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Antimycobacterial evaluation of Peruvian plants.

Summary

We present the results of an antimycobacterial screening of 270 Peruvian plant samples representing 216 species from 171 genera in 63 families. Dichloromethane extracts were tested at a concentration of 50 [micro]g/ml for inhibition of Mycobacterium tuberculosis in radiometric culture. Slightly more than half of the samples tested showed inhibition of M. tuberculosis at this concentration.

Key words: Antimycobacterial agents, plant extracts, Mycobacterium tuberculosis, Pharmacognosy, Angiosperms

* Introduction

Among adults, tuberculosis (TB) is now the worldwide leading cause of death. The etiologic agent responsible for this infectious disease, Mycobacterium tuberculosis, causes more than 25% of avoidable adult deaths in developing countries (Pio and Chaulet, 1998). Acquired drug resistance (Kuaban et al. 2000) and AIDS-related opportunistic TB infection (Ashley et al. 2000) exacerbate both the scope and scale of the current global TB epidemic (Newton et al. 2000). If current levels of TB control are not strengthened, estimates are that nearly one billion people will be infected with TB in the next 30 years (WHO, 2000).

The research presented here is a response to the clear and urgent need to find new anti-tubercular agents. Although a number of plant extracts have been shown to inhibit the growth of Mycobacteria in a variety of in vitro assay systems (Azarowicz et al. 1952; Cantrell et al. 1998; Fitzpatrick, 1954; Frisbey et al. 1954; Gottshall et al. 1949; Grange and Davey, 1990; Lucas et al. 1951; McChesney et al. 1985; Newton et al. 2000; Wang, 1950), none has so far resulted in the development of any new, clinically useful, antitubercular agents.

Our objective was to provide candidates for further antimycobacterial evaluation, with the ultimate goal of identifying preparations with potential efficacy in the treatment of TB infection. Toward this end, dichloromethane extracts of 216 Peruvian plant species were screened for antimycobacterial activity using the BACTEC 460 (Becton Dickinson Diagnostic Instrument Systems, Sparks MD) radiometric assay. Using these bioactivity data, extracts with strong inhibitory activity against M. tuberculosis will be prioritized for further analysis.

* Materials and Methods

Plant Material

Specimens of each plant were pressed and dried in the field following standard botanical procedures (Alexiades, 1996). For every plant reported here, there has been a voucher specimen deposited at the John G. Searle herbarium of the Field Museum of Natural History in Chicago, Illinois, U.S.A. Specimens were identified by one of the authors (JGG) and a number of specialists listed in the acknowledgements.

Extraction

All plant materials that were used in this experiment were collected fresh, then air-dried in situ. Any sample that showed signs of mold or spoilage was discarded. A small amount of the dried plant material was milled to a coarse powder, and ten gram portions of the dried, milled plant material were weighed out and placed into individual 400 ml glass extraction flasks. 150 ml of dichloromethane was added to each flask, and the flasks were stoppered and placed in an unlighted fume hood for 48 hours. After 48 hours, the flasks were decanted and filtered through medium filter paper, then evaporated in vacuo, yielding crude dichloromethane extracts that were used to prepare DMSO stock solutions for the antimycobacterial analyses.

Antimycobacterial activity

In vitro radiometric assays were performed using a BACTEC 460 (Becton Dickinson Diagnostic Instrument Systems, Sparks MD) detector. This semi-automated system monitors the growth of Mycobacterium tuberculosis in BACTEC 12B vials containing Middlebrook 7H 12 broth medium. The broth medium contains a [sup.14]C-labelled substrate that is utilized by the mycobacteria as it grows, with [sup.14]C[O.sub.2] being produced as a metabolic by-product. The amount of [sup.14]C[O.sub.2] detected reflects the rate and amount of growth occurring in the vial, and is expressed as a Growth Index (GI).

For this experiment, a susceptible strain (ATCC 27294) of M. tuberculosis was utilized. Crude dichloromethane extracts of plant material were reconstituted to a concentration of 1 mg per ml of 100% dimethylsulfoxide (DMSO), filtered, and injected into the Bactec 12B vials to give a final concentration of 50 ug of plant extract per one ml of broth culture. The final volume of DMSO per vial is 5%, which is sufficiently dilute so as not to affect the growth of the organism. To verify this, blank controls, containing the same volume of DMSO as the sample vials, were run with each experiment. Positive controls, containing the antimycobacterial drugs rifampin at a concentration of 2 [micro]g/ml, and ethambutol at a concentration of 7.5 [micro]g/ml, were included as well. All samples, blanks, and positive controls were run in duplicate. Following the introduction of the samples, a uniform suspension of M. tuberculosis was then introduced into each BACTEC 12B vial. The GI of the sample vials were compared with those of the control vials, and growth inhibitions calculated.

* Results

All extracts that inhibited the growth of M. tuberculosis by 50% or more are included in Table 1. Those extracts that had less than 50% inhibition of M. tuberculosis at 50 ug/ml are listed in Table 2. Several extracts with strong growth inhibition of M. tuberculosis were further analyzed to determine the minimum inhibitory concentration (MIC). Results of this experiment are listed in Table 3.

* Discussion

We have identified a number of plant extracts with substantial inhibitory effect, in vitro, on the growth of M. tuberculosis. This study represents the first phase of ongoing research to identify new agents that are safe and effective for the treatment of TB. Experiments are currently underway to further evaluate the antimyco-bacterial potential of several of the most active of these extracts.

Interestingly, only two of the six plant species for which MIC were determined (Table 3) had any previous phytochemical analysis. Neither the acetylenes isolated from the bark of Heisteria acuminata (Kraus et al. 1998) nor the isoquinoline alkaloid, steroid and lignans isolated from the stem bark of Zanthoxylum sprucei (Binutu et al. 2000) are reported to have any significant antimycobacterial activity. The triterpene lupeol, as well as the flavanone sesamin, both found in Z. sprucei, are reported to have strong in vitro activity against Mycobacterium tuberculosis (Gangadharam et al. 1953; Wachter et al. 1999), and the presence of these compounds may account for the antimycobacterial activity encountered in this species.

Two Senna species, Senna silvestris (Veil.) Irwin & Barneby var. silvestris and Senna obliqua (G. Don) Irwin & Barneby, proved to be some of the most active of the plant extracts screened in this investigation. In vitro antimycobacterial activity has not been reported previously in the genus Senna. Prior to this study, neither S. silvestris nor S. obliqua were investigated, either in terms of their biological activity or their phytochemical makeup, although one may assume that since quinoid compounds are such a notable constituent for other species in the genus (Hegnauer, 2001), they probably occur in S. obliqua and S. silvestris as well. Significant antimicrobial activities have been reported for this compound class, (Jaki et al. 2000; Kazmi et al. 1994; Rath et al. 1995; Schinazi et al. 1990; Tagahara et al. 1992), including antimycobacterial activity (Gangadharam, 1990; Kanokmedhakul, 2002).

Prioritization of leads for further investigation will be based on several general criteria, including: antimycobacterial activity, lack of phytochemical investigation, and access to sufficient material for further analysis. Based on the first criterion, all those extracts with greater than 90% inhibition of M. tuberculosis at 50 [micro]g/ml provide a pool of possible candidates for further investigation. Based on the second criterion, Zanthoxylum sprucei, because it contains previously-identified antimycobacterial compounds, will probably not be considered strongly for further investigation. Mechanisms for acquisition of sufficient plant materials for further analysis are being explored.

Various collection approaches and selection criteria have been used to prioritize plants for pharmaceutical investigation. The biodiversity-based approach (Soejarto, 1996) used in the collection of the plant samples in this experiment provided a number of strongly active leads, in this case about three percent of the total sampie, screening at crude extract concentrations of 50 [micro]g/ml. This hit-rate could undoubtedly have been increased if we had used higher concentrations of extract for the initial antimycobacterial evaluations. Several other large-scale antimycobacterial screening efforts have tested at concentrations of 100 [micro]g/ml, 1 mg/ml, or even 20 mg/ml (McChesney and Adams, 1985). We felt that the use of 50 [micro]g/ml for initial screening was appropriate, as it should identify the most potent agents and eliminate further testing for extracts with only minimal antimycobacterial activity.

In this experiment dichloromethane was chosen as an extraction solvent. This choice was made in the interest of saving time, both because the solvent has a relatively low boiling point and evaporation time is greatly reduced compared to a more polar solvent such as methanol or water, but also because it reduces the number of manipulations needed in the extraction process. The relative selectivity of this non-polar solvent allows the preclusion of a time-consuming step of partitioning between chloroform and water to remove polar components and other unwanted trivial compounds.

Plants from the Peruvian Amazon appear to be a particularly rich source of potentially novel antitubercular compounds. The combination of significant antimycobacterial activity encountered in extracts obtained from this region (Franzblau, 2001), along with the general lack of phytochemical investigation for many of these species, represents a unique collaborative research opportunity for Peruvian institutions and investigators, and provides further incentive for biodiversity conservation at local and regional levels.
Table 1. Plant extracts with greater than 50% inhibition of
Mycobacterium tuberculosis at 50 [micro] g/ml.

Family
species plant part % inhibition

Annonaceae
Annona hypoglauca Mart. bark 51

Apocynaceae
Aspidosperma parvifolium A. DC. root 52
Lacmellea peruviana
 (van Heurck & Muell. Arg.) Markgr. stem 50

Aristolochiaceae
Aristolochia cauliflora Ule stem 81

Boraginaceae
Cordia nodosa Lam. bark 80

Chrysobalanaceae
Couepia ulei Pilger bark 80

Compositae
Ambrosia peruviana Willd. leaf and flower 58
Ambrosia peruviana Willd stem 81
Egletes viscosa (L.) Lessing whole plant 54
Trichospira verticillata (L) Blake whole plant 56
Vernonia patens H.B.K. root 61
Zexmenia wedeloides Klatt whole plant 53

Connaraceae
Connarus elsae Forero bark 71

Convolvulaceae
Iseia luxurians (Moricand) O'Donell whole plant 70

Cyperaceae
Scleria melaleuca Rchb. whole plant 67
 ex Schtdl. & Cham.

Dilleniaceae
Tetracera parviflora (Rusby) Sleumer stem 75

Euphorbiaceae
Chamaesyce hirta (L.) Millspaugh whole plant 55

Flacourtiaceae
Banara nitida Spruce ex Benth. stem 56
Laetia corymbosa Spruce ex Benth. stem 51

Guttiferae
Clusia rosea L. stem 63

Lauraceae
Nectandra hihua (R. & P.) Rowher bark 98

Leguminosae
Andira sp. leaf 67
cf. Cynometra bauhiniifolia Benth. bark 88
Dalbergia sp. root 63
Erythrina fusca Loureiro bark 63
Erythrina fusca Loureiro root 54
Indigofera truxillensis H.B.K. whole plant 53
Senna silvestris (Vell.)
 I.& B. var. silvestris bark 94
Senna obliqua (G.Don) I.& B. stem and fruit 90

Loranthaceae
Phoradendron obtusissimum
 (Miq.) Eichl. stem 69
Phthrusa aff. stelis (L.) Kuijt leaf 86

Malphigiaceae
Tetrapterys discolor (G Meyer) DC. stem 89

Meliaceae
Guaria guidonia (L.) Sleumer leaf 74

Menispermaceae
Abuta grandifolia (Mart.) Sandwith leaf 57

Myrsinaceae
Stylogine cauliflora
 (Miq. & C. Mart.) Mez stem 68

Myrtaceae
Myrcia dichasialis McVaugh bark 50

Olacaceae
Heisteria acuminata (Humb.& Bonpl.)
 Engler stem 92

Piperaceae
Peperomia alata R.& P. whole plant 60
Piper enlongatum M. Vahl stem 84
Piper sp. stem 67
Piper sp. stem and leaf 93

Rubiaceae
Chomelia malaneoides Muell. Arg. stem 55
Rudgea cf. loretensis Standl. stem 59
Sommera sabiceoides Schum. stem 96

Rutaceae
Dictyoloma peruvianum Planch. leaf 56
Dictyoloma peruvianum Planch. stem 72
Monnieria trifolia L. whole plant 62
Zanthoxylum sprucei Engler bark 95

Sapindaceae
Cupania sp. bark 67
Paullinia hystrix Radlk. stem 67

Solanaceae
Cyphomandra oblongifolia Bohs stem 54

Zingiberaceae
Dimerocostus sp. leaf 56

Table 2. Plant extracts with less than 50% inhibition of
Mycobacterium tuberculosis at 50 [micro]g/ml.

Acanthaceae: Sanchezia sprucei Lindau (stem)
Amaranthaceae: Chamissoa altissima (Jacq.) H.B.K. var. altissima
 (stem), Iresine diffusa H.B.K. (stem)
Anacardiaceae: Spondias mombin L. (bark)
Annonaceae: Duguetia odorata (Diels) J.F Macbr. (bark), Rollinia
 cuspidata C. Mart. (bark)
Apocynaceae: Aspidosperma parvifolium A. DC. (bark; leaf),
 Forsteronia amblybasis Blake (stem), Rauvolfia pentaphylla
 Huber ex Ducke (stem), Rhabdadenia macrostoma
 (Benth.) Muell. Arg. (whole plant) Tabernaemontana
 heterophylla Vahl. (bark), Tabernaemontana
 siphilitica (L. f.) Leeuw. (root),
 Tabernaemontana sananho R&P (stem)
Araceae: Dracontium loretense Krause (corm)
Bignoniaceae: Anaemopegma chrysoleucum (H.B.K.) Sandwith (stem),
 Anaemopegma paraense Bureau & Schumann (stem), Arrabidaea
 cinnamomea (A. DC.) Sandw. (stem), Callichlamys latifolia
 (Richard) Schumann (stem), Crescentia amazonica Ducke (stem),
 Cydista lilacina A. Gentry (stem), Lundia corymbifera (Vahl)
 Sandw. (stem), Martinella obovata (H.B.K.) Bureau & Schum.
 (stem), Tanacium nocternum (Barb. Rodr.) Bureau & Schum. (stem)
Bombacaceae: Pachira insignis (Swartz) Swartz ex Savigny (stem)
Boraginaceae: Cordia collococca L. (bark), Heliotropium indicum L.
 (whole plant), Tournefortia setacea Killip (stem)
Capparidaceae: Capparis sp. (stem), Crateva tapia L. (bark)
Cecropiaceae: Coussapoa sp. (stem)
Chrysobalanaceae: Couepia ulei Pilger (stem)
Combretaceae: Buchenavia grandis Ducke (stem), Combretum assimile
 Eichl. (stem), Combretum laxum Jacquin (stem),
 Thiloa paraguarensis Eichler (stem)
Compositae: Vernonia canescens H. B. K. (stem & leaf), Vernonia
 patens H.B.K. (stem)
Connaraceae: Rourea amazonica (Baker) Radlk. (stem)
Cucurbitaceae: Cayaponia sp. (stem & root), Gurania spinulosa (Poepp.
 & Endl.) Cogn. (stem), Luffa operculata (L.) Cogniaux (whole plant)
Cyperaceae: Diplasia karatifolia L. C. Rich. (leaf; root)
Elaeocarpaceae: Sloanea sp. (stem)
Euphorbiaceae: Alchornea brevistyla Pax & Hoffmann (bark), Croton
 cuneatus Klotzsch (bark), Croton sp. (root), Euphorbia sp.
 (whole plant), Euphorbia heterophylla L. (whole
 plant), Mabea nitida Spruce ex Benth. (bark),
 Margaritaria nobilis L.f. (bark), Phyllanthus sp. (stem), Sapium
 marmierii Huber (stem),
Flacourtiaceae: Banara arguta Briquet (bark), Casearia sp. (bark;
 stem), Laetia sp. (stem), Lindackeria maynensis Poepp. (stem)
Gnetaceae: Gnetum nodiflorum Brongniart (stem)
Guttiferae: Garcinia madruno (Kunth) Hammel (bark), Vismia amazonica
 Ewan (stem), Vismia macrophylla Kunth (stem)
Hippocrataceae: Hippocratea volubilis L. (stem)
Lamiaceae: Leonurus sibiricus L. (root; stem & leaf)
Lauraceae: Cinnamomum triplinerve (R. & P.) Kostermans (stem),
 Nectandra sp. (bark; root), Nectandra cuneato-cordata Mez (stem),
 Ocotea cernua s.l. (Nees) Mez (bark; root),
 Pleurotherium parviflorum Ducke (bark)
Leguminosae: Acacia polyphylla DC. (bark), Acacia sp. (stem),
 Acacia farnesiana L. (stem), Albizia subimidiata (Splitb.)
 Barneby & Grimes (bark), Andira inermis (W.Wright) H.B.K.
 ex DC. (bark), Andira sp. (fruit), Bauhinia sp. (bark; root;
 stem), Browneopsis ucayalina Huber (root), Calliandra
 angustifolia Spruce ex Benth. (stem), Cassia sp.
 (stem), Crotalaria retusa L. (leaf & stem; root),
 Dalbergia sp. (stem); Dioclea sp. (stem), Entada
 polyphylla DC. (stem), Inga sp. (bark, fruit),
 Lonchocarpus densiflorus Benth. (stem), Lonchocarpus
 sp. (bark; stem), Machaerium aristulatum (Spruce ex Benth.)
 Ducke (stem), Machaerium sp. (stem), Mimosa myriadenia
 (Benth.) var. punctulata (Benth.) Barneby (stem),
 Samanea tubulosa (Benth.) Barneby & Grimes (fruit, stem), Senna
 silvestris (Vell.) I.& B. var. silvestris (stem),
 Swartzia simplex (Sw.) Spreng var. ochnacea (DC.) Cowan (bark),
 Zygia c.f. coccinea (G. Don) Rico, s. 1. (bark),
 Zygia vasquezii Rico (stem)
Loganiaceae: Strychnos jobertiana Baillon (fruit, stem), Strychnos
 tarapotensis Sprague & Sandw. (stem)
Loranthaceae: Phoradendron obtusissimum (Miq.) Eichl. (whole plant),
 Phoradendron piperoides (HBK) Trel. (whole plant),
 Phoradendron sp. (leaf; stem), Phthrusa aft. Stelis
 (L.) Kuijt (stem)
Malphigiaceae: Bunchosia argentea (Jacq.) DC. (stem), Byrsonima
 japurensis Adr. Juss. (bark) Stigmaphyllon florosum
 C. Anderson (stem)
Malvaceae: Hibiscus furcellatus Desrousseaux (stem), Sida acuta
 Burman f. (whole plant), Sida glomerata Cavanilles (whole plant),
 Wissadula excelsior (Cavanilles) C. Presl. (stem)
Melastomataceae: Miconia c.f. splendens (Swartz) Griseb. (stem),
 Tococa sp. (stem)
Meliaceae: Guaria guidonia (L.) Sleumer (bark), Trichilia rubra C.
 DC. (bark), Trichilia singularis C.DC. (stem)
Menispermaceae: Abuta grandifolia (Mart.) Sandwith (root; stem),
 Chondrodendron tomentosum R. & P. (stem), Curarea sp. (stem),
 Orthomene schomburgkii (Miers) Krukoff & Barneby (root; stem),
Monimiaceae: Siparuna poepigii (Tulasne) A. DC. (stem)
Moraceae: Batocarpus amazonicus (Ducke) Fosberg (bark), Ficus maxima
 Miller (bark), Trophis racemosa (L) Urban subsp, meridionalis
 (Bureau) W.Burger (stem)
Myrtaceae: Campomanesia lineatifolia R. & P. (stem), Eugenia egensis
 DC. (stem), Eugenia patens Poiret (stem),
 Psidium acutangulum DC. (bark; stem)
Nyctaginaceae: Neea divaricata Poepp. & Endl. (stem)
Ochnaceae: Ouratea pendula Engler (stem)
Palmae: Bactris brongniartii Mart. (bark), Oenocarpus batahua C.
 Mart. (pedicel)
Passifloraceae: Passiflora auriculata H.B.K. (leaf; stem),
 Passiflora coccinea Aubl. (root; stem), Passiflora sp. (stem)
Piperaceae: Piper sp. (root)
Polygonaceae: Coccoloba acuminata H. B. K. (root; stem), Coccoloba
 densifrons C. Mart. ex Meissner (stem), Triplaris americana L. (bark)
Rhamnaceae: Gouania lupuloides (L.) Urb. (stem)
Rubiaceae: Calycophyllum spruceanum (Benth.) Hook.f. ex Schumann
 (bark), Guettarda sp. (stem), Palicourea croceoides Ham. (stem),
 Psychotria marginata Sw. (stem), Psychotria mathewsii Standl. (stem)
Rutaceae: Zanthoxylum sprucei Engler (leaf)
Sapindaceae: Cupania cinera Poepp. (bark; root), Cupania sp. (fruit;
 leaf; root), Talisia sp. (bark; stem)
Sapotaceae: Pouteria reticulata (Engler) Eyma (bark), Sarcaulus
 brasiliensis (A. DC.) Eyma (bark)
Simaroubaceae: Picramnea latifolia Tulasne (leaf, root)
Smilacaceae: Smilaxfebrifuga Kunth, (leaf, root; stem)
Solanaceae: Brunfelsia grandiflora D. Don (leaf, root), Cestrum
 reflexum Sendtner (stem), Solanum grandiflorum R. & P.
 (root; stem), Solanum sessile R. & P. (stem)
Sterculiaceae: Guazuma crinita Mart. (bark), Guazuma ulmifolia Lam.
 (bark, stem),
Tiliaceae: Apeiba tibourbou Aubl. (bark)
Trigoniaceae: Trigonia sericea H.B.K. (stem)
Ulmaceae: Celtis iguanaea (Jacquin) Sargent (stem)
Verbenaceae: Aegiphila chrysantha Hayek (stem), Lippia alba (Mill.)
 N.E. Br. (whole plant), Lippia betulaefolia H.B.K. (whole plant),
 Priva lappulaceae (L.) Persoon (aerial parts; root),
 Vitex cymosa Bert. ex Sprengel (bark)
Violaceae: Corynostylis arborea (L.) S.F.Blake (stem), Leonia
 racemosa Mart. (bark), Leonia glycicarpa R. & P. (stem)
Zingiberaceae: Costus sp. (rhizome), Renealmia sp. (rhizome & leaf)

Table 3. Minimum Inhibitory Concentrations
(MIC) of selected plant extracts.

Family species part MIC

Leguminosae Senna silvestris (Vell.) bark <6.25 [micro]g/ml
 I. & B. var. silvestris
Rubiaceae Sommera sabiceoides stem <6.25 [micro]g/ml
 Schum.
Lauraceae Nectandra hihua bark 10 [micro]g/ml
 (R. & P.) Rowher
Leguminosae Senna obliqua fruit & 10 [micro]g/ml
 (G. Don) I. & B. stem
Olacaceae Heisteria accuminata stem 10 [micro]g/ml
 (Numb. & Bonpl.)
 Engler
Rutaceae Zanthoxylum bark 15 [micro]g/ml
 sprucei Engler


Acknowledgements

We would like to thank the Instituto Nacional de Medicina Tradicional (INMETRA), Ministry of Health, Lima, Peru, for their generous assistance, without which this project would not have been possible. Thanks to the staff at the herbarium of the Field Museum, Chicago, especially Robin Foster, Mike Dillon, Jack Regalado, Tyana Wachter and Chris Niezgoda. Thanks as well to the following botanists who assisted in the taxonomic determinations: Rupert Barneby, Charlotte Taylor, Mike Nee, Dieter Wasshausen, Tom Croat, Paul Maas, Lucia Lohmann, Ricardo Callejas, Blanca Leon, Job Kuijt, Terry Pennington, Nancy Hensold, Henk van der Werff, Gerrit Davidse, and Bruce Holst.

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* Address

J. G. Graham, Program for Collaborative Research in the Pharmaceutical Sciences, College of Pharmacy, The University of Illinois at Chicago, 833 South Wood Street, Chicago Illinois, 60612

Tel.: ++1-312-996-7254; Fax: ++1-312-413-5894; e-mail: jgraha1@uic.edu

J. G. Graham (1), S. L. Pendland (2), J. L. Prause (2), L. H. Danzinger (2), J. Schunke Vigo (3), F. Cabieses (3), and N. R. Farnsworth (1)

(1) Program for Collaborative Research in the Pharmaceutical Sciences, College of Pharmacy, The University of Illinois at Chicago, Chicago Illinois

(2) Microbiology Research Laboratory, Department of Pharmacy Practice, College of Pharmacy, The University of Illinois at Chicago, Chicago Illinois

(3) National Institute of Traditional Medicine (INMETRA), Peruvian Ministry of Health, Lima, Peru
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Author:Graham, J.G.; Pendland, S.L.; Prause, J.L.; Danzinger, L.H.; Vigo, J. Schunke; Cabieses, F.; Farnswo
Publication:Phytomedicine: International Journal of Phytotherapy & Phytopharmacology
Geographic Code:3PERU
Date:Jul 1, 2003
Words:3799
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