quina similar to that from Peru (Peckolt, 1916). Table 1. Nor-dihydrotoxiferine (NDHT) is the main alkaloid of its Consequently, several other bitter species were discovered and bark, and has been isolated and identified since 1969 (Delle received the name of quina, and had its use as substitute for Monache et al., 1969; Frederich et al., 1999). It is also interesting Cinchona as tonic and febrifuge initiated (Faria, 1935; Cunha, 1937; to note that Strychnos triplinervia (¼Strychnos trinervis (Vell.) C. Wasick, 1944; Dean, 1996). One of the earliest registers of these Martius) is known in Brazil under the name of quina cruzeiro, and substitutes of quina was made by the Brazilian naturalist Alex- is employed more recently as a bitter, tonic and febrifuge in folk andre R. Ferreira in his work Doenças endêmicas na capitania do medicine (Quetin-Leclercq et al., 1990). Many members of the Mato Grosso (Endemic diseases of the captaincy of Mato Grosso) Rutaceae family have been reported to exhibit antimalarial activ- (Fontes, 1966; Porto, 2008). Ferreira travelled throughout the ity, and in many cases, this outcome was due to the presence of Amazon and Mato Grosso, from 1783 to 1792, and described the quinoline alkaloids, as observed in Galipea longiflora K. Krause use of a quina as the best bitter and febrifuge. The German (Gantier et al., 1996). naturalist Langsdorff also travelled throughout Mato Grosso in The definition of tonic is difficult and is linked to how well the the 19th century, and in his book, he cited the intense commerce digestive system functions. The action of the tonics is directly on of a bitter bark, similar to Cinchona plant (Silva, 1997). It is possible the stomach, liver and bowels to improve appetite, aid in digestion that the quina observed by Ferreira and Langsdorff was the and help in the case of chronic fatigue. These activities help Landerbergia cujanbensis Klotzch (Cinchona cujabensis Manso ex strengthen malaria patients, as reported by Sigaud (2009),a Kl., Rubiaceae), which occurred in that region. French clinical doctor who lived in Rio de Janeiro in 19th century. Barks of other Rubiaceae also sparked intense interest due to its Many species from Table 1 showed beneficial activity in the similarity with Cinchona species. Among them are that from Laden- treatment of different digestive disorders in pharmacological bergia hexandra Klotzch., discovery in Rio de Janeiro in 1805 (Costa, studies, which can explain their use as tonic. The barks of 1960; Liberalli, 1965)andL. oblongifolia, described by Vellozo (1799). Strychnos pseudoquina, for example, showed beneficial gastroin- For this last one, chemical studies have shown the presence of testinal effects in mice (Silva et al., 2005; Bonamin et al., 2011) and alkaloids with structures very similar to quinine (Okunade et al., Bathysa cuspidata showed significant effect as hepatoprotective 2001). The same interest is registered in historical bibliography for (Gonçalves et al., 2012). Baccharis genisteloides is currently used to Coutarea hexandra (Jacq.) K. Schum., which barks were introduced in treat liver disorders and digestive troubles in Brazil and studies Europe (Italy) in 1768 (Comparetti, 1801). Extracts from barks of have shown that this activity is due to the presence of phenolic Hintonia latiflora (Sessé &Moc.) Bullok (¼Coutarea latiflora (Sessé substances (Soicke and Leng-Peschlow, 1987; Biondo et al., 2011). &Moc.) ex DC.) have shown antiplasmodial activity, both in vivo and Coutarea hexandra (¼Hintonia latiflora) shows the presence of 4- in vitro (Noster and Kraus, 1990; Argotte-Ramos et al., 2006). These phenylcoumarins that has antimalarial activity (Argotte-Ramos results show the potential of the bitter quinas from Rubiaceae as et al., 2006) and extracts from this plant were also gastroprotec- sources of antimalarial substances. tive (Cristians et al., 2013). For Solanum species, studies have In fact, the most cited plant in the studied literature was the shown that steroidal alkaloids are active directly against the liver Rubiaceae Remijia ferruginea (A. St.-Hil.). The use of its barks was stages of the malaria parasite in vivo (Londoño et al., 2006; López described by 11 of the 14 authors listed in Table 1. Saint-Hilaire et al., 2009; Ramazani et al., 2010). These results show that bitter included information about this species in all his books, and Von plants used as tonic are effective to treat different digestive Martius (1843) also included this species in his Systema. In 1850, disorders and that for some of them, these activities could be the alkaloid velosina was obtained from its barks and the absence linked to an antimalarial effect. Studies in order to verify this of quinine and cinchonine was confirmed in 1951 (Souza, 1951). supposition are necessary. Previous studies show that extracts from the bark of this plant had Many species from Table 1 were also used for decades by antimalarial activity in vivo (Andrade-Neto et al., 2003). Quinine- Brazilian Laboratories to prepare their medicines (Botsaris, 2007). like alkaloids were detected in the bark of Remijia peruviana One example was the Ierobina, a phytomedicine prepared with Standl., and such substances are certainly present in the Brazilian Remijia ferruginea, besides other bitter species (Botion et al., 2005). Remijia species (Ruiz-Mesia et al., 2005). However, the lack of studies confirming the activities and security The Apocynaceae family is also rich in bitter species, including of these traditional remedies has impaired their production and Aspidosperma illustris (Vell.) Kuhlm & Pirajá (Coutinia illustris, quina- commercialization nowadays (Brandão et al., 2010). The barks of de-camamu) described by Vellozo (1799).DifferentspeciesofAspidos- Remijia ferruginea and Strychnos pseudoquina were also included in perma have indole alkaloids that show promising antiplasmodial the 1st Edition of Brazilian Official Pharmacopoeia, published in activity against Plasmodium falciparum in culture (Andrade-Neto 1926, but they were excluded from the subsequent editions et al., 2007; Dolabela et al., 2012; Rocha e Silva et al., 2012). The bark (Brandão et al., 2009). As a consequence, plants named quina of Geissospermum velosii Allemão (¼Geissospermum laeve in Table 1) can be currently found only in popular markets but, in the most was a long time ago studied, and in 1938, the alkaloid pereirine was cases, the quality is very poor and the traditional use is different as obtained and used to treat patients with malaria (Pessoa and the observed in the past (Brandão et al., 2013). On the other side, Sacramento, 1942). In recent studies, the extracts from this plant studies with the aim to specifically search plants used to treat proved to be active against Plasmodium falciparum in vitro and malaria show that few species of quinas are still in use in Brazil Plasmodium berghei in vivo (Muñoz et al., 2000; Vigneron et al., (Brandão et al., 1992; Milliken, 1997a, 1997b; Oliveira et al., 2003). 2005; Mbeunkui et al., 2012). Recent ethnobotanical studies, performed with populations Other bitter quina species from Table 1 belong to the Celas- including the descendants of Amerindians, also showed that these traceae, Loganiaceae and Rutaceae families. The use of Cheilocli- populations no longer know or use any medicinal plant named nium cognatum (Miers) A.C. Sm. (Salacia cognata (Miers) Peyr.) quina (Begossi et al., 2002; Di Stasi and Hiruma-Lima, 2002; from the Celastraceae as quina is described in the manuscript of Fonseca-Kruel and Peixoto, 2004; Miranda and Hanazaki 2008; John Miers. Quinonomethides obtained from Salacia kraussii Borges and Peixoto, 2009; Britto and Senna-Valle, 2011, 2012). (Harv.) Harv. showed antiplasmodial activity in vitro, demonstrat- These results showed that several bitter species named as quina ing a potential therapeutic value for the Brazilian species were use in traditional and official medicine, but there is a (Schwikkard and Heerden, 2002; Lião et al., 2008). The use of progressive loss of these remedies. This situation confirms the Strychnos pseudoquina from the Loganiaceae is widely described in urgent need to recover informations and to perform studies to the historical literature and was cited by nine authors listed in evaluate the pharmacological potential of these old remedies. G.P. Cosenza et al. / Journal of Ethnopharmacology 149 (2013) 790–796 795

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