Revista Brasileira de Farmacognosia
Available online 24 May 2016
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doi:10.1016/j.bjp.2016.03.014
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Abstract

Piper marginatum Jacq., Piperaceae, is a widely distributed Neotropical species abundant in the Caribbean, exhibiting a characteristic winged petiole and a heart-shaped leaf, its two vegetative landmarks for rapid identification. The species has been employed by traditional indigenous cultures for its reputed medicinal properties. The plant is most frequently employed by local healers in Central America, the Antilles and South America, for alleviating gastrointestinal ailments, administered as a decoction or infusion for its tonic, diuretic and carminative effects. These beneficial properties may be attributed to the presence of various phytochemicals within P. marginatum, with most of the studies focusing on the essential oil of the plant. Monoterpenoids, sesquiterpenoids and phenylpropanoids of a varied chemical structure have been identified in the essential oil, while phenylalkanoids, aristolactams, amides and flavonoids have been purified by chromatographic techniques from the extracts. The biological and pharmacological examination of P. marginatum showed that the plant may be a valuable source of mosquitocidal, antifungal, antitumoral and hemostatic agents. Future bioguided research may yield biologically relevant molecules useful in medicine or agriculture.

Graphical abstract

Keywords

  • Piper marginatum Jacq.;
  • Piperaceae;
  • Folk medicine;
  • Phytochemistry;
  • Pharmacology;
  • Biological applications

Introduction

The species Piper marginatum Jacq., Piperaceae, was first described in 1781 by Dutch botanist Nikolaus Joseph von Jacquin. The species had been collected during excursions to Central and South America, and the morphological characters were recorded as heart-shaped, acuminated, multi-veined and reticulated leaves, with a marginal, grooved and winged petiole, and solitary flowers ( Jacquin, 1786). The Swiss botanist Anne Casimir Pyrame de Candolle was the first to observe small morphological differences between different collections of P. marginatum, and recognized three subspecies: P. marginatum Jacq, P. marginatum var. anisatum (Kunth) C.DC. and P. marginatum var. catalpifolium (Kunth) C.DC. ( Candolle, 1902). In the comprehensive work “The Piperaceae of Northern South America”, William Trelease and Truman G. Yuncker, differentiated the subspecies based on the puberulent (var. anisatum) or pillose (var. catalpifolium) nature of the nerves on the upper surface of the leaves ( Trelease and Yuncker, 1950). However the difficulty to characterize specimens at the subgenus level given its extensive homoplasy (the development of similar characters by parallel or convergent evolution) was recognized by Ricardo Callejas (Callejas, 1986), and thus the modern classifications consider the subspecies as synonyms of P. marginatum Jacq. ( Andrade et al., 2008). In this work, the sensu lato of P. marginatum was considered, following the criteria of the Missouri Botanical Garden ( Tropicos.org, 2015), which collates under P. marginatum several species and subspecies, including Piper san-joseanum C. DC., Piper patulum Bertol., Piper uncatum Trel., Piper quiriguanum Trel., among others.
The phylogenetic analysis of the genus Piper using the sequence alignment of the internal transcribed spacer (ITS) of the 18S-26S nuclear ribosomal DNA and the chloroplast intron region psbJ-petA, indicated that the species P. marginatum is closely related to P. multiplinervium and P. schwakei, and together these three species build the P. marginatum complex ( Jaramillo et al., 2008). Moreover the Pothomorphe group species (which includes P. auritum, P. peltatum and P. umbellatum) showed to be phylogenetically related to the P. marginatum complex.
The species P. marginatum has been widely recognized for its medicinal purposes within a number of indigenous cultures located in the Caribbean and Amazon regions, from Central America and the Antilles to Brazil ( de Núñez and Johnson, 1943, Braga, 1960, D’Angelo et al., 1997 and Di Stasi and Hiruma-Lima, 2002). In addition the dried leaves have been used as a natural sweetener ( Hussain et al., 1990 and Surana et al., 2006). Its major secondary metabolites are terpenoids and phenylalkanoids (Andrade et al., 2008). In addition a number of biological and pharmacological published data (Sequeda-Castañeda et al., 2015) seems to support its use in traditional medicine. This review covers the ethnomedicinal, phytochemical and biological literature published on P. marginatum with the aim to identify the research voids for future investigation and critically assess the potential application of the species in medicine and agriculture.

Folk medicine and traditional uses

The indigenous communities in Central America, the Antilles and South America repeatedly reported to use P. marginatum for treating a varied array of diseases and ailments. Gastrointestinal problems are the most common therapeutic use in the traditional medicine, spanning different locations and cultures ( Fig. 1, Box 1). The plant is recurrently employed either as a decoction or infusion for its tonic, diuretic and carminative effects ( Foungbe et al., 1976, Johnson, 1998, Di Stasi and Hiruma-Lima, 2002 and de Albuquerque et al., 2007). It is also used to treat gallbladder, liver, stomach, spleen, urinary and gastrointestinal ailments ( van den Berg, 1982, Pereira et al., 2011 and Yukes and Balick, 2011), but also dysentery (de Núñez and Johnson, 1943). In Central America, the species is known as “Aniseto” and it is employed as an infusion for treating flatulence disorders, in a similar way to star anise.
Frequency of application of Piper marginatum in the traditional medicine based ...
Fig. 1. 
Frequency of application of Piper marginatum in the traditional medicine based on the type of ailment to treat.
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Box 1. Traditional medicine applications of Piper marginatum by local communities.
LocationOrgan of the plantMedicinal properties, or afflictions treatedMode of applicationReferences
Amazon regionRootsCarminative, diuretic, tonic, useful against toothache and cobra venomBathsDi Stasi and Hiruma-Lima (2002)
RootsTo alleviate pain and itching of insect bitesCataplasm
Fruits and leavesStimulantnd
Stem, leavesAgainst itching from ant bitesCataplasmElisabetsky and Gely (1987)
ndAs antispasmodic and against liver and gallbladder diseasesDecoctionvan den Berg (1982)

BrazilLeavesRheumatism, bleeding skin wounds, toothache and tumorsDecoctionCorrêa and Pena (1984), D’Angelo et al. (1997)
LeavesTo reduce swellingsRubbed with fat as cataplasm, poulticeBranch and Silva (1983), Duke and Vasquez (1994)
RootsTo alleviate hitching caused by insect bites, and also as a teeth pain relieverMacerationPereira et al. (2011)
Leaves and fruitsAs antispasmodic, to treat cough, and affections of the spleen, liver and intestinal problemsUsed topicallyPereira et al. (2011)
Stem, leaves, rootsAgainst high blood pressure, asthma, erysipelas, problems with urinary system and as a diureticndde Albuquerque et al. (2007)
ndTo treat hemorrhoidsInfusionRodrigues and Andrade (2014)
ndHemostatic, snake-bite medicinendBraga (1960), D’Angelo et al. (1997)

ColombiaLeaves, stemFor protecting teeth against cavitiesChewedDuke and Vasquez (1994), García (1974)
LeavesAnalgesicInfusion and cataplasmGiraldo Tafur (1996)
RootsUsed against malaria and as stimulantJuiceGarcía (1974)
Entire plantTo reduce feversDecoctionGarcía (1974)

Costa RicaLeavesTo treat headachesDecoctionHazlett (1986)

CubandAntiseptic, astringent, antihemorrhagic and hemostaticndSánchez et al. (2011)

Dominican RepublicLeavesIndigestion and flatulence disorders but also against stomach painInfusionYukes and Balick (2011)

French GuianaLeavesUsed in combination with Quassia amara to treat malariaDecoctionVigneron et al. (2005)
LeavesTo treat cutaneous eruptions and insect bitesDecoctionFoungbe et al. (1976)
RootsDiuretic and sudorificInfusionFoungbe et al. (1976)
ndUsed to treat skin rashesndD’Angelo et al. (1997), Morton (1977)

PanamandCarminative, diuretic, emmenagogue, hemostaticndJohnson (1998)
ndReduce fever and lung secretionsndD’Angelo et al. (1997), Morton (1977)

Puerto RicoLeavesHemostaticCataplasmde Núñez and Johnson (1943)
LeavesAs treatment to dysenteryInfusionde Núñez and Johnson (1943)
ndReduces menstruation flowndMorton (1977)

SurinameLeavesTo cleanse the vagina, cleanse the uterus, disguise bad smell, enhance sexual pleasure amongst other applicationsSteam bathvan Andel et al. (2008)

Trinidad and TobagondTo help parturitionInfusion or decoction drankLans and Georges (2011)
nd refers to no data.
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Pain relief is the second most frequent use of P. marginatum in the traditional medicine ( Fig. 1, Box 1). The plant is used to relieve toothache, headaches and pain caused by itching, and as a general analgesic ( Hazlett, 1986, Giraldo Tafur, 1996, Di Stasi and Hiruma-Lima, 2002 and Pereira et al., 2011). The plant is employed topically as a cataplasm to alleviate the pain of the limbs or abdomen, or as a decoction or infusion for teeth, head and stomach aches ( García, 1974, Giraldo Tafur, 1996 and Yukes and Balick, 2011).
The species P. marginatum is also commonly used as a hemostatic ( Fig. 1, Box 1). The plant has been reported to stop bleeding particularly in the case of ophidian accidents ( de Núñez and Johnson, 1943, Braga, 1960, D’Angelo et al., 1997, Sánchez et al., 2011 and Ortega-Galvan, 2014). Reports of the topical application of the plant to alleviate itching and scratching from insect bites including ants (Elisabetsky and Gely, 1987) has been recurrently reported (Box 1), and it remains to be determined if this property is due solely to the analgesic effect. In addition P. marginatum displays antimicrobial properties with recorded applications in Brazil ( Corrêa and Pena, 1984 and D’Angelo et al., 1997), Colombia (Duke and Vasquez, 1994), Cuba (Sánchez et al., 2011) and Puerto Rico (de Núñez and Johnson, 1943). The species is also employed to treat female disorders, skin problems and insect bites ( van Andel et al., 2008, Lans and Georges, 2011 and Pereira et al., 2011). In Suriname, Trinidad and Puerto Rico, the plant is widely used to treat female disorders such as to clean female sexual organs, to help parturition, and to reduce the menstruation flow, respectively ( Morton, 1977, van Andel et al., 2008 and Lans and Georges, 2011). In the French Guiana, P. marginatum is used to treat cutaneous eruptions and skin rashes ( Foungbe et al., 1976, Morton, 1977 and D’Angelo et al., 1997), and in Brazil it is used to alleviate hitching caused by insect bites (Pereira et al., 2011).

Phytochemistry

The species P. marginatum shows a distinct phytochemistry with the presence of specific secondary metabolites, not found in other Piper species. For instance, P. marginatum is the only Piper species containing anethole, estragole, isoeugenol methyl ether, the phenylalkanoids 3-farnesyl-4-hydroxybenzoic and 3-farnesyl-4-methoxybenzoic acids and the glycosides marginatoside and vitexin ( Parmar et al., 1997). No other Piper species have shown the presence of these chemotaxonomic markers.
According to the essential oil (EO) components, seven chemotypes were recognized by Andrade et al. in their comprehensive study with 22 samples of P. marginatum collected throughout the Brazilian Amazon ( Andrade et al., 2008). The existence of seven chemotypes may induce to consider the assumption of ancient character of P. marginatum, allowing potential speciation events to occur during recent evolution. This hypothesis may be tested in the future by molecular phylogenetic analysis. The composition of the EO of the leaf, stem and inflorescence from a P. marginatum species collected in near Recife, Brazil, showed that the major component was (Z)-asarone (30.4%) on the EO of the leaf, (E)-asarone (32.6%) on the EO of the stem, and patchoulol (23.4%) on the EO of the inflorescence ( Autran et al., 2009). A P. marginatum species from Costa Rica ( Vogler et al., 2006) was rich in anethole (45.9%) and anisaldehyde (22.0%), while P. marginatum collected near Guantanamo in Cuba ( Sánchez et al., 2011) showed high amounts of isosafrole (37.3%) and nothosmyrnol (22.7%). Moreover, the EO obtained from P. marginatum collected near Acandi, Colombia, had high concentration of anethole (46.3%) followed by estragol (28.9%), whereas the same species collected in Turbaco, Colombia, showed an EO rich in germacrene D (36.6%) ( Jaramillo-Colorado et al., 2015). These studies suggest that there are more than seven chemotypes on the EO of P. marginatum sensu lato. These results point out to a dramatic variation in chemical composition for a set of related marginatum-phenotype species but it in addition it is necessary to consider the variability associated to chronobiological phenomena (monthly, weekly and daily variation) as hypothesized by Moraes et al. (2014).
Most of the phytochemical studies on P. marginatum have been carried out on the EO of the plant. Twenty five monoterpen(e)-oids (1–25, Box 3), and fifty seven sesquiterpen(e)-oids (26–82, Box 3) have been identified from the EO of P. marginatum species collected in different locations, at different moments and studied under different conditions. Thus there are reasons to explain the variation observed on the chemical composition of the EO differentiated in seven chemotypes ( Andrade et al., 2008). But in addition to this variability, the assembly of previously described sub-species collated under the sensu-lato name P. marginatum may contribute to the notable chemical variation, as each subspecies may have a different secondary metabolism. It remains to be verified if the populations ascribed as P. marginatum are undergoing speciation events, moreover considering its widespread geographical distribution.

The sole sesquiterpenoid which has been purified using chromatographic techniques is caryophyllene oxide (40) (de Oliveira Chaves and de Oliveira Santos, 2002). Among the thirty-nine phenylalkanoids (83–122, Box 2) reported for P. marginatum, most of them were identified by CG-MS analysis of the EO of the plant, while some of them were isolated to purity by chromatographic techniques (apiol (87), (E)-asarone (89), croweacin (92), 2,6-dimethoxy-3,4-methylenedioxy-1-(2-propenyl)-benzene (95), 3-farnesyl-4-hydroxybenzoic acid (99) and 3-farnesyl-4-methoxybenzoic acid (100), 2-hydroxy-3,4-methylenedioxypropiophenone (101), marginatine (106), 3,4-methylenedioxypropiophenone (108), 2-methoxy-4,5-methylenedioxypropiophenone (109), pipermargine (118) piperonal (119), 1-(1-(Z)-propenyl)-2,4,6-trimethoxybenzene (120), safrole (121), 2,4,5-trimethoxypropiophenone (122)) ( de Diaz and Gottlieb, 1979, Maxwell and Rampersad, 1988, de Oliveira Santos et al., 1997, Santos et al., 1998, de Oliveira Santos and de Oliveira Chaves, 1999b and de Oliveira Chaves and de Oliveira Santos, 2002).

Box 2. Reported phytochemicals identified in Piper marginatum.
ClassCompoundPresent in organReference
Monoterpene and monoterpenoidsAllocymene (1)Leaf, stemRamos et al. (1986)
Borneol (2)LeafAndrade et al. (2008)
Camphene (3)LeafAndrade et al. (2008)
Camphor (4)LeafAndrade et al. (2008)
δ-3-Carene (5)Leaf, stemAndrade et al. (2008), Autran et al. (2009), Moraes et al. (2014), Ramos et al. (1986), Vogler et al. (2006)
p-Cymene (6)Leaf, stemAndrade et al. (2008), Ramos et al. (1986), Vogler et al. (2006)
8-p-Cymenol (7)Leaf, stemVogler et al. (2006)
Isoborneol (8)LeafAndrade et al. (2008)
Isopentyl isovalerate (9)LeafAutran et al. (2009), Moraes et al. (2014)
Isosylvestrene (10)LeafAndrade et al. (2008)
Limonene (11)Leaf, stemAndrade et al. (2008), Ramos et al. (1986), Vogler et al. (2006)
Linalool (12)Leaf, stemAndrade et al. (2008), Autran et al. (2009), Moraes et al. (2014), Ramos et al. (1986), Vogler et al. (2006)
p-Mentha-1-(7),8-diene (13)LeafAndrade et al. (2008)
Myrcene (14)Leaf, stemAndrade et al. (2008), Ramos et al. (1986)
(E)-β-ocimene (15)Leaf, stemAndrade et al. (2008), Ramos et al. (1986)
(Z)-β-ocimene (16)Leaf, stemAndrade et al. (2008), Autran et al. (2009), Moraes et al. (2014), Ramos et al. (1986)
α-Phellandrene (17)Leaf, stemAndrade et al. (2008), Ramos et al. (1986)
α-Pinene (18)Leaf, stemAndrade et al. (2008), Ramos et al. (1986)
β-Pinene (19)Leaf, stemAndrade et al. (2008), Autran et al. (2009), Moraes et al. (2014), Ramos et al. (1986)
Sabinene (20)LeafAndrade et al. (2008)
Sylvestrene (21)LeafAutran et al. (2009), Moraes et al. (2014)
α-Terpinene (22)Leaf, stemAndrade et al. (2008), Ramos et al. (1986)
γ-Terpinene (23)Leaf, stemAndrade et al. (2008), Ramos et al. (1986)
α-Terpineol (24)LeafAutran et al. (2009), Moraes et al. (2014)
α-Terpinolene (25)Leaf, stemAndrade et al. (2008), Ramos et al. (1986)

Sesquiterpene and sesquiterpenoidsα-Acoradiene (26)Leaf, inflorescenceAutran et al. (2009), Moraes et al. (2014)
β-Acoradiene (27)LeafAutran et al. (2009), Moraes et al. (2014)
Alloaromadendrene (28)LeafAndrade et al. (2008)
Alloaromadendrene epoxide (29)LeafAndrade et al. (2008)
Aromadendrene (30)LeafAndrade et al. (2008)
Bicycloelemene (31)LeafSánchez et al. (2011)
Bicyclogermacrene (32)LeafAndrade et al. (2008), Autran et al. (2009), Moraes et al. (2014), Sánchez et al. (2011)
β-Bourbonene (33)Leaf, stemAndrade et al. (2008), Ramos et al. (1986)
α-Cadinene (34)LeafMoraes et al. (2014)
δ-Cadinene (35)Leaf, stemAndrade et al. (2008), Ramos et al. (1986)
γ-Cadinene (36)Leaf, stem, inflorescenceAutran et al. (2009), Moraes et al. (2014)
α-Cadinol (37)LeafAndrade et al. (2008)
δ-Cadinol (38)StemRamos et al. (1986)
β-Caryophyllene (39)Leaf, stem, inflorescenceAndrade et al. (2008), Autran et al. (2009), Moraes et al. (2014), Ramos et al. (1986)
Caryophyllene oxide (40)Leaf, stemAndrade et al. (2008), Autran et al. (2009), de Oliveira Chaves and de Oliveira Santos (2002)
α-Copaene (41)Leaf, stem, inflorescenceAndrade et al. (2008), Ramos et al. (1986), Autran et al. (2009), Moraes et al. (2014), Sánchez et al. (2011)
α-Cubebene (42)Leaf, stem, inflorescenceAndrade et al. (2008), Autran et al. (2009)
β-Cubebene (43)LeafAndrade et al. (2008)
Cyclosativene (44)LeafAndrade et al. (2008)
β-Dihydroagarofuran (45)LeafAndrade et al. (2008)
ar-Dihydroturmerone (46)StemAutran et al. (2009)
β-Elemene (47)Leaf, stem, inflorescenceAndrade et al. (2008), Autran et al. (2009), Moraes et al. (2014), Ramos et al. (1986), Sánchez et al. (2011)
δ-Elemene (48)Leaf, stemAutran et al. (2009), Moraes et al. (2014), Ramos et al. (1986)
γ-Elemene (49)Leaf,Ramos et al. (1986)
Elemol (50)Leaf, stemAndrade et al. (2008), Autran et al. (2009), Moraes et al. (2014), Ramos et al. (1986), Sánchez et al. (2011)
α-Eudesmol (51)LeafAndrade et al. (2008), Sánchez et al. (2011)
β-Eudesmol (52)Leaf, stemBernal et al. (2011), Ramos et al. (1986), Andrade et al. (2008), Sánchez et al. (2011)
10-epi-γ-Eudesmol (53)LeafAndrade et al. (2008)
γ-Eudesmol (54)LeafAndrade et al. (2008)
Germacrene A (55)LeafAndrade et al. (2008)
Germacrene D (56)Leaf, inflorescenceAndrade et al. (2008), Autran et al. (2009)
Germacrene D-4ol (57)LeafAndrade et al. (2008)
Globulol (58)LeafAndrade et al. (2008)
α-Guaiene (59)Leaf, inflorescenceAutran et al. (2009), Moraes et al. (2014)
(E)-β-guaiene (60)LeafAutran et al. (2009), Moraes et al. (2014)
(Z)-β-guaiene (61)Leaf, inflorescenceAutran et al. (2009), Moraes et al. (2014)
β-Gurjunene (62)LeafAndrade et al. (2008)
γ-Gurjunene (63)InflorescenceAutran et al. (2009)
γ-Himachalene (64)LeafAutran et al. (2009), Moraes et al. (2014)
α-Humulene (65)Leaf, stem, inflorescenceAndrade et al. (2008), Autran et al. (2009), Moraes et al. (2014), Ramos et al. (1986)
Humulene epoxide II (66)LeafAndrade et al. (2008)
Isoledene (67)LeafAutran et al. (2009), Moraes et al. (2014)
(Z)-Isolongifolanone (68)StemAutran et al. (2009)
Ledol (69)LeafAutran et al. (2009), Moraes et al. (2014)
α-Muurolene (70)LeafAndrade et al. (2008)
γ-Muurolene (71)Leaf, stemRamos et al. (1986)
epi-α-Muurolol (72)LeafAndrade et al. (2008)
(E)-Nerolidol (73)LeafAndrade et al. (2008), Sánchez et al. (2011)
(Z)-Nerolidol (74)StemAutran et al. (2009)
Patchoulol (75)Leaf, stem, inflorescenceAutran et al. (2009), Moraes et al. (2014)
α-Selinene (76)LeafAndrade et al. (2008)
β-Selinene (77)Leaf, stemAndrade et al. (2008), Autran et al. (2009)
7-epi-α-Selinene (78)LeafAndrade et al. (2008)
Selin-11-en-4α-ol (79)LeafAndrade et al. (2008)
Seychellene (80)StemAutran et al. (2009)
Spathulenol (81)LeafAndrade et al. (2008)
Valencene (82)InflorescenceAutran et al. (2009)

Phenylalkanoids(E)-anethole (83)Leaf, stemAndrade et al. (2008), Sánchez et al. (2011), Vogler et al. (2006)
(Z)-anethole (84)LeafAndrade et al. (2008)
p-Anisaldehyde (85)Leaf, stemVogler et al. (2006)
Anisyl ketone (86)Leaf, stemVogler et al. (2006)
Apiol (87)RootSantos et al. (1998)
Asaricin (88)LeafAndrade et al. (2008)
(E)-asarone (89)Leaf, stem, root, inflorescenceAndrade et al. (2008), Autran et al. (2009), Moraes et al. (2014), Sánchez et al. (2011), Sánchez et al. (2011), Santos et al. (1998)
(Z)-asarone (90)Leaf, stem, inflorescenceAndrade et al. (2008), Autran et al. (2009), Moraes et al. (2014)
γ-Asarone (91)LeafAndrade et al. (2008)
Croweacin (92)RootAndrade et al. (2008), de Oliveira Santos et al. (1997)
Dillapiole (93)Leaf, stemAndrade et al. (2008), Ramos et al. (1986), Sánchez et al. (2011)
3,4-Dimethoxycinnamic acid (94)LeafSánchez et al. (2011)
2,6-Dimethoxy-3,4-methylenedioxy-1-(2-propenyl)-benzene (95)RootSantos et al. (1998)
Elemicin (96)Leaf, stemAutran et al. (2009), Moraes et al. (2014), Ramos et al. (1986), Sánchez et al. (2011)
Estragole (97)Leaf, stemAndrade et al. (2008), Ramos et al. (1986), Sánchez et al. (2011), Vogler et al. (2006)
Exalatacin (98)LeafAndrade et al. (2008)
3-Farnesyl-4-hydroxybenzoic acid (99)Leaf, stemde Oliveira Chaves and de Oliveira Santos (2002), Maxwell and Rampersad (1988)
3-Farnesyl-4-methoxybenzoic acid (100)Leaf, stemMaxwell and Rampersad (1988)
2-Hydroxy-3,4-methylenedioxypropiophenone (101)Leaf, stemAndrade et al. (2008), de Diaz and Gottlieb (1979), Ramos et al. (1986)
Isocroweacin (102)LeafSánchez et al. (2011)
Isolelemicin (103)Leaf, stemAndrade et al. (2008), Ramos et al. (1986)
(E)-Isoosmorhizole (104)LeafAndrade et al. (2008)
Isosafrole (105)LeafSánchez et al. (2011)
3,4-Methylenedioxy-1-(2E-octenyl)-benzene (marginatine, 106)RootSantos et al. (1998)
1-(3,4-Methylenedioxyphenyl)-propan-1-ol (marginatumol, 107)LeafReigada et al. (2007)
3,4-Methylenedioxypropiophenone (108)Leaf, stemAndrade et al. (2008), de Diaz and Gottlieb (1979), Ramos et al. (1986), Reigada et al. (2007)
2-Methoxy-4,5-methylenedioxypropiophenone (109)Root, leafAndrade et al. (2008), de Diaz and Gottlieb (1979), Oliveira Santos and Oliveira Chaves (2000), Reigada et al. (2007)
Methyleugenol (110)Leaf, stemAndrade et al. (2008), Ramos et al. (1986), Sánchez et al. (2011)
Methyl 3-farnesyl-4-hydroxybenzoate (111)Leaf, stemMaxwell and Rampersad (1988)
Methyl 3-farnesyl-4-methoxybenzoate (112)Leaf, stemMaxwell and Rampersad (1988)
(E)-methyl isoeugenol (113)Leaf, stem, inflorescenceAutran et al. (2009), Moraes et al. (2014)
Methyl piperonate (114)LeafAndrade et al. (2008)
Myristicin (115)Leaf, stemAndrade et al. (2008), Ramos et al. (1986), Sánchez et al. (2011)
Norepinephrine (116)LeafD’Angelo et al. (1997)
Nothosmyrnol (117)LeafSánchez et al. (2011)
1-(1E-propenyl)-2,4,6-trimethoxybenzene (pipermargine, 118)RootSantos et al. (1998)
Piperonal (119)Leaf, stemde Diaz and Gottlieb (1979)
1-(1-(Z)-propenyl)-2,4,6-trimethoxybenzene (120)Fruitde Oliveira Chaves and de Oliveira Santos (2002)
Safrole (121)Leaf, stemAndrade et al. (2008), de Diaz and Gottlieb (1979), Ramos et al. (1986), Sánchez et al. (2011)
2,4,5-Trimethoxypropiophenone (122)Rootde Oliveira Santos and de Oliveira Chaves (1999b)

Alkaloids and amidesCepharanone B (123)Whole plantde Oliveira Chaves et al. (2006)
Cinnamoyl pirrolidide (124)Stemde Oliveira Chaves et al. (2003)
(E,E)-N-isobutyl-2,4-octadienamide (125)Rootde Oliveira Santos and de Oliveira Chaves (1999a)
Piperolactam A (126)Whole plantde Oliveira Chaves et al. (2006)

Flavonoids5,4′-Dihydroxy-7-methoxyflavanone (127)LeafReigada et al. (2007)
5,7-Dihydroxy-4′-methoxyflavanone (128)LeafReigada et al. (2007)
Marginatoside (129)LeafTillequin et al. (1978)
Vitexin (130)LeafTillequin et al. (1978)

OthersNoradrenaline (131)LeafD’Angelo et al. (1997)
Stearic acid (132)Leaf, stemde Diaz and Gottlieb (1979)
Table options
The alkaloids or amides so far identified from P. marginatum are the aristolactams cepharanone B (123) and piperolactam A (124), (E,E)-N-isobutyl-2,4-octadienamide (125) and cinnamoyl pirrolidide (126) ( de Oliveira Santos and de Oliveira Chaves, 1999a, de Oliveira Chaves et al., 2003 and de Oliveira Chaves et al., 2006). Two flavanones 5,4′-dihydroxy-7-methoxyflavanone (127) and 5,7-dihydroxy-4′-methoxyflavanone (128), and two flavonoid glycosides marginatoside (129) and vitexin (130) have been isolated from the leaves of P. marginatum ( Tillequin et al., 1978 and Reigada et al., 2007). The catecholamine noradrenaline (131) was identified by high performance liquid chromatography (D’Angelo et al., 1997), and the fatty acid stearic acid (132) has been purified from the leaves (de Diaz and Gottlieb, 1979).

Biological and pharmacological applications

The sweetening effect of the plant recorded in the traditional application was attributed to the presence of (E)-anethole (83), a sweet phenylpropanoid and major compound in certain chemotypes of the EO of P. marginatum but also present in fennel (Foeniculum vulgare), star anise (Illicium verum), cicely (Myrrhis odorata) and anise root (Osmorhiza longistylis) ( Hussain et al., 1990). (E)-Anethole has been reported to provide protection against chemically-induced apoptosis and genotoxicity ( Abraham, 2001 and Galicka et al., 2014), and to be non-carcinogenic in mice (Miller et al., 1983) posing no risk to human health (Newberne et al., 1999).
Most studies evaluating the biological and pharmacological properties of P. marginatum have focused on the essential oil ( Box 3). The leaf EO demonstrated growth inhibition of Escherichia coli bacteria with a minimum inhibitory concentration (MIC) value between 700 and 900 μg/ml against two pathogenic strains STEC0157 and EPEC0312 respectively (Duarte et al., 2007). A much lower MIC value of 120 μg/ml was found against the phytopathogenic bacterium Xanthomonas albilineans ( Sánchez et al., 2012). The leaf EO was also screened for fungal inhibition against both Alternaria solanii and Fusarium oxysporum, displaying moderate activity in disk diffusion assays ( dos Santos et al., 2011 and Duarte et al., 2013). However another study reported that the EO from P. marginatum was inactive against F. oxysporum with an MIC value higher than 500 μg/ml, while it was found to be slightly more active against Trichophyton rubrum and Trichophyton mentagrophytes with respective MIC values of 500 and 250 μg/ml (Tangarife-Castaño et al., 2014). Moreover both the EO and the ethanolic extract of P. marginatum were reported to be inactive against Candida albicans with MIC values higher than 2.0 mg/ml (Duarte et al., 2005). The EO obtained from the leaf, steam and flower of P. marginatum were tested for activity against Aedes aegypti, and found to be potent larvicidal mixtures (LC50 ranging from 19.9 to 23.8 μg/ml) with the EO from stem and flower being slightly more active than the EO from the leaf (Autran et al., 2009). A lower LC50 value of 8.3 μg/ml was reported for a leaf EO obtained from Paraiba, Brazil (Costa et al., 2010) whereas a LC50 value of 34 μg/ml was found for a leaf EO from a plant collected in the Rondonia state in Brazil (Santana et al., 2015). Moreover in the presence of the EO at 100 μg/ml, the gravid A. aegypti females reduced the number of eggs laid by one-third compared to the negative control ( Autran et al., 2009). The effect of the P. marginatum EO on brine shrimp (Artemia franciscana) lethality and Vero cells cytotoxicity was found to be comparable in the concentration-response with a LC50 value of 22.4 μg/ml against the A. franciscana nauplii after 24 h of exposition (Olivero-Verbel et al., 2009), and an IC50 value of 30.3 μg/ml against the Vero cells (Tangarife-Castaño et al., 2014). In addition the EO also demonstrated antiparasitic and insecticidal properties, with 90% of the population of Schistosoma mansoni being inhibited with 5 mg of the EO (Frischkorn et al., 1978), and 90% of the population of the fire ant Solenopsis saevissima being inhibited with a concentration of 427–480 μg/ml (Souto et al., 2012). The EO of P. marginatum showed significant antioxidant activity with a DPPH IC50 value between 1.2 and 1.5 μg/ml while the control ascorbic acid showed a DPPH IC50 value of 1.0 μg/ml (Jaramillo-Colorado et al., 2015). Furthermore the EO demonstrated repellent activity of the red flour beetle Tribolium castaneum from a concentration of 0.01 μl/ml, and also a considerable anti-alimentary effect against the cotton moth Spodoptera littoralis, being non-phytotoxic against Latucca sativa, and thus suggesting a potential application as an natural agent to control beetles and moths in agricultural settings ( Jaramillo-Colorado et al., 2015).
Box 3. Biological and pharmacological activities of Piper marginatum.
Extract or compoundBiological activityAssayPotencyReferences
Leaf EOAntibacterialIn vitro against two pathogenic strains of Escherichia coliMIC (STEC0157) = 700 μg/ml
MIC (EPEC0312) = 900 μg/ml		Duarte et al. (2007)
In vitro against Xanthomonas albilineansMIC = 120 μg/mlSánchez et al. (2012)
AntifungalIn vitro against Fusarium oxysporumInhibition diameter = 22.5 mm, Control diameter = 69.9 mmdos Santos et al. (2011)
In vitro against Alternaria solaniiInhibition % = 57 with 10 μl of EODuarte et al. (2013)
LarvicidalIn vitro against Aedes aegypti larvaeLC50 = 8.3 μg/ml
Control temefos LC50 = 0.3 μg/ml		Costa et al. (2010)
LC50 = 34 μg/ml
LC90 = 85 μg/ml		Santana et al. (2015)

EOAntifungalIn vitro against Candida albicansMIC > 2.0 mg/mlDuarte et al. (2005)
Antifungal and cytotoxicityIn vitro activity against Fusarium oxysporum, Trichophyton rubrum and Trichophyton mentagrophytes and cytotoxicity against Vero cell lineF. oxysporum MIC > 500 μg/ml
T. rubrum MIC = 500 μg/ml
T. mentagrophytes MIC = 250 μg/ml.
IC50 = 30.3 μg/ml against Vero cell line		Tangarife-Castaño et al. (2014)
Antioxidant, repellent, anti-alimentary and phytotoxicIn vitro DPPH antioxidant, Tribolium castaneum repellent, Spodoptera littoralis, antialimentary, and Latucca sativa and Lolium perenne phytotoxicity activitiesDPPH inhibition with IC50 = 1.2–1.5 μg/ml, while the control ascorbic acid showed IC50 = 1.0 μg/ml.
EO repellent of >50% T. castaneum from 0.01 μl/ml
EO anti-alimentary to S. littoralis with 64–80% effect with 100 μg/cm2
EO (at unknown concentration) inhibited root growth of L. perenne by 54–62%, but increased root growth of L. sativa by 119–170%		Jaramillo-Colorado et al. (2015)
Brine shrimp lethalityIn vitro against Artemia franciscana cystsLC50 = 22.38 μg/ml (at 24 h)
LC50 = 12.64 μg/ml (at 48 h)		Olivero-Verbel et al. (2009)
CercaricidalIn vitro against Schistosoma mansoniAt 10 mg, 96% of cercariae died
At 5 mg, 90% of cercariae died
At 1 mg, 24% of cercariae died		Frischkorn et al. (1978)
LarvicidalIn vitro against Aedes aegypti larvaeLeaf EO LC50 = 23.8 μg/ml
Stem EO LC50 = 19.9 μg/ml
Flower EO LC50 = 19.9 μg/ml		Autran et al. (2009)
InsecticidalIn vitro against the workers of the fire ant Solenopsis saevissima (Smith)LC50 = 122–167 μg/ml
LC90 = 427–480 μg/ml		Souto et al. (2012)
OvipositionIn vitro on gravid Aedes aegypti females and counting the number of eggs laid% eggs laid (leaf) = 33%
% eggs laid (stem) = 32%
% eggs laid (flower) = 35%
At 100 μg/ml with respect to the negative control		Autran et al. (2009)

Ethanolic extractCytotoxicityIn vitro against murine melanoma B16/BL6, human colon carcinoma HT-29, human lung carcinoma A549, human cervical carcinoma HeLa, and human pancreatic carcinoma PANC-1Leaf:
B16/BL6 GI50 > 300 μg/ml
HT-29 GI50 = 55 μg/ml
A549 GI50 > 300 μg/ml
HeLa GI50 > 300 μg/ml
PANC-1 GI50 > 300 μg/ml
Root:
B16/BL6 GI50 > 300 μg/ml
HT-29 GI50 = 298 μg/ml
A549 GI50 = 240 μg/ml
HeLa GI50 > 300 μg/ml
PANC-1 GI50 = 65 μg/ml		Villasmil et al. (2006)
AntitumoralIn vivo murine tumor induction assayThe leaf extract (and not the root extract) of P. marginatum showed antitumoral activityVillasmil et al. (2006)

Methanolic extractAntifungalIn vitro against Colletotrichum scovilleiThe percentage of inhibition of mycelial growth (PIC) was 50% with a concentration of 750 μg/ml, and reached 70% at 1.5 mg/mlAraújo et al. (2014)

Hydro-alcoholic extractAnti-leishmanialIn vitro against Leishmania infantum amastigotesIC50 = 25 μg/ml
The positive control pentamidine showed IC50 = 2.43 μg/ml		Iwanaga et al. (2014)

Water extractToxicityIn vivo on Wistar adult rat and albino miceLD100 = 1 g/kg (intraperitoneal)
LD > 2 g/kg (orally)		D’Angelo et al. (1997)
Blood pressureIn vivo on ratDose-dependent hypertension was observed with intravenous and oral administrationsD’Angelo et al. (1997)
Vas deferens contractilityIn vivo on ratDose-dependent contractions with EC = 38.02 μg/mlD’Angelo et al. (1997)
Atria contractilityIn vivo on guinea pigDose-dependent contractions with doses between 2.5 and 10 μg/mlD’Angelo et al. (1997)
Perfused mesenteric bed pressureIn vivo on ratDose-dependent increase of the perfusion pressure of mesenteric arteria with EC = 159.6 μgD’Angelo et al. (1997)
AnalgesiaIn vivo on miceA reduction of twist movements was observed in treated animals with 0.5 and 1.0 mg/kg oral dosesD’Angelo et al. (1997)
Anti-inflammatory of paw edemaIn vivo on ratDose-dependent reduction of swelling with 0.5 and 1.0 mg/kg oral dosesD’Angelo et al. (1997)
Pleural leukocyte countIn vivo on ratNo effect on exudate volume and leukocyte count with 0.5 and 1.0 mg/kg oral dosesD’Angelo et al. (1997)

Purified flavonoidsAntifungalIn vitro autobiography against Cladosporus cladosporioides and Cladosporus sphaerospernumAmount required to inhibit both C. cladosporioides and C. sphaerospernum:
(107) – 10.0 μg
(108) – 5.0 μg
(109) – 5.0 μg
(127) – 1.0 μg
(128) – 1.0 μg		Reigada et al. (2007)
Table options
Both leaf and root from P. marginatum collected in Yutaje, Venezuela were extracted with ethanol and the ethanolic extracts were tested for cytotoxicity against a collection of cancer cell lines ( Villasmil et al., 2006). The leaf extract was active against the human colon carcinoma line HT-29 with a GI50 of 55 μg/ml but inactive against the other cancer lines, whereas the root extract was found active against the human pancreatic carcinoma PANC-1 (GI50 65 μg/ml), and moderately active against colon HT-29 (GI50 298 μg/ml) and lung A549 (GI50 240 μg/ml) carcinoma cell lines (Villasmil et al., 2006). A murine in vivo experiment was performed and the leaf extract showed a marked antitumoral effect decreasing by half the size of the tumors compared to the negative control. Interestingly the root extract was inactive suggesting that potential antitumoral compounds are present in the leaf but absent in the root, and thus these compounds could be easily differentiated by HPLC analysis of the extracts. The methanolic extract obtained from P. marginatum leaf collected in Pernambuco, Brazil, was examined for antifungal activity against the phytopathogenic fungi Colletotrichum scovillei, which causes anthracnose on bell peppers ( Araújo et al., 2014). The methanolic extract displayed a dose-dependent inhibition of mycelial growth, achieving 50% inhibition with a concentration of 750 μg/ml. Although the methanolic extract was fractioned by column chromatography and a significantly active fraction was separated, the active antifungal compounds remains to be identified. Moreover the hydroalcoholic extract was screened for activity against Leishmania infantum amastigotes and showed an IC50 value of 25 μg/ml, while the positive control pentamidine showed an IC50 value of 2.43 μg/ml (Iwanaga et al., 2014).
P. marginatum has recurrently being employed in the traditional medicine as water decoction or infusion, and therefore D’Angelo and collaborators focused on the evaluation of in vivo pharmacological properties of the water extract ( D’Angelo et al., 1997). There were no toxic effects observed on Wistar rats or albino mice when the water extract was administered orally up to 2 g/kg. However when administered intraperitoneally, a dose higher than 0.1 g/kg caused piloerection, quietness, lacrimation, muscle relaxation and dyspnea. At a intraperitoneal dose of 1.0 g/kg all animals died within 15 min (D’Angelo et al., 1997). The water extract also had a significant effect on blood pressure. The mean blood pressure of the control rats was 95.5 mmHg, while the intravenous administration of 0.1–0.5 mg/kg doses of P. marginatum water extract, clearly induced a dose-dependent increase to values ranging from 121.1 to 141.5 mmHg (D’Angelo et al., 1997). The hypertensive effect was also observed after oral administration of the water extract at 1 mg/kg. A dose-dependent increase of the rat mesenteric arterial pressure was also detected. In addition both in the vas deferens duct of the rat and the atria in the heart of the guinea pig, the frequency of contractions increased in a dose-dependent manner with the administration of the water extract. The water extract when administered orally at 0.5 and 1.0 mg/kg displayed analgesia in the writhing test in mice and a significant reduction on the edema (inflammation) of the rat paw induced by carrageenan. There was no effect of the P. marginatum water extract on leukocyte counts in the pleurisy induced by carrageenin, suggesting that the anti-inflammatory effect is related to a vasoconstriction action of the water extract of P. marginatum, and not a specific anti-inflammatory action ( D’Angelo et al., 1997).
Among all the identified secondary metabolites present in P. marginatum, only five have been tested for a biological activity and these are three arylpropanoids 1-(3,4-methylenedioxyphenyl)-propan-1-ol (marginatumol, 107), 3,4-methylenedioxypropiophenone (108), 2-methoxy-4,5-methylenedioxypropiophenone (109), and the two flavanones 5,4′-dihydroxy-7-methoxyflavanone (127) and 5,7-dihydroxy-4′-methoxyflavanone (128). A bioautographic method was employed to evaluate their antifungal effect against Cladosporus cladosporioides and Cladosporus sphaerospernum and the most active compounds were the two flavanones (127) and (128), which inhibited both microorganisms with an amount as little as 1 μg (Reigada et al., 2007). The two propiophenones (108) and (109) inhibited the growth of the fungi with 5 μg, whereas the alcohol marginatumol, (107) required 10 μg to inhibit the fungi.

Conclusion

The species P. marginatum, widely used in the traditional medicine of the Caribbean region, primarily to treat gastrointestinal problems but also employed as analgesic, hemostatic and to cure insect bites, contains a variable mixture of terpenoids, phenylalkanoids, amides and flavonoids. Some of these compounds, including anethole, estragole, isoeugenol methyl ether, 3-farnesyl-4-hydroxybenzoic and 3-farnesyl-4-methoxybenzoic acids, marginatoside and vitexin, are not present in other Piper species, and are thus chemotaxonomic markers for P. marginatum. The high variability of chemotypes observed within P. marginatum sensu lato may reflect upon speciation events, or other factors which remains to be fully investigated. The distinctiveness of the chemical composition translate into a range of biological and pharmacological applications, which according to the reported potency, the larvicidal effect against A. aegypti, the antifungal activity against phytopathogenic fungi and the hemostatic and antitumoral potential, are worth highlighting for future research.

Ethical disclosures

Protection of human and animal subjects

The authors declare that the procedures followed were in accordance with the regulations of the relevant clinical research ethics committee and with those of the Code of Ethics of the World Medical Association (Declaration of Helsinki).

Confidentiality of data

The authors declare that they have followed the protocols of their work center on the publication of patient data.

Right to privacy and informed consent

The authors have obtained the written informed consent of the patients or subjects mentioned in the article. The corresponding author is in possession of this document.

Authors’ contributions

JB and JDG searched the literature. JB collected data in tables. JDG organized the information, prepared the figures and wrote the paper.

Conflicts of interest

The authors have no conflicts of interest to declare.

Acknowledgments

The authors acknowledge financial support from the Universidad del Norte (Agenda Interna 2014-0014) for the project “Búsqueda de nuevos agentes anti-tuberculosis en inflorescencias de Piper del Caribe Colombiano”. The authors are grateful to Dr. Maria Cristina Martinez-Habibe (Uninorte) for useful discussions.

References

    • Bernal et al., 2011
    • H.Y. Bernal, H.G. Martínez, G.F.Q. Sánchez
    • Pautas para el conocimiento, conservación y uso sostenible de las plantas medicinales nativas en Colombia: Estrategia nacional para la conservación de plantas, Bogotá, Colombia
    • (2011), p. 167
    • Braga, 1960
    • R. Braga
    • Plantas do Nordeste, especialmente do Ceará
    • Imprensa Oficial, Fortaleza, Brasil (1960) 540 pp.
    • Callejas, 1986
    • R. Callejas
    • Taxonomic revision of Piper subgenus Ottonia (Piperaceae)
    • (Ph.D. thesis) City University of New York, New York (1986) 150 pp.
    • Candolle, 1902
    • C.D. Candolle
    • Piperaceae. vol 3. Lipsiae, Borntraeger
    • Geneva Botanical Garden (1902) 124 pp.
    • Corrêa and Pena, 1984
    • M.P. Corrêa, L.d.A. Pena
    • Dicionário das plantas úteis do Brasil e das exóticas cultivadas
    • Ministério da Agricultura, Instituto Brasileiro de Desenvolvimento Florestal, Rio de Janeiro (1984) 747 pp.
    • Costa et al., 2010
    • J. Costa, P.F.d. Santos, S.A. Brito, F.F. Rodrigues, H.D. Coutinho, M.A. Botelho, S.G.d. Lima
    • Composição química e toxicidade de óleos essenciais de espécies de Piper frente a larvas de Aedes aegypti L. (Diptera: Culicidae)
    • Lat. Am. J. Pharm., 29 (2010), pp. 463–467
    • View Record in Scopus
       | 
      Citing articles (4)
    • Di Stasi and Hiruma-Lima, 2002
    • L.C. Di Stasi, C.A. Hiruma-Lima
    • Plantas medicinais na Amazônia e na Mata Atlântica
    • Editor UNESP, São Paulo (2002), pp. 125–126
    • dos Santos et al., 2011
    • M.R.A. dos Santos, R.A. Lima, C. de Freitas Fernandes, A.G. Silva, V.A. Facundo
    • Atividade fungicida do óleo essencial de Piper marginatum L. (Piperaceae) sobre Fusarium oxysporum (Schlecht) in vitro. Saude Pesq. 4
    • (2011)
    • Duarte et al., 2013
    • Y. Duarte, O. Pino, D. Infante, Y. Sánchez, M.d.C. Travieso, B. Martínez
    • Efecto in vitro de aceites esenciales sobre Alternaria solani Sorauer
    • Rev. Protec. Veg., 28 (2013), pp. 54–59
    • Duke and Vasquez, 1994
    • J.A. Duke, R. Vasquez
    • Amazonian Ethnobotanical Dictionary
    • Taylor & Francis, CRC Press, Boca Raton (1994), pp. 138–139
    • García, 1974
    • H. García
    • Flora medicinal de Colombia: botánica médica
    • (Segunda edición ed.)Tercer Mundo Editores (1974)
    • Iwanaga et al., 2014
    • C.C. Iwanaga, B. F.L., C. J.A., D.A.G. Cortez
    • Antileishmnaial evaluation activity of crude hydroalcoholic extract of Piper marginatum Jacq.
    • VI Simpósio Internacional de Pós-Graduacao e Pesquisa, Sao Paulo, Brasil (2014), p. 9
    • Jacquin, 1786
    • N.J. Jacquin
    • Icones plantarum rariorum. Lugduni Batavorum, Argentorati Wappler, White et filium, Luchtmans and König, London
    • (1786), p. 2
    • Jaramillo-Colorado et al., 2015
    • B. Jaramillo-Colorado, J. Julio-Torres, E. Duarte-Restrepo, A. Gonzalez-Coloma, L.F. Julio-Torres
    • Estudio comparativo de la composición volátil y las actividades biológicas del aceite esencial de Piper marginatum Jacq. Colombiano
    • Bol. Latinoam. Caribe, 14 (2015), pp. 343–354
    • View Record in Scopus
    • Johnson, 1998
    • T. Johnson
    • CRC Ethnobotany Desk Reference
    • Taylor & Francis, CRC Press, Boca Raton (1998), p. 631
    • Lans and Georges, 2011
    • C. Lans, K. Georges
    • Women's knowledge of herbs used in reproduction in Trinidad and Tobago
    • M. Rai, D. Acharya, J.L. Rios (Eds.), Ethnomedicinal Plants: Revitalizing of Traditional Knowledge of Herbs, CRC Press (2011), pp. 115–134
    • Full Text via CrossRef
    • Miller et al., 1983
    • E.C. Miller, A.B. Swanson, D.H. Phillips, T.L. Fletcher, A. Liem, J.A. Miller
    • Structure-activity studies of the carcinogenicities in the mouse and rat of some naturally occurring and synthetic alkenylbenzene derivatives related to safrole and estragole
    • Cancer Res., 43 (1983), pp. 1124–1134
    • View Record in Scopus
       | 
      Citing articles (248)
    • Oliveira Santos and Oliveira Chaves, 2000
    • B.V.d. Oliveira Santos, M.C.d. Oliveira Chaves
    • Assignments of 1H and 13C resonante signals in 2-methoxy-4,5-methylenedioxypropiophenone with the assistance of 1D and 2D NMR experiments
    • Acta Farm. Bonaer., 19 (2000), pp. 45–48
    • Ortega-Galvan, 2014
    • J. Ortega-Galvan
    • Mi familia usa Piper marginatum para curar la mordedura de serpiente, Megua, Baranoa, Atlántico, Colombia
    • (2014) (Personal communication)
    • Santana et al., 2015
    • H. Santana, F. Trindade, S. RG, A. Silva, J. Militao, V. Facundo
    • Essential oils of leaves of Piper species display larvicidal activity against the dengue vector, Aedes aegypti (Diptera: Culicidae)
    • Rev. Bras. Plantas Med., 17 (2015), pp. 105–111
    • View Record in Scopus
       | 
      Citing articles (2)
    • Sequeda-Castañeda et al., 2015
    • L. Sequeda-Castañeda, C. Celis, S. Gutiérrez, F. Gamboa
    • Piper marginatum Jacq. (Piperaceae): phytochemical: therapeutic, botanical insecticidal and phytosanitary uses
    • Pharmacol. Online, 3 (2015), pp. 136–145
    • View Record in Scopus
    • Trelease and Yuncker, 1950
    • W. Trelease, T.G. Yuncker
    • The Piperaceae of Northern South America, vol. 1, University of Illinois Press, Urbana (1950), pp. 73–78
    • van den Berg, 1982
    • M.E. van den Berg
    • Plantas medicinais na Amazônia: contribuição ao seu conhecimento sistemático
    • Conselho Nacional de Desenvolvimento Científico e Tecnológico, Programa Trópico Umido/Museo Paraense Emílio Goeldi, Belém (1982) 223 pp.
    • Villasmil et al., 2006
    • J. Villasmil, M.J. Abad, M. Arsenak, A. Fernández, M.-C. Ruiz, B. Williams, F. Michelangeli, F. Herrera, P. Taylor
    • Cytotoxic and antitumor activities of Venezuelan plant extracts in vitro and in vivo
    • Pharmacol. Online, 3 (2006), pp. 808–816
    • Yukes and Balick, 2011
    • J.E. Yukes, M.J. Balick
    • Dominican Medicinal Plants: A Guide for Health Care Providers
    • (2nd ed.)The New York Botanical Garden, New York (2011), p. 25
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