Piper umbellatum L.: A comparative cross-cultural analysis of its medicinal uses and an ethnopharmacological evaluation

Carles M.F.B. Roersch

This paper reports for the first time the effect of an acetone extract of Umbilicaria crustulosa on the micronucleus distribution of human lympho-cytes, and on the cholinesterase activity and antioxidant activity by the cupric ion reducing antioxidant capacity (CUPRAC) method. Additionally, the total phenolic compounds (TPC) and the antioxidant properties were estimated via DPPH, ABTS and TRP assays. Moreover, the antibacterial activity against two Gram-positive and three Gram-negative bacteria were determined. Acetone extract of U. crustulosa at concentration of 1 and 2 µg mL-1 decreased a frequency of micronuclei (MN) by 10.8 and 16.8 %, respectively, acting more or slightly less than the synthetic protector amifostine (AMF, WR-2721, 11.4 %, at concentration of 1 µg mL-1). The tested extract did not inhibit cholinesterase activity nor did it exhibit activity toward the examined bacteria. The extract reduced the concentration of DPPH and ABTS radicals by 88.7 and 96.2 %, respectively. Values for total reducing power (TRP) and cupric reducing capacity (CUPRAC) were 0.6197±0.0166 µg ascorbic acid equivalents (AAE) per mg of dry extract, and 19.7641±1.6546 µg trolox equivalents (TE) per mg of dry extract, respectively. The total phenol content was 350.4188 ±14.587 µg gallic acid equivalents (GAE) per mg of dry extract. The results of the present study showed that U. crustulosa acetone extract is a promising candidate for in vivo experiments considering its antioxidant activity and protective effect on human lymphocytes.

The growing interest in Natural Healthcare has led to multi-dimensional research in various traditional systems of medicines in recent years which mainly use plant for therapeutic purposes. These systems mainly depend on plant origin drugs and hold promise for safe and effective healthcare through plant based medicines. A large body of research work over the last few decades indicates certain trends that may prove quite meaningful in the near future. The study attempts to showcase the gains made in fields of plant research in recent past.

Despite the advances in anticancer drug discovery field, the worldwide cancer incidence is remarkable, highlighting the need for new therapies focusing on both cancer cell and its microenvironment. The tumor microenvironment offers multiple targets for cancer therapy, including inflammation. Nowadays, almost 75% of the anticancer agents used in chemotherapy are derived from natural products, and plants are an important source of new promising therapies. Continuing our research on Piper umbellatum species, here we describe the anticancer (in vitro antiproliferative activity and in vivo Ehrlich solid tumor model) and anti-inflammatory (carrageenan-induced paw edema and peritonitis models) activities of a standardized dichloromethane extract (SDE) from P. umbellatum leaves, containing 23.9% of 4-nerolidylcatechol. SDE showed in vitro and in vivo antiproliferative activity, reducing Ehrlich solid tumor growth by 38.7 and 52.2% when doses of 200 and 400 mg/kg, respectively, were administ...

Journal of Ethnopharmacology 131 (2010) 522–537 Contents lists available at ScienceDirect Journal of Ethnopharmacology journal homepage: www.elsevier.com/locate/jethpharm Review Piper umbellatum L.: A comparative cross-cultural analysis of its medicinal uses and an ethnopharmacological evaluation Carles M.F.B. Roersch a,b,∗ a Instituto de Medicina Dominicana, P.O. Box 160, Santo Domingo, Dominican Republic Instituto de Ciencias Fisiológicas y Medicina Experimental Dr. “Dr. José de Jesús Álvarez Perelló”, Universidad Nacional Pedro Henriquez Ureña, Av. J.F.Kennedy Km 6½, Santo Domingo, Dominican Republic b a r t i c l e i n f o Article history: Received 18 February 2010 Received in revised form 21 July 2010 Accepted 21 July 2010 Available online 1 August 2010 Keywords: Piper umbellatum Piperaceae Medicinal plant Traditional medicine Pharmacological activity Cross-cultural uses Dominican Republic a b s t r a c t Aim of the study: This review assesses the botany, traditional medicinal uses, phytochemistry, pharmacology and toxicology of P. umbellatum. Materials and methods: Information on P. umbellatum was gathered via the internet (using Scirus, Google Scholar, CAB-Abstracts, MedlinePlus, Embase, Scielo, and Web of Science) and libraries. Additionally, previously unpublished work on the traditional uses of P. umbellatum from our National Study of the Medicinal Plants of the Dominican Republic has been included. Results: Piper umbellatum is a Neotropical plant species widely distributed in Mexico, Central America, South America and the West Indian Islands. It has also been introduced to Africa and South-East Asia. Traditional uses for this plant are recorded in 24 countries in three continents, America, Africa and Asia for a wide range of ailments such as kidney, women diseases, diarrhea, skin affections, burns, rheumatism, malaria, intestinal parasites, inflammation and fever. We have analyzed the cross-cultural agreement among traditional uses in different countries and found a high degree of consensus for the indications kidney/diuretic, stomachache and wounds. Phytochemical studies of P. umbellatum have demonstrated the presence of terpenes (mainly found in the essential oil), alkaloids, flavonoids, sterols and other classes of secondary metabolites. The extracts and pure compounds derived from P. umbellatum show a wide spectrum of pharmacological activities including antibacterial, anti-inflammatory, analgesic, antioxidant, cytotoxic, antimalarial, antileishmanial, and antitrypanosomal activity. A first commercial product is in development, based on the plant’s protective characteristics against UV irradiation. Conclusions: The interesting biological activities of P. umbellatum need further research in in vivo experiments and clinical studies. The outcome of these investigations will determine the possible development of drugs from P. umbellatum. © 2010 Elsevier Ireland Ltd. All rights reserved. Contents 1. 2. 3. 4. 5. 6. 7. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Botany . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Traditional medicinal uses of P. umbellatum in a cross-cultural context . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Phytochemistry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1. Antifungal activity: . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.2. Antioxidant activity and skin protection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.3. Antimalarial activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.4. Other biological activities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.5. Pharmacological activities versus traditional medicinal uses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Toxicology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ∗ Tel.: +809 568 7570; fax: +809 568 7570. E-mail address: croersch@imd-medicina-dominicana.org. 0378-8741/$ – see front matter © 2010 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.jep.2010.07.045 523 523 523 524 530 530 532 532 532 532 532 535 C.M.F.B. Roersch / Journal of Ethnopharmacology 131 (2010) 522–537 523 Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 535 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 535 1. Introduction Since 1978, the World Health Organization has promoted the development of Primary Health Care (PHC) and the importance of the involvement of traditional health care systems, including the use of medicinal plants (Anonymous, 1979, 1988; WHO, 1978). Several authors have described ways in which medicinal plants could be a part of PHC (Farnsworth et al., 1985; Le Grand and Sri-Ngernyuang, 1989; Wondergem et al., 1989). Our own experience in Peru and the Dominican Republic has demonstrated that PHC will fail if traditional medicine, including medicinal plants, is not taken into account (Hoogte and Roersch, 1984, 1988; Roersch, 1994; Roersch and Hoogte, 1987). In the Dominican Republic, two medical systems can be distinguished: the formal medical system and the informal medical system. The formal medical system is based on the Western conventional medical system (in which the biomedical model predominates) and involves hospitals, clinics, drugstores, insurance companies and teaching facilities (universities). The informal medical system can also be called the Traditional Dominican Health System (TDHS), which is based on ancient concepts and practices in the Dominican culture. These concepts and practices have several origins, including the slaves, who contributed a polytheistic African cosmology (Deive, 1981, 1992); the Spaniards, with their medieval cosmology, including spiritualism and alchemy (Kuschick, 1995); and elements of the Taina culture (the original inhabitants of the island) (Davis, 1987). Locally, the following terms are used: ‘medicina de farmacia’ (‘drugstore medicine’) for the formal health system and ‘plantas (‘matas’) de la tierra’ (‘plants of the earth’) for the informal health system (Roersch, 1995). Medicinal plants play an important role in the Traditional Dominican Health System. Medicinal plants and other ingredients of this traditional medical system are offered at local markets, on street corners and in special stores (boticas). In a study concerning the market for medicinal plants, we found that in the capital, Santo Domingo, the annual sales total for medicinal plants amounts to $702,000 USD (Roersch, 1999). Publications about the use of medicinal plants in the Dominican Republic are not abundant, and most are descriptions of popular uses (Cordero, 1986; IMD et al., 1994a,b,c, 1997, 1999a,b,c,d; Liogier, 1990; Mañon et al., 1992; Peguero, 2002; Peguero et al., 2001; Polanco et al., 1998); some include experimental data (phytochemistry and biological characteristics) (Bonnelly et al., 1985; Germosén-Robineau, 1995). Recently, studies have been undertaken to determine the relation between the uses of medicinal plants by Dominican immigrants in New York and their country of origin (Ososki et al., 2007; Reiff et al., 2003; Vandebroek et al., 2007). However, there has been no extensive, systematic research on the use of medicinal plants in the Dominican Republic. For the integration of medicinal plants in the official health system and for the development of a national policy on alternative and complementary health practices, it will be necessary to have a broad knowledge of the uses of the medicinal plants within the TDHS. As stated by the WHO (WHO, 2002), it is necessary for a country with an active traditional health system, to formulate a national health care policy, to have a broad knowledge of traditional health practices. Therefore, the Instituto de Medicina Dominicana (IMD, or the Dominican Institute of Medicine) formulated a project for this purpose, calling it the National Study of the Medicinal Plants of the Dominican Republic. In 2000, together with the Pan-American Health Organization (PAHO), a questionnaire was developed. With the help of students from the Universidad Nacional Pedro Henriquez Ureña (UNPHU), we have thus far conducted more than 5000 interviews with about 1000 persons in each of the provinces of the Dominican Republic. With the outcome of these interviews, an ethnopharmacological database has been constructed. P. umbellatum appears to be an important plant in the treatment of, among other conditions, leucorrhoea, locally known as ‘vaginal flow’. This disorder is very common in the Dominican Republic. A first step in the validation of this ethnopharmacological application is the assessment of the existing literature on this plant. The presented review is the result of this process and includes previously unpublished work. 2. Botany Piper umbellatum L. (Piperaceae, syn. based on Tropicos: Pothomorphe umbellata (L.) Miq., Lepianthes umbellata (L.) Raf., Heckeria umbellata (L.) Kunth., Peperomia umbellata (L.) Kunth) is a perennial scrambling shrub or woody herb, 1–2.5(−4) m tall. Stems numerous, succulent, ribbed, forming a dense clump, rooting at the nodes, main roots woody. Leaves alternate, almost circular to reniform, 5–40 cm × 5–40 cm, blade dark green above, grayish below, base deeply cordate, apex shortly acuminate to rounded, margins entire or crenulate, sparsely to densely hairy on the veins on both sides, venation palmate, 11–15 veins, petiole 6.5–30 cm long, dilated and sheathing basally. Inflorescence 5.5–15 cm long, 2–8 together in false umbels, peduncle 3–12 cm long, 1–3 peduncles together, peduncular bracts narrow, 6–8 mm long, white, soon falling. Flowers small, bisexual; floral bracts triangular to rounded, 0.5–0.8 mm wide, subpeltate, margins fimbriate, white, cream or yellow; perianth absent; stamens 2; ovary superior, 1-locular, stigmas 3. Fruit a drupe, obpyramidal, 3-angled, 0.6–1 mm × 0.4–0.6 mm, brownish seed globose (Schmelzer, 2001). This is a Neotropical species widely distributed in Mexico, Central America, South America and the West Indian islands. It has been introduced to Africa and South-East Asia and is now broadly naturalized (Domis and Oyen, 2008; Liogier, 2000; Saralegui, 2004; Schmelzer, 2001). 3. Traditional medicinal uses of P. umbellatum in a cross-cultural context Besides the medicinal uses of P. umbellatum, the plant is also used in medical-magic rituals in Cameroon (Agbor et al., 2005) and Gabon (Akendengue and Louis, 1994). It is also used in Gabon as a fetish to cause compassion (Domis and Oyen, 2008), to change the sex of a child at birth in Cameroon (Jiofack et al., 2008), in religious affairs in Brazil (Azevedo and Silva, 2006), as a fragrance against ‘mal aire’ (bad air) in Ecuador (Pohle and Reinhardt, 2004) and in Ghana as bait to attract fish (Domis and Oyen, 2008). In the Dominican Republic, the leaves are used by farmers to protect themselves against the heat by putting the leaves under their hats. In many countries, P. umbellatum is used as a vegetable or condiment (young leaves and inflorescences eaten raw, boiled or steamed) in people’s daily diets. In tropical Asia, the fruits are eaten as a delicacy (Schmelzer, 2001). The Shuar in Ecuador use it as a condiment (Pohle and Reinhardt, 2004). The nutritional values and mineral contents of P. umbellatum (leaves) are as follows: ascorbic acid: 181 mg/100 g DM, carbohydrates: 3.8 g/100 g DM, protein: 3.9 g/100 g DM, moisture: 80% fiber: 2.2 g/100 g DM; and minerals: Ca: 2.36, K: 4.1, Mg: 0.88, Na: 0.12, Fe: 0.05 mg/100 g) (Mensah et al., 2008). 524 C.M.F.B. Roersch / Journal of Ethnopharmacology 131 (2010) 522–537 In general, traditional, local uses of medicinal plants are the starting point for the development of new drugs from the same plants (Farnsworth et al., 1985; Farnsworth and Loub, 1983). Numerous ethnopharmacological studies have been performed all over the world in different cultures (Heinrich et al., 2009). To determine the effectiveness of medicinal plants, Trotter and Logan (1986) proposed a method known as the Informant Consensus. They argued that within and between cultural groups plants with scientifically (i.e., pharmacologically) proven effectiveness are more likely to be found, and will have a consistent pattern of usage. Moerman (2007) stated that “consensus will identify plants with significant and appropriate pharmacological properties”. This in turn leads to the hypothesis that the same (or consensus) uses of a plant in different cultures should have a scientific basis. We have examined this cross-cultural agreement in the case of P. umbellatum. The medicinal uses of P. umbellatum in traditional medicine health systems are recorded in 24 countries across three continents. In Table 1 , these uses are ordered according to the disease classification used in the modern Western biomedical system (Anonymous, 2007). It was necessary to extend this classification with categories such as Women diseases, Liver and Fever, which are used in various traditional medicine health systems. A total of 94 traditional medicinal uses for P. umbellatum are registered. In the American continent information has been found for Brazil, Mexico, Jamaica, Cuba, Dominican Republic, Haiti, Costa Rica, French Guyana and Venezuela; in Africa, information was found for Nigeria, Cameroon, Ivory Coast, Gabon, Zimbabwe, Liberia, Congo, Guinea, São Tomé and Príncipe, Burundi, Comoros Islands, Guinea Equatorial and Ghana; and in Asia, the Philippines and Malaysia are mentioned. There are also references to the West Indies, to Africa as a whole, and to East Africa, Central Africa, Southeast Asia and Indochina. In this review, they will be considered a country. The country with by far the most indications is Brazil (35), which also has the largest number of authors (21). In the majority of these countries, literature on this subject has just one author (14). In Asia, one author published a monograph on P. umbellatum within the PROSEA project for Southeast Asia (Schmelzer, 2001). A similar project, called PROTA, exists in Africa; in it, Domis and Oyen elaborated on a monograph on P. umbellatum (Domis and Oyen, 2008). In the case of the Dominican Republic, our own data, collected in our National Study, are added. We have distinguished 13 categories of illnesses. The first one, Urinary tract, has only two groups of traditional treatments, diuretic and kidneys, but they are present in nine countries in three continents. The majority of the traditional uses in the category of Women Diseases have their origin in Africa. Only leucorrhoea, accelerated labor and emmenagogue are also treatments in the American continent. In the Digestive tract we see the same pattern as in Women Diseases with the exception that two traditional uses are also mentioned in Asia, while in Women Diseases no application is found in Asia. In Skin the three continents are present, with Asia only represented by one indication, abscesses. In the Respiratory tract, America is represented by four treatments and four countries, Africa with two indications and one country and Asia with just one indication and one country. Liver is mentioned by 10 authors for Brazil. Fever (and sudorific and febrifuge) is mentioned for Brazil, Gabon and Africa. Eight different traditional treatments for Pain are recorded in nine countries in two continents (if we include stomachache, up to 13 countries in three continents). The plant is used as an antiinflammatory in Brazil, Mexico and Cuba and for inflamed tumors in Africa. Also important are the Wound healing properties. This category is found in six countries in the three continents. The category of Swellings, contusions is found in the three continents. These last two more or less related categories have 11 diseases indications combined (including inflammation increases this number to 14). Rheumatism is mentioned in Africa and the West Indies. From the 94 medicinal uses, 59 are uses for just one country in one continent; 10 are uses for two or more countries in one continent, 21 are uses for two or more countries in two continents and four are uses for four or more countries in three continents. In Fig. 1, the traditional medicinal uses that occur in two or more countries in one or more continents are ordered. Women diseases are represented by four traditional uses out of a total of 14 (Table 1); the Digestive tract has three uses out of 17, Skin has three uses out of six, Pain has four uses out of eight, the group Inflammation, Wounds and Swellings, contusions has six out of 14 and Urinary tract has two out of two. The cross-cultural uses with most consensus are kidneys, diuretic, stomachache and wounds. These traditional medicinal uses are present in more than four countries in three continents. These uses, together with the categories Pain (with stomachache used in three continents), Inflammation, Wounds, Swellings, Contusions (with wounds used in three continents) and Skin (with three out of six disease indications mentioned in five countries in two continents), can be categorized as highly indicated for further investigation. 4. Phytochemistry Phytochemical studies of P. umbellatum have demonstrated the presence of terpenes (mainly found in the essential oil), alkaloids, flavonoids, sterols and other classes of secondary metabolites. A catechol, 4-nerolidylcatechol (Fig. 2), is considered the main bioactive compound. It is found in the whole plant (Bergamo et al., 2005; De Oliveira and Akisue, 1984; Desmarchelier et al., 1997; Kijjoa et al., 1980; Núñez et al., 2005; Tabopda et al., 2008; Viana et al., 2000). From the branches, Tabopda et al. (2008) isolated some interesting new bioactive alkaloids, which they named piperumbellactams A–D (Fig. 2). Another bioactive alkaloid, N-benzoylmescaline, was found by Isobe et al. (2002) in the aerial parts of a Brazilian P. umbellatum (Table 2). Various studies have analyzed the composition of the essential oil of the leaves of P. umbellatum. Three studies were carried out in Brazil, one in Costa Rica, one in Cuba and one in São Tomé and Príncipe. Another study was done in Cameroon, and it detected the presence of cadinene, caryophyllene and phellandrene (Chartol, 1964). This study is not included because the oil was extracted from the leaves and flowers, while the other studies only used the leaves. As one can see in Table 3, there are considerable differences between the presented essential oils. Most striking is the contrast between the essential oil from Africa and the essential oils from the American continent. In São Tomé and Príncipe, the main constituents are the monoterpenoids ␣- and ␤-pinene, while in Brazil, Cuba and Costa Rica the sesquiterpenoids ␤-caryophyllene and germacrene D are the important elements. Within the American continent a salient feature is the singularity of the essential oil of Cuba, where one component, safrole, is most significant (48.7%). The essential oil of Costa Rica has (E,E)-␣-farnesene as one of the three main constituents. This compound is only mentioned by Martins et al. (1998) in São Tomé and Príncipe. Mesquita et al. (2005) present two series of data. One concerns a sample collected in 1999 and the other one in 2001, both in the ‘Parque Estadual do Rio Doce’ in the state of Minas Gerais. The main components are present in both samples, but the percentages are not the same. Principal differences are in the presence of germacrene D and trans-dihydroagarofurane. The last component was not even detected in the sample of 2001! The recently elucidated role played by ␤-caryophellene to produce anti-inflammatory effects (Gertsch et al., 2008) and the traditional uses of P. umbellatum related to inflammation (Table 1) deserve more investigation. The presented differences in the contents of the essential oils of P. umbellatum make it very clear that for further comparison of experimental data, C.M.F.B. Roersch / Journal of Ethnopharmacology 131 (2010) 522–537 525 Table 1 Cross-cultural medicinal uses of P. umbellatum. Part used Application* Country References Not specified Root Not specified Not specified Brazil Brazil Leaf, root Bark Decoction, infusion Decoction Brazil Brazil Leaf Leaf, root Leaf, root Fruit Infusion Not specified Not specified Not specified Cuba Dominican Republic Haiti Nigeria Leaf Leaf Juice Decoction Africa South-East Asia Britto et al. (2007) Brandão et al. (2008), Hegnauer (1969) Grandi et al. (1989) Schultes (1980), in Hammer and Johns (1993) Pino et al. (2005) Liogier (2000) Liogier (2000) Ndukwu and Ben-Nwadibia (in press) Domis and Oyen (2008) Schmelzer (2001) Inflorescence Leaf Root Decoction Decoction or infusion Not specified Brazil Brazil Brazil Leaf Leaf Leaf and fruit Leaf or root Decoction Maceration Not specified Decoction Africa Cameroon Indochina Dominican Republic Not specified Decoction Ivory Coast Aerial parts Leaf Leaf Leaf, root Not specified Juice Juice Decoction, infusion Ivory Coast Africa Brazil Brazil Whole plant Decoction Ivory Coast Aerial parts Not specified Ivory Coast Aerial parts Not specified Central Africa Not specified Not specified Gabon Women diseases Leaf Decoction Guinea Pain and abundant bleeding during menstruation Antihemorrhagic Painful menstruation Menstruation Accelerate labor Calms birth pains Expulsion of the placenta To clean the belly of women after giving birth Galactogogue Leucorrhoea Leaf Maceration Cameroon Vasileva (1969), in Hammer and Johns (1993) Noumi et al. (1999) Aerial parts Leaf Leaf or root Not specified Flower, leaf Root (with Hyptis pectinata) Leaf Not specified Maceration Not specified Decoction Decoction Decoction Juice, as an enema Ivory Coast Cameroon Africa Mexico Cameroon Ivory Coast Zimbabwe Schmelzer (2001) Noumi and Yomi (2001) Domis and Oyen (2008) Browner (1985) Jiofack et al. (2008) Kerharo et al. (1950) Yamada (1999) Leaf Leaf or root Leaf, root Juice Decoction Decoction, infusion Africa Africa Brazil Domis and Oyen (2008) Domis and Oyen (2008) Grandi et al. (1989) Vaginal flow Leaf (with roots of Agave sp., leaves of Momordica charantia and Argemone mexicana) Leaf Leaf (with leaves of Momordica charantia) Decoction Dominican Republic Roersch** Infusion Decoction Dominican Republic Dominican Republic Roersch** Roersch** Root Maceration and drunk with white wine Poultice, external Brazil Hammer and Johns (1993) Mexico Browner (1985) Decoction Decoction Decoction Maceration (with juice of old banana spike) Maceration Africa Africa Africa Cameroon Domis and Oyen (2008) Domis and Oyen (2008) Domis and Oyen (2008) Noumi and Yomi (2001) Cameroon Noumi and Dibakto (2000) Medicinal use Urinary tract Diuretic Kidneys Women diseases Emmenagogue Anti–abortive Digestive tract Diarrhea Leaf Digestive Dyspepsia Constipation Dysentery Root Root Root Leaf Peptic ulcer Leaf Agra et al. (2007) Santos and Lima (2008) Rodrigues and Guedes (2006) Domis and Oyen (2008) Chartol (1964) Schmelzer (2001) Roersch** Bouquet and Debray (1974), in Hammer and Johns (1993) Schmelzer (2001) Domis and Oyen (2008) Roig (1945) Grandi et al. (1989) Bouquet and Debray (1974), in Hammer and Johns (1993) Schmelzer (2001), Domis and Oyen (2008) Schmelzer (2001), Domis and Oyen (2008) Bodinga-bwa-Bodinga and Van der Veen (1993) C.M.F.B. Roersch / Journal of Ethnopharmacology 131 (2010) 522–537 526 Table 1 (Continued ) Medicinal use Part used Application* Country References Laxative for pregnant women Not specified Decoction Guinea Leaves with palm kernel oil Boiled with local palm kernel oil Nigeria Vasileva (1969), in Hammer and Johns (1993) Ndukwu and Ben-Nwadibia (in press) Edema (stomach) Intestinal parasites Leaf Leaf Leaf Leaf Leaf Plant Not specified Tied on the stomach Maceration Not specified Not specified Not specified Not specified Not specified South-East Asia Cameroon Central Africa Congo Guinea French Guyana Jamaica Schmelzer (2001) Noumi and Dibakto (2000) Domis and Oyen (2008) Domis and Oyen (2008) Domis and Oyen (2008) Schmelzer (2001) Mitchell and Ahmad (2006) Filariasis Diarrhea with blood Stomachache Not specified Leaf Leaf Root Leaf Leaf or root Leaf Not specified Decoction Decoction Not specified Infusion Decoction Infusion Brazil Mexico Mexico Brazil Cuba Africa Nigeria Leaf Leaf Not specified Decoction Nigeria South-East Asia Britto et al. (2007) Robinson and López (1999) Robinson and López (1999) Brandão et al. (2008) Pino et al. (2005) Domis and Oyen (2008) Ndukwu and Ben-Nwadibia (in press) Mensah et al. (2008) Schmelzer (2001) Colic Leaf Leaf and fruit Infusion Not specified Liberia Indochina Domis and Oyen (2008) Schmelzer (2001) Emollient Rectal prolapse Piles Nausea Scurvy Burps Leaf Leaf Flower, leaf Not specified Seed (essential oil) Leaf Not specified Crushed, as an enema Decoction Not specified Oral Decoction Africa Africa Cameroon Cameroon West Indies Dominican Republic Domis and Oyen (2008) Domis and Oyen (2008) Jiofack et al. (2008) Chartol (1964) Chenu (1986) Roersch** Leaf Decoction in poultice Mexico Leaf Leaf Poultice in water Not specified Brazil São Tomé and Príncipe Zamora-Martínez and Pola (1992) Hammer and Johns (1993) Martins et al. (1998) External ulcers Abscesses Leaf Leaf Leaf, root Leaf Decoction, infusion Applied on the abscesses Not specified Not specified Brazil South-East Asia Dominican Republic Haiti Grandi et al. (1989) Schmelzer (2001) Liogier (2000) Liogier (2000) Boils Leaf Leaf, root Root Not specified Decoction, infusion Not specified Brazil Brazil Jamaica Not specified Leaf Not specified Poultice Jamaica Africa Fenner et al. (2006) Grandi et al. (1989) Asprey and Thornton (1954) Mitchell and Ahmad (2006) Domis and Oyen (2008) Root Leaf, root Not specified Not specified Leaf Not specified Decoction, infusion Sap Sap Poultice Brazil Brazil Dominican Republic Haiti Africa Brandão et al. (2008) Grandi et al. (1989) Liogier (2000) Liogier (2000) Domis and Oyen (2008) Root Root Whole plant Syrup Syrup Tea Jamaica Jamaica Jamaica Not specified Leaf, root Leaves with Piper auritum Not specified Decoction, infusion Tea Jamaica Brazil Costa Rica Grieve (in press) Grieve (in press) Asprey and Thornton (1954) Mitchell and Ahmad (2006) Grandi et al. (1989) Hazlett (1986) Bronchitis Cough Leaf, root Leaves with Piper auritum Fruit with Piper betle Decoction, infusion Tea Chewed Brazil Costa Rica Malaysia Grandi et al. (1989) Hazlett (1986) Schmelzer (2001) Breast infection Angina Lung indications Flower, leaf Not specified Seed Decoction Not specified Powder externally Cameroon Cameroon West Indies Jiofack et al. (2008) Chartol (1964) Chenu (1986) Liver Liver Root Not specified Brazil Desmarchelier et al. (1997), Rodrigues and Guedes (2006) Skin Pimples and purulent pimples Skin irritation Burns Respiratory tract Catarrhs Cold C.M.F.B. Roersch / Journal of Ethnopharmacology 131 (2010) 522–537 527 Table 1 (Continued ) Part used Application* Country References Root Inflorescence Not specified Root Leaves with almond oil Brazil Brazil Brazil Brazil Brazil Kijjoa et al. (1980) Agra et al. (2007) Britto et al. (2007) Mentz et al. (1997) Mentz et al. (1997) Leaf Leaf Decoction Decoction Not specified Decoction Decoction, in lotion, externally Tea Not specified Brazil Brazil Leaf Leaf, root Root Root Macerate in water Decoction, infusion Not specified Not specified Brazil Brazil Dominican Republic Haiti Coelho and Silva (in press) Coelho et al. (2002), Vieira and Martins (2000) Di Stasi et al. (2002) Grandi et al. (1989) Liogier (2000) Liogier (2000) Jaundice Leaf or root Leaf, root Decoction Decoction, infusion Africa Brazil Domis and Oyen (2008) Grandi et al. (1989) Spleen Root Decoction Brazil Bile Leaf Not specified Africa Mentz et al. (1997), Rodrigues and Guedes (2006) Domis and Oyen (2008) Fever Sudorific Fever, Febrifuge Root Leaf Not specified Decoction Brazil Brazil Leaf Leaf Not specified Leaf, root Leaf Brazil Brazil Brazil Brazil Gabon Not specified Eaten, fresh or dried Body, rub Not specified Decoction, infusion Pounded with water, as a bath Not specified Leaf Decoction, as a wash Africa Not specified Leaf Not specified Infusion Infusion Not specified Brazil Brazil Gabon Stehmann and Brandâo (1995) Di Stasi et al. (2002) Bodinga-bwa-Bodinga and Van der Veen (1993) Inflorescence Leaf Leaf Decoction External, warm Not specified Brazil Dominican Republic Africa Leaf Not specified Not specified Tied on the head Not specified Not specified Jamaica Jamaica Cameroon Agra et al. (2007) Roersch** Domis and Oyen (2008), Schmelzer (2001) Asprey and Thornton (1954) Mitchell and Ahmad (2006) Chartol (1964) Inflorescence Leaf Decoction Massage Brazil Africa Not specified Not specified Gabon Leaf Venezuela Díaz and Ortega (2006) Medicinal use Pains Body ache Muscular pain Headache Migraine Analgesic Gabon Brandão et al. (2008) Hammer and Johns (1993), Oliveira et al. (2003) Hammer and Johns (1993) Estrella (1995) Britto et al. (2007) Grandi et al. (1989) Akendengue and Louis (1994) Bodinga-bwa-Bodinga and Van der Veen (1993) Domis and Oyen (2008), Schmelzer (2001) Agra et al. (2007) Domis and Oyen (2008), Schmelzer (2001) Bodinga-bwa-Bodinga and Van der Veen (1993) Leaf Warm, placed on the affected area Not specified Congo Bioka and Abena (1990) Toothache Leaf Maceration Cameroon Abdominal pains Earache Root Leaf Infusion Juice, as drops São Tomé and Príncipe Africa Noumi et al. (1999), Noumi and Dibakto (2000) Sequeira (1994) Domis and Oyen (2008) Root Leaf Brazil Mexico Desmarchelier et al. (1997) Kashanipour and McGee (2004) Leaf Not specified Wrapped around the irritated area Not specified Cuba Pino et al. (2005) Not specified Not specified Brazil Britto et al. (2007) Root Decoction in alcohol (dry gin) Decoction Nigeria Ndukwu and Ben-Nwadibia (in press) Domis and Oyen (2008) Inflammation Anti-inflammatory Swelling and inflammation of the legs Inflamed tumors Leaf or root Africa C.M.F.B. Roersch / Journal of Ethnopharmacology 131 (2010) 522–537 528 Table 1 (Continued ) Medicinal use Wounds Wounds Antiseptic Erysipelas Swellings, contusions Contusions, bruises Part used Application* Country References Root Leaf Leaf Leaf or root Leaf Leaf Not specified Not specified Decoction, in bath Not specified Decoction Fresh, applied on wounds Decoction Not specified Brazil Brazil São Tomé and Príncipe Africa South-East Asia Cameroon Gabon Brandão et al. (2008) Rodrigues and Guedes (2006) Martins et al. (1998) Domis and Oyen (2008) Schmelzer (2001) Chartol (1964) Bodinga-bwa-Bodinga and Van der Veen (1993) Leaf Not specified Not specified Not specified Africa Brazil Domis and Oyen (2008) Britto et al. (2007) Leaf Leaf South-East Asia Brazil Schmelzer (2001) Hammer and Johns (1993) Brazil Estrella (1995) Brazil Hammer and Johns (1993) São Tomé and Príncipe Africa Zimbabwe Martins et al. (1998) Domis and Oyen (2008) Yamada (1999) Brazil Hammer and Johns (1993) Leaf Fresh, applied on wounds Warm, placed on the affected area Poultice (with cow intestines) Warm, placed on the affected area Not specified Poultice Juice, rubbed on the affected part Warm, placed on the affected area Not specified Nigeria Ndukwu and Ben-Nwadibia (in press) Schmelzer (2001) Leaf Cuts and sprains Leaf Swellings Leaf Leaf Leaf Leaf Dropsy Leaf and fruit Not specified Indochina Ascites Leaf Infusion Nigeria Ndukwu and Ben-Nwadibia (in press) Rheumatism Rubefacient Fruit Not specified Nigeria Rheumatic pains Fruit Not specified Nigeria Rheumatism Root Decoction in alcohol (dry gin) Friction Powder, externally Nigeria Ghana West Indies Ndukwu and Ben-Nwadibia (in press) Ndukwu and Ben-Nwadibia (in press) Ndukwu and Ben-Nwadibia (in press) Domis and Oyen, 2008 Chenu, 1986 Burundi Polygenis-Bigendako (1990) Burundi Polygenis-Bigendako (1990) Africa Brazil Domis and Oyen (2008) Grandi et al. (1989) Leaf Seed Sundries Tonic Leaf, stem Kwashiorkor Leaf, stem Syphilis Leaf or root Leaf, root Stems and leaves ashes on scarification Stems and leaves ashes on scarification Decoction Decoction, infusion Gonorrhea Depurative Conjunctivitis Anemia Against poisons Hypertension Leaf or root Leaf, root Leaf Leaf and fruit Root Leaf Leaf Decoction Decoction, infusion Juice Not specified Not specified Maceration Decoction Africa Brazil Philippines Indochina Jamaica Cameroon Comoros Islands Domis and Oyen (2008) Grandi et al. (1989) Schmelzer (2001) Schmelzer (2001) Grieve (in press) Noumi et al. (1999) Kaou et al. (2008) Diabetes Malaria Leaf Leaf Leaf or root Leaf and root Decoction Nasal drops Decoction Not specified Comoros Islands Guinea Equatorial Africa Brazil Kaou et al. (2008) Akendengue (1992) Domis and Oyen (2008) Oliveira et al. (2003) Epilepsy Root Root Decoction Not specified Brazil Brazil Kijjoa et al. (1980) Britto et al. (2007) Aphrodisiac Root Decoction East Africa Infertility Root Not specified Congo Sedative Tiredness (Asthenia) Immunostimulant Not specified Root Root Not specified Not specified Not specified Congo Brazil Brazil Kokwaro (1976), in Hammer and Johns (1993) Nkounkou-Loumpangou et al. (2005) Bioka and Abena (1990) Brandão et al. (2008) Brandão et al. (2008) * ** If not specified, decoction, infusion, juice and maceration are used orally. Data from our National Study. C.M.F.B. Roersch / Journal of Ethnopharmacology 131 (2010) 522–537 529 Table 2 Chemical constituents of Piper umbellatum. Component Plant part References Alkaloids N-Benzoylmescaline N-Hydroxyaristolam II Piperumbellactams (A–D) Potomorphine Aerial parts Branches Branches Leaves Isobe et al. (2002) Tabopda et al. (2008) Tabopda et al. (2008) Hegnauer (1969) Flavonoids Acacetin 6-C-␤-D-glucopyranoside Acacetin 3-O-␤-D-[6′ -dodecanoyl]-glucopyranoside Acacetin 3-O-␤-D-glucopyranoside Apigenin 8-C-neohesperidoside Uvangoletin Wogonin Branches Branches Branches Branches Aerial parts Aerial parts Tabopda et al. (2008) Tabopda et al. (2008) Tabopda et al. (2008) Tabopda et al. (2008) Isobe et al. (2002) Isobe et al. (2002) Sterols Campesterol ␤-Sitosterol Aerial parts Aerial parts ␤-Sitosterol Stigmasterol Leaves, roots Aerial parts Sacoman et al. (2008) Isobe et al. (2002), Sacoman et al. (2008), Tabopda et al. (2008) Kijjoa et al. (1980) Sacoman et al. (2008) Terpenes ␤-Amyrin Bicyclogermacrene Branches Essential oil* , leaves Cadinene ␦-Cadinene Essential oil, leaves Essential oil, leaves ␤-Caryophyllene Essential oil, leaves Caryophyllene oxide ␣-Copaene ␣-Cubebene Cubebol 10-epi-gamma-Eudesmol Epizonarene (E,E)-␣-Farnesene Friedelin ␣-Humulene Germacrene D Essential oil, leaves Essential oil, leaves Essential oil, leaves Essential oil, leaves Essential oil, leaves Essential oil, leaves Essential oil, leaves Branches Essential oil, leaves Essential oil, leaves Limonene Linalool (E)-Nerolidol Essential oil, leaves Essential oil, leaves Essential oil, leaves (E)-␤-Ocimene (Z)-␤-Ocimene Phellandrene Phytol ␣-Pinene ␤-Pinene Spathulenol Essential oil, leaves Essential oil, leaves Essential oil, leaves Essential oil, leaves Essential oil, leaves Essential oil, leaves Essential oil, leaves Trans-Dihydroagarofurane ␤-Elemene ␤-Gurjunene ␣-Acorenol Essential oil, leaves Essential oil, leaves Essential oil, leaves Essential oil, leaves Others 4-Nerolidylcatechol Roots, whole plant, leaves Dillapiol E-3-(3,4-dihydroxyphenyl)-N-2-[4hydroxyphenyletyl]-2-propenamide Heneicosane N-p-Coumaroyl tyramine N-trans-Feruloyl tyramine Safrole Cinnamic acid 2-(4′ ,8′ -dimethylnona-3′ 7′ -dienyl)-8-hydroxy-2methyl-2H-chromene-6-carboxylic methyl ester * Only the main components of the essential oil are mentioned (>1.0%). Tabopda et al. (2008) Luz et al. (1999), Mesquita et al. (2005), Pino et al. (2005) Chartol (1964) Luz et al. (1999), Mesquita et al. (2005), Pino et al. (2005) Luz et al. (1999), Maia and Andrade (2009), Martins et al. (1998), Mesquita et al. (2005), Pino et al. (2005), Vogler et al. (2006), Chartol (1964) Luz et al. (1999), Mesquita et al. (2005) Luz et al. (1999) Luz et al. (1999) Luz et al. (1999) Mesquita et al. (2005) Luz et al. (1999) Vogler et al. (2006) Tabopda et al. (2008) Luz et al. (1999) Luz et al. (1999), Maia and Andrade (2009), Mesquita et al. (2005), Pino et al. (2005), Vogler et al. (2006) Martins et al. (1998) Martins et al. (1998) Maia and Andrade (2009), Martins et al. (1998), Mesquita et al. (2005), Pino et al. (2005) Martins et al. (1998) Martins et al. (1998) Chartol (1964) Martins et al. (1998) Martins et al. (1998) Martins et al. (1998) Luz et al. (1999), Mesquita et al. (2005), Pino et al. (2005) Mesquita et al. (2005) Mesquita et al. (2005) Luz et al. (1999) Luz et al. (1999) Leaves Branches Bergamo et al. (2005), De Oliveira and Akisue (1984), Desmarchelier et al. (1997), Kijjoa et al. (1980), Núñez et al. (2005), Tabopda et al. (2008), Viana et al. (2000) Bernhard and Thiele (1978) Tabopda et al. (2008) Essential oil, leaves Branches Branches Essential oil, leaves Leaves Branches Maia and Andrade (2009) Tabopda et al. (2008) Tabopda et al. (2008) Pino et al. (2005) Chartol (1964) Núñez et al. (2005) C.M.F.B. Roersch / Journal of Ethnopharmacology 131 (2010) 522–537 530 Fig. 1. Traditional medicinal uses in two or more countries in one or more continents. the chemical identification or the use of fingerprints in the extracts must be taken into account. 5. Pharmacology The extracts and pure compounds derived from P. umbellatum show a wide spectrum of pharmacological activities, including antibacterial, anti-inflammatory, analgesic, antioxidant, cytotoxic, antimalarial, antileishmanial, antitrypanosomal and other activities (Table 4). Pharmacological activities in in vitro and in vivo experiments are taken as starting points for the development of clinical studies. The concentrations by which these activities occur, whether expressed in IC50 , MIC, ED50 , etc., are crucial. Lately, efforts have been undertaken to obtain a more coherent, standardized approach. Adequate concentrations for anti-infective bioassays should be less than 100 ␮g/ml for extracts and mixtures and below 25 ␮M for compounds (Cos et al., 2006). Gertsch (2009) goes even References see Table 1. further and proposes 50 ␮g/ml for extracts and 5 ␮M for compounds. For in vivo experiments, Gertsch (2009) questions if doses of 200 mg/ml or more are of any practical use. Inclusion of controls in bioassays is very important and determines the effective dose order of the extract or isolated compound. In the following assessment of the various pharmacological activities of P. umbellatum, these criteria will be applied. 5.1. Antifungal activity: In the case of the Dominican Republic, it is very interesting to know whether antifungal activity is demonstrated for P. umbellatum. In our study, the main traditional use is vaginal flow (locally called ‘flujo blanco’ or ‘flor blanca’), which is frequently caused by a Candida albicans infection. Tabopda et al. (2008) tested three secondary metabolites, Piperumbellactam D, N-hydroxyaristolam II and 4-nerolidylcatechol, which showed high activity against a Table 3 Comparison of the essential oils of P. umbellatum in different countries. Component (% in samples) Country ␤-Caryophellene Germacrene D Heneicosane (E)-Nerolydol ␤-Pinene ␣-Pinene Bicyclogermacrene ␦-Cadinene (E,E)-␣-Farnesene ␤-Elemene Trans-dihydroagarofurane Safrole * Brazil (Maia and Andrade, 2009)* Brazil (Luz et al., 1999) Brazil (Mesquita et al., 2005) Costa Rica (Vogler et Cuba (Pino et al., al., 2006)* 2005) São Tomé and Príncipe (Martins et al., 1998) 37.5 11.9 1.2 9.1 – – – – – – – – 14.8 27.4 – 0.7 – – 11.5 13.3 – – – – 12.6/10.2 8.6/27.4 – 7.0/7.9 0.1 Trace 10.1/8.8 – – 6.7/6.4 6.6/– – 28 17 – – – – – – 15 – – – 9.8 – – 12.4 17.6 26.8 – 0.1 0.7 – – – Only the main constituents were mentioned. 4.6 7.9 – 1.1 0.2 0.1 3.7 5.6 – – – 48.7 C.M.F.B. Roersch / Journal of Ethnopharmacology 131 (2010) 522–537 531 Fig. 2. Structures of some chemical constituents of P. umbellatum. series of fungi, including C. albicans. The first two demonstrated an even higher activity against S. flavus and T. longifusus than did amphotericin B. The authors suggested that the presence of the methylenic carbon in methylenedioxyphenyl (MDP) is more able to form a stable carbene under oxidation. However, further research is needed in in vivo and in clinical studies to confirm these initial findings. A classification system that was apparently proposed by Aligiannis et al. (2001) is used in the literature and is based on MIC values (for extracts), as follows: strong inhibitors – MIC up to 0.5 mg/ml; moderate inhibitors – MIC between 0.6 and 1.5 mg/ml; weak inhibitors – MIC above 1.6 mg/ml. However, the indicated reference proposes anything but a classification. These concentra- 532 C.M.F.B. Roersch / Journal of Ethnopharmacology 131 (2010) 522–537 tions are much higher than those suggested by Cos et al. (2006) and Gertsch (2009). 5.2. Antioxidant activity and skin protection The extracts of various parts of P. umbellatum and several isolated compounds show interesting antioxidant activities. It is known that one of the traditional medicinal uses with consensus is in the treatment of wounds, and antioxidants play a well-known role in wound healing (Sen et al., 2002; Soneja et al., 2005). Thus, we have indirectly confirmed our hypothesis. We recommend that further research be pursued in this area. Some problems need to be taken into account, however. It is observed that the extract shows a higher value compared to 4NC, which could imply the presence of other antioxidant compounds in the extract (Desmarchelier et al., 1997). The free and total antioxidant capacity of several Piper sp. (methanolic leaf extract) were studied, using two different methods, the Folin–Ciocalteu reagent (Folin) and the ferric reducing antioxidant power (FRAP). There was no significant correlation between the Folin and FRAP free oxidant capacity, though there was a highly significant correlation between the Folin and FRAP total antioxidant capacity. It was concluded that the results of antioxidant activity using different methods should be interpreted carefully (Agbor et al., 2005). In Brazil, this antioxidant activity was the starting point for studying the effect of the root extract of P. umbellatum on skin damage produced by UV radiation. Prolonged UV exposure can cause severe depletion of skin antioxidants (like ␣-tocopherol), which could lead to skin cancer and photoaging. The depletion of ␣-tocopherol was avoided by applying a gel with the ethanolic extract of the roots of P. umbellatum on the skin of hairless mice exposed to UV-B radiation (Ropke et al., 2003). Also, after chronic exposure to UV-B radiation, these hairless mice were clearly protected from skin wrinkling. This means that the plant can be used as a photoprotective agent (Ropke et al., 2005). Investigating the possible underlying mechanism of the prevention of photoaging by P. umbellatum, Ropke et al. (2006) looked at the relationship between the root extract of P. umbellatum and matrix metalloproteinases (MMP), specifically MMP-2 and MMP-9. The ethanolic extract was able to inhibit MMP-9 activity in vitro as well as in vivo. The effect of the extract was stronger than that of 4NC (Ropke et al., 2006). The synthesis of these MMP is upregulated by the exposure of human skin to UV radiation. Possible application of the gel of the ethanolic extract of the roots can endanger the existence of the species. Therefore, Almeida et al. (2008) investigated the photostability of the ethanolic extract of the leaves of P. umbellatum, which contain 30% less 4NC. The outcome was that the extract is stable under UV-B radiation and inhibits the MMP-2 and MMP-9 activity of hairless mice in vitro. In the USA and other countries, Barros and Ropke have patented the effects of P. umbellatum on the skin (Anonymous, 2004). Optimization of the emulsion concerning the appearance, centrifuge stability and permeation has already been performed (Noriega et al., 2008). (normally the day when antimalarial activity is evaluated). Intravenously infected animals did not show this effect. The presented studies show that it is important to consider the particular strain of Plasmodium falciparum. Andrade-Neto et al. (2007) and Kamanzi Atindehou et al. (2004) have positive results at very interesting concentrations using strain K1. On the contrary, Kaou et al. (2008) consider the dichloromethane, methanol and methanol/water (1/1) extracts (aerial parts) as having no activity against the chloroquineresistant strain W2 of P. falciparum. A comparable finding is given by Bidla et al. (2004) concerning the chloroquine-sensitive F32 strain. Unfortunately, the promising result of the active principle, 4-nerolidylcatechol, concerning the chloroquine, pyrimethamine and cycloguanil resistant P. falciparum strain K1 (Andrade-Neto et al., 2007), has not been evaluated so far in vivo. 5.4. Other biological activities There are several biological activities investigated for P. umbellatum, which show positive effects at interesting concentrations. These studies demonstrated potential cytotoxic and anti-tumoral activity (Anonymous, 1976; Brohem et al., 2009; Kamanzi Atindehou et al., 2004; Sacoman et al., 2008; Werka et al., 2007), antibacterial activity (Isobe et al., 2002), antileishmanial activity (Braga et al., 2007) and antitrypanosomal activity (Kamanzi Atindehou et al., 2004). These studies are still at an initial stage and need to be reproduced and confirmed. No follow-up research has been reported so far. 5.5. Pharmacological activities versus traditional medicinal uses In traditional medical systems P. umbellatum covers a wide range of medicinal uses (Table 1). Comparing these uses with the existing pharmacological literature (Table 4) shows us that the majority of the traditional uses lack a pharmacological basis. Some traditional uses are being investigated, like malaria, which caught the interest of several authors (see Section 5.3), and vaginal flow (see Section 5.1). Analgesic and anti-inflammatory activity has been shown for the water and water–ethanolic extract of P. umbellatum. However, these effects are registered at relatively high concentrations. The traditional uses with consensus for P. umbellatum are kidney, diuretic, stomachache and wounds. Also, skin affections are mentioned in many countries. Up to now, pharmacological experiments directly dealing with these traditional uses have not been performed. The proposed hypothesis – the same (consensus) uses of a plant in different cultures should have a scientific basis – has not been confirmed. However, in the case of wounds (see Section 5.3), there is indirect proof for this hypothesis. It would be challenging to see if these claimed traditional uses with consensus indeed have a pharmacological justification. One can argue that the world is not waiting for a new diuretic, but validating this broadly diffused medicinal use will be important for the incorporation of P. umbellatum as a diuretic in Primary Health Care in many countries. 5.3. Antimalarial activity 6. Toxicology Several studies have been performed on the antiplasmodial activity of P. umbellatum. The ethanolic extract of the leaves, applied orally as well as subcutaneously in mice, has antimalarial activity against Plasmodium berghei (Amorim et al., 1988). However, Ferreira-da-Cruz et al. (2000) found that mice infected intraperitoneally with P. berghei Pasteur is not a good test system to detect the antiplasmodial activity. They discovered a ‘slow’ and ‘fast’ pattern of parasitemia. Some of the infected animals have a normal (fast) pattern, in which parasitemia increases quickly from the day of infection, and part of the animals have a low pattern, in which the parasitemia only starts to increase at day four of the infection Applied orally to mice, the ethanolic extract (70%, conc.: 500–2000 mg/kg) of the aerial parts did not produce any deaths during the 72-h period in the acute toxicity test, which means a LD50 higher than 2.0 g/kg (Perazzo et al., 2005). However, the dichloromethane extract of the aerial parts, given intraperitoneally, resulted in a LD50 of 533.71 mg/kg. The highest applied dose of 1000 mg/kg produced death (Sacoman et al., 2008). A water suspension of the dried root ethanolic extract was given, via catheter, to rats in a concentration of 1, 2 and 5 g/kg. For 14 days the rats were observed. No deaths or signs of intoxication were registered. Subchronic toxicity was determined by giving the rats, via C.M.F.B. Roersch / Journal of Ethnopharmacology 131 (2010) 522–537 533 Table 4 Biological and pharmacological activities (in vitro and in vivo) of P. umbellatum extracts and pure compounds. Extract/compound ANTIBACTERIAL ACTIVITY N-Benzoylmescaline (conc. 2.5 ␮g/ml) Essential oil (leaf, conc. 100 ␮g/ml) ANTIFUNGAL ACTIVITY: Methanol extract of the leaves (conc. 100 mg/ml) Piperumbellactam D (conc. 200 ␮g/ml or 0.68 ␮M) N-hydroxyaristolam II (conc. 200 ␮g/ml or 0.71 ␮M) 4-Nerolidylcatechol (4NC) (conc. 200 ␮g/ml or 0.64 ␮M) ANTIOXIDANT ACTIVITY Methanolic extract of the roots 4-Nerolidylcatechol (4NC) Ethanolic extracts of the root, stem and leaves Methanolic extract and methanolic extract with HCl of the leaves Methanolic extract of the leaves Piperumbellactam A Piperumbellactam B Piperumbellactam C N-p-Coumaroyl tyramine (conc. 10 ␮M) CYTOTOXIC ACTIVITY Water–ethanol extract of the stem Dichloromethane extract of the aerial parts Dichloromethane extract of the aerial parts (conc. 100, 200, 300, and 400 mg/ml) 4-Nerolidylcatechol Ethanolic extract of the stem and leaf Essential oil (leaf, conc. 100 ␮g/ml) ANTIMALARIAL ACTIVITY Ethanolic extract of the stem and leaf Dichloromethane extract of aerial parts Methanol extract of aerial parts Methanol/water (1/1) extracts of aerial parts 4-Nerolidylcatechol Chloroform/methanol extract (1/1) of the leaves Biological and pharmacological activity References In vitro antibacterial activity against Helicobacter pylori Inhibition of the growth of Bacillus cereus (MIC = 1250 ␮g/ml) and Staphylococcus aureus (MIC = 156 ␮g/ml) Isobe et al. (2002) Werka et al. (2007) In vitro inhibitory activity against Candida albicans (MIC = 2.50 mg/ml) and C. neoformans (MIC = 625 ␮g/ml) using the agar-well diffusion assay with amphotericin B as positive control Inhibition of radial growth of Trichophyton longifusus (73%), Candida albicans (101%), Aspergillus favus (35%), Microsporum canis (90%), Fusarium solani (63%) and Candida glabrata (101%) using the agar tube dilution method (with miconazole and amphotericin B as controls) Inhibition of radial growth of Trichophyton longifusus (89%), Candida albicans (108%), Aspergillus favus (51%), Microsporum canis (87%), Fusarium solani (65%) and Candida glabrata (99%) using the agar tube dilution method (with miconazole and amphotericin B as controls) Inhibition of radial growth of Trichophyton longifusus (50%), Candida albicans (55%), Aspergillus favus (10%), Microsporum canis (50%), Fusarium solani (49%) and Candida glabrata (78%) using the agar tube dilution method (with miconazole and amphotericin B as controls) Braga et al. (2007) In vitro antioxidant activity measured as total reactive antioxidant potential (TRAP) and the total antioxidant reactivity (TAR) using the luminol-enhanced chemiluminescence by peroxyl radicals method and catechin as a standard (extract/4NC/catechin: TRAP 97.2 ± 10.8 ␮M/33.6 ± 23.0 ␮M/20.4 ± 9.0 ␮M; TAR 0.6 ± 0.1 ␮M/4.9 ± 0.2 ␮M/3.1 ± 1.0. IC50 values were: 13.3 ␮g/ml (extract) and 4.9 ␮g/ml (4NC)) In vitro inhibition of free radical-mediated DNA-sugar damage induced by the presence of Fe(II) salts (extract/4NC: IC50 : 21 and 8 ␮g/ml) In vitro antioxidant activity in brain tissue auto-oxidation evaluated by using malondialdehyde (MDA) and chemiluminescence (CL). Q1/2 of the ethanolic extracts of the roots, stems and leaves were 4.0, 19.3 and 38.5 ␮g/ml, respectively In vitro antioxidant activity in the Folin–Ciocalteu reagent (Folin) and the ferric reducing antioxidant power (FRAP) method In vitro scavenging effect on DPPH (1,1-diphenyl-2-picrylhydrazyl) (79.8–89.9% at a dose level of 10 mg/ml), nitric oxide (85.1–97.9%, dose level 10 mg/ml), the superoxide radical (47.1–51.6%, dose level 8 mg/ml) and the hydroxyl radical (57–76.1%, dose level 5 mg/ml) and a 0.4–0.6 reducing power and a 88.3–93.9% metal chelating activity at a dose level of 8 mg/ml In vitro inhibitory activity in the DPPH radical scavenging assay with caffeic acid as positive control (13.1%, 67.8%, 86.4% and 61.8%, respectively, at a conc. of 10 ␮M) Desmarchelier et al. (1997) In vitro cytotoxic activity against CA-9KB In vitro antiproliferative activity against the human cancer cell lines MCF-7, NCI-ADR/RES, OVCAR-3, PC-3, HT-29, NCI-H460, 786-O, UACC-62, K-56 (total growth inhibition, TGI, between 4.0 and 9.5 ␮g/ml) and the leukemia cell line K-652 (TGI = 1.55 ␮g/ml) In vivo anti-tumor activity by intraperitoneal administration, evaluated with the Ehrlich ascites tumor model in mice In vitro cytotoxic activity against melanoma cell lines SK-Mel-28, SK-Mel-103 and SK-Mel-147 (IC50 = 20–40 ␮M) In vitro cytotoxic activity against L-6 rat skeletal myoblast cells (IC50 = 61.3 ␮g/ml) In vitro cytotoxic activity against Hep G2 (hepatocellular carcinoma) (10% kill); no activity (0% kill) found against MCF-7 and PC-3 human tumor cells Anonymous (1976) Sacoman et al. (2008) In vitro antiplasmodial activity against Plasmodium falciparum (strain K1, resistant to chloroquine and pyrimethamine) (IC50 = 3.74 ␮g/ml) In vitro antimalarial activity against the chloroquine-resistant strain W2 of Plasmodium falciparum (IC50 = >50, >50 and 50 ␮g/ml, respectively) In vitro activity against the chloroquine, pyrimethamine and cycloguanil resistant P. falciparum strain K1 (IC50 = 0.67 nM) In vitro inhibition of chloroquine-sensitive F32 strain of P. falciparum (70% inhibition at 40 ␮g/ml) Kamanzi Atindehou et al. (2004) Tabopda et al. (2008) Tabopda et al. (2008) Tabopda et al. (2008) Barros et al. (1996) Agbor et al. (2005) Agbor et al. (2007) Tabopda et al. (2008) Sacoman et al. (2008) Brohem et al. (2009) Kamanzi Atindehou et al. (2004) Werka et al. (2007) Kaou et al. (2008) Andrade-Neto et al. (2007) Bidla et al. (2004) 534 C.M.F.B. Roersch / Journal of Ethnopharmacology 131 (2010) 522–537 Table 4 (Continued ) Extract/compound Biological and pharmacological activity References Ethanolic extract of the leaves In vivo dose-dependent reduction in parasitemia (orally as well as subcutaneously) in mice (conc. orally 250 and 1250 mg/ml; subcutaneously 100 and 500 mg/ml) Amorim et al. (1988) In vivo analgesic effect in rats by intraperitoneal administration (no concentrations given, abstract only) Significant in vivo analgesic activity in rats by granulomatous tissue induction and the writhing test by a daily oral administration of 550 mg/kg extract Bioka and Abena (1990) ANALGESIC ACTIVITY Water extract of the leaves Water–ethanolic extract of the leaves ANTIINFLAMMATORY ACTIVITY Water–ethanolic extract of the aerial parts OTHER PHARMACOLOGICAL ACTIVITIES 4-Nerolidylcatechol 4-Nerolidylcatechol Water extract of the leaves Essential oil of the leaves Water extract of the leaves Piperumbellactam A Piperumbellactam B Piperumbellactam C Ethanolic extract of the root Ethanolic extract of the root in gel containing 0.1% 4-nerolidylcatechol Ethanolic extract of the root in gel containing 0.1% 4-nerolidylcatechol Ethanolic extract of the root Ethanolic extract of the root in gel containing 0.1% 4-nerolidylcatechol Methanolic extract of the leaves Ethanolic extract of the stem and leaf Water extract of the leaves Perazzo et al. (2005) Significant in vivo anti-inflammatory activity by using carrageenan-induced rat paw edema (ED50 = 550 mg/kg, orally) Perazzo et al. (2005) In vitro inhibition of myotoxin I, a phospholipase A2 of Bothrops asper (IC50 = 987 ␮M) Significant in vivo reduction of myotoxic and edema-inducing activities produced by Bothrops myotoxins in mice (preincubation with 100 or 200 ␮g 4NC) Anti-crustacean activity (Artemia salina) (LD50 = 122.5 mg/ml) Anti-crustacean activity (Artemia salina) (LD50 = 29.1 ␮g/ml) No significant inhibition in vitro of ␣- and ␤-glycosidase (no conc. given) In vitro activity against ␣-glycosidase (IC50 = 98.07, 43.80 and 29.64 ␮M, respectively) Núñez et al. (2005) In vitro dose-related reduction of MMP-2, pro-MMP-2 and MMP-9 in the cornea of the rabbit (dose 50, 100, 250 ␮g/ml) (matrix metalloproteinases, MMP, are related to the failure of the cornea to re-epithelialize after injury) In vivo prevention (100%) of ␣-tocopherol depletion in the skin of hairless mice treated with P. umbellatum root extract gel after UV-irradiation In vivo photoprotective effect of P. umbellatum root extract gel against UV irradiation-induced chronic skin damage (skin wrinkling) in hairless mice Strong in vitro inhibitory effect of P. umbellatum extract (100 ␮g/ml extract containing 7.09 ␮g/ml 4NC) on MMP-2 and MMP-9 measured by gelatin zymography In vivo inhibition of constitutive MMP-9 activity in mice sacrificed 2 h after UVB irradiation as measured by gelatin zymography and histological analysis In vitro antileishmanial activity against Leishmania amazonensis and Leishmania chagasi with amphotericin B as control drug (IC50 = 39 ␮g/ml and IC50 = >250 ␮g/ml, respectively) In vitro antitrypanosomal activity against Trypanosoma brucei rhodesiense (IC50 = 2 ␮g/ml) Hypothermic and tranquilizing activity; ataxia and reduction of the spontaneous activity in rats by intraperitoneal administration (no concentration given; abstract only) Barros et al. (2007) catheter, a water suspension of the dried root ethanolic extract (conc. 500 mg/kg) for 40 days (5 days a week). No signs of intoxication or deaths were registered. The hematological parameters (conc. hemoglobin, erythrocytes, leukocytes) showed no alteration; concerning the serum biochemical parameters, the triglycerides increased 39% in male rats and the AST activity decreased 24% in female rats; serum proteins decreased in both sexes. There were no alterations in the liver, spleen, kidneys and heart; also, no mutagenic activity was detected in the bone marrow micronucleus test (Barros et al., 2005). Lajide et al. (1998) investigated the toxicity of P. umbellatum to the maize weevil (Sitophilus zeamais Mots.). Maize grains were treated with the plant powder at the rate of 0, 1, 5 and 10% by weight of maize grains and then infested with 10 adult weevils. P. umbellatum, at the 1% treatment level, gave 100% kill at 28 days of treatment. Chartol (1964) also described an effective action of P. umbellatum as an insecticide, but of the essential oil from the leaves. Andrade et al. (2005) evaluated the mutagenic potential of the water–ethanolic extract (70%) of the aerial parts. The extract was given orally to Wistar rats at concentrations of 500, 1000 and 1500 mg/kg. This did not induce an increase in the average number Núñez et al. (2005) Hammer and Johns (1993) Werka et al. (2007) Hammer and Johns (1993) Tabopda et al. (2008) Ropke et al. (2003) Ropke et al. (2005) Ropke et al. (2006) Braga et al. (2007) Kamanzi Atindehou et al. (2004) Bioka and Abena (1990) of DNA damage in the liver cells and in the micronucleus in the bone marrow cells. There was, however, a significant increase in DNA damage in peripheral blood cells. In the Salmonella/mammalianmicrosome assay, no mutagenic effect of the ethanolic extract (plant parts not specified; conc. 50, 100, 250, and 500 ␮g) was observed (Felzenszwalb et al., 1987). The ethanolic extract of the roots of P. umbellatum (dosis 50, 100 and 200 mg/kg/day, orally) did not demonstrate a mutagenic effect in mice using the micronucleus test. On the contrary, there was a protective effect against genotoxicity induced by cyclophosphamide. The effect of the isolated 4-nerolidylcatechol (dosis 12.5, 25 and 50 mg/kg/day, orally) was even better (Valadares et al., 2007). From the above, one may conclude that the different extracts of P. umbellatum are not toxic and do not possess mutagenic effects, and even better, show protective qualities. Nevertheless, in the southwest of the Ivory Coast, in South-East Asia and in South America, Piper umbellatum is applied as a component of an arrow poison to hunt monkeys and wild pigs. In Colombia, the scraped, boiled bark of the lower part of the stem and root is used for this purpose (Domis and Oyen, 2008; Schmelzer, 2001; Schultes, 1980 in Hammer and Johns, 1993; Schultes and Raffauf, 1990). This finding C.M.F.B. Roersch / Journal of Ethnopharmacology 131 (2010) 522–537 and the fact that the pulverized plant and the essential oil of the leaf have insecticidal activity make it necessary to do more research on the toxicity of P. umbellatum. 7. Conclusions P. umbellatum is a widely appreciated medicinal plant and has cross–cultural uses in three continents. Traditional uses, on which major consensus exists, are kidney/diuretic, wounds and stomachache. Indirectly, the traditional use for wounds is supported. This interesting fact is the result of the demonstrated antioxidant effect of the plant and the role antioxidants play in wound healing. In Brazil, the antioxidant activity has been the starting point in the study of the effect of the root extract of P. umbellatum on skin damage produced by UV radiation. The outcome of this study is the formulation of a skin-protecting agent against UV radiation. These findings have been patented and the development of a cosmetic product is in progress. Critical assessment of the biological and pharmacological activities has shown that P. umbellatum may have interesting clinical applications, but there is still a tremendous distance between the existing pharmacological knowledge and any clinical application. Most experiments are at an initial, in vitro stage. There is an enormous shortage of in vivo studies, not to mention clinical studies. Moreover, the existing pharmacological data show differences in the activity of the extracts and the supposedly active compound, 4-nerolidylcatechol. The recently discovered bioactive constituents, piperumbellactams, indicate that much work still has to be done on the phytochemistry of the species. The presented differences in the contents of the essential oils of P. umbellatum make it very clear that for further comparison of experimental data, the chemical identification or the use of fingerprints in the extracts must be taken into account. The incongruent information about the toxicity of the species urges more research. This review indicates that P. umbellatum has a potential as a therapeutic agent, but the road to any clinical application is still very long. Acknowledgments I would like to thank the following persons for their support and their critical and constructive comments and corrections: Michael Heinrich, University of London; Rob Verpoorte, University of Leiden; Brent Berlin, University of Georgia; Norman Farnsworth, University of Illinois at Chicago; Paul Maas and Tinde van Andel, University of Wageningen; Arnaldo Bandoni, University of Buenos Aires; Eduardo Garcia and Amelia Parra, UNPHU, Santo Domingo; and Jacques van Rossum, University of Nijmegen. Also, I’m indebted to my friend Jan Adriaanse for revising the English text and to Juan Newton Ovalles Mella for drawing the chemical structures. 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