Journal of Ethnopharmacology 121 (2009) 1–13

Contents lists available at ScienceDirect

Journal of Ethnopharmacology
journal homepage: www.elsevier.com/locate/jethpharm

Review

Red Lapacho (Tabebuia impetiginosa)—A global

ethnopharmacological commodity?
J. Rubén Gómez Castellanos 1 , José M. Prieto, Michael Heinrich ∗
Centre for Pharmacognosy and Phytotherapy, The School of Pharmacy, University of London,
29/39 Brunswick Square, London WC1N 1AX, UK

a r t i c l e i n f o a b s t r a c t

Article history: Red Lapacho (Tabebuia impetiginosa, syn. Tabebuia avellanedae), a canopy tree indigenous to the Amazonian
Received 23 April 2008 rainforest and other parts of South America, has been acclaimed to be one of the “miraculous” cures for
Received in revised form 13 August 2008 cancer and tumours. For the first time, during the 1960s, it attracted considerable attention in Brazil
Accepted 5 October 2008
and Argentina as a ‘wonder drug’. Traditionally, the botanical drug is widely used in local and traditional
Available online 1 November 2008
phytomedicine, usually ingested as a decoction prepared from the inner bark of the tree to treat numerous
conditions like bacterial and fungal infections, fever, syphilis, malaria, trypanosomiasis, as well as stomach
Keywords:
and bladder disorders.
Red Lapacho (Pau d’arco)
Anti-cancer agents
As early as 1873, biomedical uses of Red Lapacho (“Pau D’Arco”) were reported. In 1967 after reports in
Drug history the Brazilian press it came back to the light of clinicians (and the public in general). The news magazine
Tabebuia impetiginosa O’Cruzeiro started reporting “miraculous” cures in cancer patients in a hospital. Natural sciences interest
in the plant also began in the 1960s when the United States National Cancer Institute (NCI) systematically
began researching plant extracts all over the world looking for active compounds against cancer and
looked at Tabebuia impetiginosa in considerable detail.
Two main bioactive components have been isolated from Tabebuia impetiginosa: lapachol and ␤-
lapachone. ␤-Lapachone is considered to be the main anti-tumour compound, and pro-apoptotic effects
were observed in vitro. Some mechanistic studies on this compound’s molecular effects have been con-
ducted. The other main constituents isolated from Red Lapacho are also reviewed briefly.
The drug appears to be generally safe and one of the most important interactions of Tabebuia impetiginosa
has been associated with interference in the biological cycle of Vitamin K in the body.
The botanical (drug) material available on the international markets seems to be of varying quality
and composition, making a specific assessment of the products’ therapeutic claims problematic. This also
highlights the need for appropriate analytical techniques, which are reviewed as well.
The bioscientific evidence for products derived from Tabebuia impetiginosa is insufficient and one of
the core challenges of future research will be – based on the recognition of the drug’s widespread use
– to establish appropriate quality control procedures. Further research into the clinical effects and the
pharmacology of chemically characterized extracts is also warranted.
© 2008 Elsevier Ireland Ltd. All rights reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
2. Ethnobotanical uses of Red Lapacho . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
3. Early pharmacological research on the drug . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
4. Approved uses of T. impetigionosa . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3

Abbreviations: DS, dietary supplement; DSHEA, Dietary Supplement Health and Education Act.
∗ Corresponding author. Tel.: +44 20 7753 5844; fax: +44 20 7753 5909.
E-mail address: michael.heinrich@pharmacy.ac.uk (M. Heinrich).
1
Current address: Escuela de Ciencias Químicas, Universidad La Salle, Benjamín
Franklin 47, Hipódromo Condesa, México, DF 06140, Mexico.

0378-8741/$ – see front matter © 2008 Elsevier Ireland Ltd. All rights reserved.
doi:10.1016/j.jep.2008.10.004
2 J.R. Gómez Castellanos et al. / Journal of Ethnopharmacology 121 (2009) 1–13

5. Constituents of Tabebuia impetiginosa and Red Lapacho tea . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4

5.1. Lapachol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
5.2. ␤-Lapachone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
5.3. Miscellaneous compounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
6. Anti-cancer molecular pharmacology of Red Lapacho . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
6.1. The quinone structure in chemotherapeutics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
6.2. Molecular pharmacology of lapachol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
6.3. Anticancer molecular pharmacology of ␤-lapachone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
7. Other pharmacological properties of Tabebuia impetiginosa . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
7.1. Antibacterial activity of Tabebuia impetiginosa . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
7.2. Inhibitory effects of Tabebuia impetiginosa on platelet aggregation and vascular smooth muscle cell (VSMC) proliferation . . . . . . . . . . . . . . . . 9
7.3. Tabebuia impetiginosa compounds as antipsoriatic agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
8. Metabolism, pharmacokinetics and clinical trials of the components of Red Lapacho . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
8.1. Vitamin K metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
8.2. Clinical trials and metabolism of lapachol and ␤-lapachone in mammals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
9. Qualitative and quantitative analysis of Tabebuia impetiginosa . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
9.1. Quality control issues of the plant material obtained from Tabebuia impetiginosa . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
9.2. HPLC analysis of the components of Tabebuia impetiginosa . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
10. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11

1. Introduction fevers, trypanosomiasis, fungal and bacterial infections and stom-

ach disorders (Gonçalves et al., 1980; Suffnes and Douros, 1980;
Red Lapacho tea refers to decoctions prepared from the inner Anesisni and Pérez, 1993; Guiraud et al., 1994; Tyler, 1999; Mans
bark and heartwood of the tree Tabebuia impetiginosa (Mart. ex DC) et al., 2000; Portillo et al., 2001; Dos Santos et al., 2004; Cragg
Standl (synonym. Tabebuia avellanedae Lor. ex Griseb, Tabebuia ser- and Newman, 2005). At the arrival of the Spanish and Portuguese
ratifolia (Vahl) Nichols, Handroanthus impetiginosus (Mart. ex DC.) conquerors in South America, they described the use of Tabebuia
Mattos, Tecoma impetiginosa Mart. ex DC.; family Bignoniaceae), impetiginosa in great quantities by the Guarani, the Tupi-Nambo,
peeled and rasped one to two times a year, and offered as loose and, in the High Andes, the Callawaya, the Quechua, the Aymara
tea or in tea bags (Schultes and Raffauf, 1990; García Barriga, 1992; and other tribes (Mowrey, 2001; Taylor, 2005).
Luebeck, 1999; Taylor, 2005). From an ethnopharmacological per- As early as 1873, a physician, Dr. Joaquin Almeida Pinto had
spective this botanical drug is of interest for two reasons. One the already described many of the therapeutic properties of Red
one hand, in South America there is a long tradition of local and Lapacho: “Pau D’Arco: Medicinal Properties: prescribed as a fever-
traditional use but may be even more importantly, the drug is now reducer; the bark is used against ulcers; also used for venereal
often acclaimed to be a wonder drug for curing most notably ‘can- and rheumatic disorders and especially useful for skin disorders,
cer’ (Heinrich, 1998). Therefore, this botanical drug is an interesting especially eczema, herpes and the mange” (Mowrey, 2001).
example of the globalisation of local knowledge (Dixon et al., 1999; Red lapacho came back to the light of clinicians in March 1967,
Pardo de Santayana et al., 2005; Heinrich and Prieto, 2008) or of the after the Brazilian news magazine O’Cruzeiro (March 18 and March
commodification of the sacred (Posey, 2002). This merits a detailed 25, 1967) started reporting “miraculous” cures in cancer patients in
review of the drug’s potential health benefits and risks including the Hospital of Clinics in Sāo Paulo and in the Municipal Hospital of
a detailed assessment of the drug’s ethnopharmacological (chemi- Santo André (de Montmorency, 1981; Jones, 1995) The O’Cruzeiro
cal, pharmacological, toxicological) profile. However, this botanical reporters tracked down the persons who where most championing
drug raises some important questions about the role of modern the bark: Professor emeritus Dr. Valter Accorsi, a botanist at the
media and other means of world wide dissemination as a tool for University of Sāo Paulo, and physician Dr. Orlando dei Santi.
popularising a ‘wonder drug’. As in the case of other ‘wonderdrugs’, these reports highlight
the miraculous curing of a seriously ill (in this case very young)
2. Ethnobotanical uses of Red Lapacho patient. Dr. dei Santi came into contact with Red Lapacho dur-
ing a dinner in Sāo Paul, hosted by a family returning form Rio
Tabebuia impetiginosa is an evergreen, canopy tree, with rosy (or de Jainero. During the dinner, Dr. dei Santi heard the story of
purple) flowers, indigenous to the Amazon rain forest, but found all young girl from Rio that, while being gravely sick with cancer,
over Argentina, Bolivia, Brazil, Colombia, Ecuador, French Guinea, had been given up by the medical establishment. A great aunt
Paraguay, Perú, Surinam, Trinidad and Tobago, and Venezuela. Com- of the girl had contacted a tribal medicine man, who had told
monly known in Portuguese as Pau d’arco (bow tree), its indigenous her that the girl could be cured using the bark of Red Lapacho
names are ipê roxo (red thick bark), taheebo (ant wood), tajy (“to (Tabebuia impetiginosa). The family of the girl would not follow
have strength and vigor” in Guarani and Tupi) or red (or purple) the advice at first, but after the girl had not one, but two strange
lapacho (Luebeck, 1999; Mowrey, 2001; Taylor, 2005). The family dreams, where a monk promised her recovery should she drink
name Tabebuia is derived from an Indian language spoken in Brazil, the tea brewed from the bark of Red Lapacho trees growing in
while the species name impetiginosa comes from the customary use Pernambuco and Bahía (northeast Brazil), the family heeded and
of the bark against impetigo (Luebeck, 1999). the girl regained her health. The most immediate result was the
Tabebuia impetiginosa has been used by native Americans of cessation of all pain from the girl, followed by the complete dis-
Brazil, northern Argentina, Paraguay, Bolivia and Peru for thousands appearance of the malignancy. After hearing this account, Dr. dei
of years, with indications that may pre-date the Incas as an eth- Santi returned to the Hospital in Santo André, where his brother
nobotanical preparation (Duke, 1985; Schwontkowski, 1993; Pérez was sick with cancer, laying near death. Contrary to what he was
Sacau et al., 2003) against diseases like cancer, syphilis, malaria, taught in medical school against the use of empirical remedies
 J.R. Gómez Castellanos et al. / Journal of Ethnopharmacology 121 (2009) 1–13
used by Indian tribes, Dr. dei Santi decided to test Red Lapacho
tea on his dying brother. Reportedly, he concocted a brew of dry
lapacho bark in white wine, mixed with orange juice, and adminis-
tered it to his brother while fasting (de Montmorency, 1981); after
a month of uninterrupted treatment with the concoction, Dr. dei
Santi’s brother was discharged from hospital, without a trace of
cancer. After this, Dr. dei Santi started to treat his patients with
Red Lapacho, and the practice spread rapidly among other physi-
cians in the hospital (de Montmorency, 1981; Mowrey, 1996; Taylor,
2005).
Parallel to the past events, Professor Accorsi was contacted by
O’Cruzeiro reporters while travelling to Piracicaba (Jones, 1995).
There, Professor Accorsi was treating around 2000 people a day
with the tea from the bark. After hearing about the case of the girl
in Rio, Professor Accorsi started studying lapacho trees in his state in
Sāo Paulo, and comparing them with the trees in Bahia and Pernam-
buco. By comparing the effects in leukaemia patients, he realized
that the Bahia trees had more potent effect in patients, and was able
to verify “two great truths”: first, that lapacho tea eliminated the
pain caused by the diseases, and second, that it also caused a sig-
nificant increase in red blood cells (Schwontkowski, 1993; Mowrey,
1996, 2001; Taylor, 2005).
Independent of Dr. dei Santi and Professor Accorsi, Dr. Theodoro
Meyer, Professor of Botany and Plant Geography of the National Uni-
versity of Tucuman in Argentina documented the first clinical cases
of cancer chemotherapy using extracts from various lapacho inner
barks in 1966 (Walters, 1993). Dr. Meyer’s work, though it lacked
adequate controls and statistical evaluations, provided observa-
tional evidence for the efficacy of lapacho, but he was not able to
convince the medical community of his findings, before dying in
1972 (Luebeck, 1999; Mowrey, 2001).
The traditional preparation of Red Lapacho consists of a decoc-
tion of one-half to one cup of the bark and/or the heartwood, taken
orally two to four times per day. This decoction can also be used as
a douche for yeast infection, or topically on the skin against fungal
infections (Taylor, 2005).
Currently, the use of lapacho as a tincture has also been reported,
ingested orally or applied over mucous tissue against inflammation
(Taylor, 2005), as well as in capsules, though this pharmaceutical
form is not recommended. (Mowrey, 2001; Taylor, 2005).
3. Early pharmacological research on the drug
For thirty years, between 1960 and 1990, the United States of
America National Cancer Institute carried on a program for the
extensive recollection and screening of plants in temperate regions,
with the aim of isolating compounds effective in cancer chemother-
apy (Cragg and Newman, 2005). One of the compounds isolated as
part of this effort, lapachol, was identified as the compound respon-
sible for the anticancer activity of Tabebuia impetiginosa (Cassady
and Douros, 1980).
Tabebuia impetiginosa has shown activity against the following
cancer cell lines: carcinoma (Walker 256), prostate cancer (DU-145,
PC-3, LNCaP) (Li et al., 1995), human promyelocytic leukaemia (HL-
60), breast carcinoma, ovarian carcinoma, epidermoid laryngeal
carcinoma (HEp-2) (Boothman et al., 1987), radio-resistant human
malignant melanoma (U1-Mel) (Boothman et al., 1989), human
breast cancer (MCF-7:WS8) (Wuerzberger et al., 1998), human
lung adenocarcinoma (A549), human cervical cancer (HeLa) and
osteosarcoma (HuO9) (Simamura et al., 2003).
Although the preparation made of Lapacho is referred as a tea,
Taylor reports that a decoction of 8–10 min, is actually needed
to secure the extraction of lapachol and ␤-lapachone, which are
not readily soluble in water (Taylor, 2005). It is important to
3
note that the best part of the plant to be used in the prepara-
tion of Red Lapacho tea is the bark, specifically the inner lining
of the bark, the phloem, and not the whole bark, which contains
the dead wood of the tree, diluting the activity of the biologi-
cal material (Mowrey, 2001). Often, research has been done on
the heartwood of the tree, rather than the inner bark of it, which
may be explained by the quantities of the compounds found
there, which are just sufficient for experimental work (Mowrey,
2001).
The rationale of using the inner bark of Red Lapacho is
exquisitely explained in popular terms by Mowrey (2001):
‘The life processes of a mature tree are carried out in the thin
corridor lying between the outer bark and the inner heartwood.
Pull the bark off a tree and you will notice moist, very thin
layers of tissue that seem to shred when picked at with the
hands. This is the cambium layer. Its purpose is to create new
tree tissues, such as phloem, through cell division. The newest,
youngest phloem cells are just outside the cambium. As new
phloem is added, older cells are crushed and pressed into the
bark. Younger, newer cells added to the inside of the cambium
layer are called xylem. Newer xylem is called sapwood; older
xylem is crushed and pressed into the heart of the tree. It is
therefore known as heartwood. The actively conducting tissues
of a tree are the thin layers of fresh xylem and phloem on each
side of the cambium. The outer bark and heartwood are, essen-
tially, inactive materials that only serve to provide strength to
the tree. Indiscriminate combining of older, less active layers of
bark and tree with the younger, living tissues results in a dra-
matic dilution of active principle and medicinal value. Yet it is a
common practice.’
4. Approved uses of T. impetigionosa
The United States Food and Drug Administration (FDA) has reg-
istered the use of Red Lapacho tea as a Dietary Supplement (DS)
(FDA, 1999), as a “Herb used to alleviate conditions and symp-
toms of cancer” A DS, as defined by the Dietary Supplement Health
and Education Act (DSHEA) of 1994, is a product taken by mouth
that contains a “dietary ingredient” intended to supplement the
diet, a dietary ingredient being any component of a dietary sup-
plement. Whatever the composition or presentation of a DS, the
DSHEA places all of them in the general category of food, not drugs,
and requires that every supplement to be labelled as a dietary sup-
plement. Consequently, manufactures and retailers are allowed to
make claims that describe the role of the dietary ingredient in
affecting part of the structure or a function of the human body,
or that describe the way the dietary ingredient acts to maintain
body function and structure, but they must as well place a dis-
claimer stating that the ‘product is not intended to diagnose, cure,
or prevent a disease.’
Tabebuia impetiginosa has been given a Generally Regarded as
Safe Status (GRAS) by the FDA. Although, the isolated compounds,
like lapachol, have shown Vitamin K toxicity, the ‘synergistic’ effect
of the mixture of compounds in Red Lapacho tea, appear to cancel
this, since there are some pro-Vitamin K compounds in Red Lapacho
(Mowrey, 2001).
In the United Kingdom Medicines and Health Care Products Reg-
ulatory Agency (MHRA) contemplates the many herbal medicinal
products that have arisen from traditional use in Britain and else-
where in the world. A herbal medicinal product is any product
containing exclusively as active ingredients one or more herbal sub-
stances or one or more herbal preparations, or one or more such
herbal substances in combination with one or more such herbal
preparations (MHRA, 2005a,b).
4 J.R. Gómez Castellanos et al. / Journal of Ethnopharmacology 121 (2009) 1–13

5.1. Lapachol

Lapachol (2-hydroxy-3-(3-methyl-2-butenyl-)-1,4-naphtoquin-
one, C15 H14 O3 , molecular weight 242.2738 g/mol, Fig. 1a), known
since 1858, was the first natural compound isolated from Tabebuia
impetiginosa, and is known to be the most abundant quinone com-
pound in the family Bignoniaceae (Thomson, 1971).

5.2. ˇ-Lapachone

Fig. 1. Chemical structure of lapachol and ␤-lapachone.
Wichtl (2002) recommends the barks usage as an immunos-
timulant, but considers that all other uses have not been validated
sufficiently.
The use of the inner bark and wood of Red Lapacho as a medicine
and as a cosmetic has been noted by the MHRA (Suttie, 1996; MHRA,
2005a), and lapachol has been reported to be commercially avail-
able in Brazil for anti-tumor therapy (da Consolaçào et al., 1975;
Thomson, 1987).
5. Constituents of Tabebuia impetiginosa and Red Lapacho
tea
The bark and heartwood of Red Lapacho contains a number of
natural occurring compounds, in particular those in the methanolic
extract (Park et al., 2004), among them flavonoids (Blatt et al., 1996),
cyclopentene dialdehydes (Koyama et al., 2000), benzoic acid and
benzaldehyde derivatives (Wagner et al., 1989), quinones (Sharma
et al., 1988), furanonaphthoquinones (Zani et al., 1991; de Oliveira
et al., 1993; Díaz and Medina, 1996) and, most importantly, naphto-
quinones and anthraquinones (Thomson, 1971; Manners and Jurd,
1976).
From the 18 most relevant quinones registered so far, lapachol
and ␤-lapachone are of some clinical importance since they have
been related to the pharmacological activity of Red Lapacho tea, as
described later (Oswald, 1993).
␤-Lapachone (3,4-dihydro-2,2-dimethyl-2H-naphtol[1,2-b]
pyran-5,6-dione, C15 H14 O3 , molecular weight 242.2738 g/mol,
Fig. 1b), as well as ␣-lapachone, is an isomer of lapachol, firstly
obtained by acid treatment of lapachol but later described as a
natural product too of Tabebuia sp. (Thomson, 1971; de Oliveira et
al., 1993).
5.3. Miscellaneous compounds
As with lapachol and ␤-lapachone, the other occurring com-
pounds found in Tabebuia impetiginosa are the naphto[2,3-b]furan-
4,9-diones (furanonaphtaquinone) and anthracene-9,10-diones
(anthraquinones) (Steinert et al., 1995; Steinert and Rimpler, 1996).
Some of these are shown in Fig. 2.
Steinert and co-workers have provided with a good com-
pendium of the components found in the inner bark and heart wood
of Red Lapacho (Table 1).
Other compounds isolated from Tabebuia impetiginosa include
volatile compounds like those reported by Wagner et al. (1989),
3,4-dimethoxybenzaldehyde, 4-hydroxy-3-methoxybenzaldehyde
(vainillin) and 4-methoxybenzaldehyde, and those isolated by
Park et al. (2004) using three different techniques: solvent-
assisted flavour evaporation (SAFE), which yielded 4-methoxyben-
zaldehyde, 4-methoxyphenol, 4-methoxybenzyl alcohol and
1,2-propanediol; steam distillation under reduced pressure, fol-
lowed by continuous liquid-to-liquid extraction (DRP-LLE), which
yielded 4-methoxybenzaldehyde, 4-methoxyphenol, 5-(2-prope-
nyl)-1,2,3-trimethoxybenzene (elemicin) and 1-methoxy-4-(1E)-
1-propenylbenzene (trans-anethole); and high-flow dynamic

Fig. 2. Miscellaneous compounds found in Red Lapacho. 3: General structure of naphto[2,3-b]furan-4,9-diones: R1 = H, R2 = COCH; R1 = H, R2 = CH(OH)CH3 ;
R1 = OH; R2 = COCH3 ; R1 = OH, R2 = CH(OH)CH3 ; R1 = H, R2 = C(CH3 ) = CH2 . 4: General structure of anthraquinone. 5: Anthraquinone-2-carboxylic acid. 7:
2-(Hydroxymethyl)anthraquinone (b). 6: General structure of the cyclopenten dialehydes isolated by Koyama; 6.1 2-formyl-5-(4 -methoxybenzoyloxy)-3-
methyl-2-cyclopentene-1-acetaldehyde, R = 4 -methoxybenzoyl, and for 2-formyl-5-(3 ,4 -dimethoxyben-zoyloxy)-3-methyl-2-cyclo-pentene-1-acetaldehyde,
R = 3 ,4 -dimethoxybenzoyl. Steinert et al. (1995), Steinert and Rimpler (1996) and Park et al. (2005a, 2006).
 J.R. Gómez Castellanos et al. / Journal of Ethnopharmacology 121 (2009) 1–13 5

Table 1 anions can be reduced by the enzyme superoxide dismutase (SOD)

Compounds isolated from Red Lapacho and its location in the plant (Steinert et al.,
to hydrogen peroxide, and then hydroxyl radicals can be formed
1995).
by the iron-catalyzed reduction of peroxide via the Fenton reaction
Compound Localisation (Buettner, 1993).
Lapachol Heartwood, inner bark
Dehydro-␣-lapachone Heartwood, inner bark 6.2. Molecular pharmacology of lapachol
␣-Lapachone Heartwood
␤-Lapachone Heartwood
Lapachol first grasped the National Cancer Institute attention
Lapacholmethylether Heartwood
Menaquinone-1 Heartwood after being isolated from the active extract of the Indian plant
Desoxylapachol Heartwood Stereospermum suaveloens (Bignoniaceae) against the Walker 256
1-Hydroxyanthraquinone Heartwood tumour system in 1967 (Rao et al., 1968). An Investigational New
1-Methoxyanthraquinone Heartwood
Drug Application (IND) was filed, and phase I clinical trials were
2-Methylanthraquinone Heartwood
2-Hydroxymethylanthraquinone Heartwood
initiated, with doses up to 4000 mg/day administered orally. No
2-Acetoxymethylanthraquinone Heartwood therapeutic response was observed, and it was determined that
Anthraquinone-2-carboxylic acid Heartwood satisfactory blood levels could not be obtained by oral administra-
Lapachenol Heartwood tion; also, some toxicity was observed. The IND was closed in 1970
2-Acetyl-furanonaphtaquinone Inner bark
(Suffnes and Douros, 1980).
2-Hydroxyethyl-furanonaphtoquinone Inner bark
8-Hydroxy-2-acetyl-furanonaphtoquinone Inner bark
8-Hydroxy-2-hydroxyethyl-furanonaphtoquinone Inner bark 6.3. Anticancer molecular pharmacology of ˇ-lapachone
2-Ethyl-furanonaphtoquinone Inner bark
2-Isopropyl-furanonaphtoquinone Inner bark
After lapachol was discarded by the NCI as an effective anti-
2,3-Dihydro-2-(2-methylethenyl)-furanonaphtoquinone Inner bark
cancer chemotherapeutic, ␤-lapachone succeeded it as the research
molecule of interest from Red Lapacho.
␤-Lapachone revealed to have significant activity against a range
headspace sampling (DHS), which yielded 4-methoxybenzal-
of tumour cell lines, including breast, leukaemia and prostate, as
dehyde, 4-methoxyphenol, 2-methyl-5-(1-methylethylene)-2-
well as several multridrug resistance cell lines (Ravelo et al., 2004).
cyclohexen-1-one (carvone) and 3,7-dimethyl-1,6-octadiene-3-ol
Schuerch and Wehrli (1978) have reported that ␤-lapachone
(linalool).
has been shown to inhibit reverse transcriptase from myeloblastus
Koyama et al. (2000) also reported the isolation of ␤-
virus and Rauscher murine leukaemia virus (as well as eukaryotic
sitosterol, stigmasterol, 4 -methoxybenzyl-4-methoxybenzoate,
DNA polymerase-␣); the effect in both enzymes may be related to
9-hydroxy-3-methylnaphto[2,3-b]pyran-2,5,10-trione, (−)-3,4-
their structure, which posses similar exposed thiol groups in their
dihydro-6,8-dihy-droxy-3-methylisocumarin, and two new
actives sites.
cyclopentene dialdehydes: 2-formyl-5-(4 -methoxybenzoyloxy)-
DNA topoisomerases are the enzymes that control the supercoil-
3-methyl-2-cyclopentene-1-acetaldehyde and
ing of DNA by breaking and creating phosphodiester bonds, altering
2-formyl-5-(3 ,4 -dimethoxyben-zoyloxy)-3-me-thyl-2-
the topological state (linking number) but not the covalent struc-
cyclopentene-1-acetaldehyde.
ture of circular DNA. Topoisomerase I differs in its activity from
Warashina et al. (2004, 2005, 2006) isolated a number of new
topoisomerase II in that the previous changes DNA linking num-
compounds including eight iridoid glycosides, three lignan glyco-
bers in steps of one, and does not require a co-factor, while the
sides, two isocumarin glycosides, four phenylethanoid glycosides
later does, and does it in steps of two. This difference also accounts
and thirteen phenolic glycosides (Fig. 3).
for the difference in the inhibitors which act in each topoisomerase
(Wang, 1985; Voet and Voet, 1995).
6. Anti-cancer molecular pharmacology of Red Lapacho Camptothecin was the first known and well characterized
inhibitor of topoisomerase I, its mechanisms being the stabiliza-
As previously stated, anecdotal and observational data link Red tion of the cleavable complex between topoisomerase I and DNA
Lapacho with anti-cancer properties, derived from two of its naph- by blocking the rejoining step of the breakage–reunion reaction
taquinoid compounds, lapachol and ␤-lapachone. (Hsiang et al., 1985). After research on ␤-lapachone started, it
was discovered that it had the ability to inhibit topoisomerase I
6.1. The quinone structure in chemotherapeutics (Boorstein and Pardee, 1984; Wuerzberger et al., 1998), although
␤-lapachone and camptothecin were not structurally related,
The quinone structure (including anthraquinones and naph- implying a different mechanism of action.
toquinones) is known to be important in many natural products The first evidence of this was provided by Li et al. (1993), who
involved in anti-cancer and other anti-microbial activities (O’Brien, reported that ␤-lapachone inhibited catalytic activity of eukaryotic
1991; Boik, 2001). The biological activity of the quinone structure topoisomerase I, but not topoisomerase I-mediated DNA cleavage.
is related to the ability of the quinone moiety to accept electrons to This is done via a direct interaction of ␤-lapachone with topoiso-
form radical anion or dianion species, and thus stimulating intra- merase I that blocks the formation of the topoisomerase I–DNA
cellular free radical production and reactive oxygen species (ROE) cleavable complex, but not the assembly of the enzyme–DNA com-
formation in mitochondrial and microsomal fractions (Dubin et al., plex. These conclusions were drawn from the observation that
1990; Fry and Pudney, 1992; Henry and Wallace, 1995). ␤-lapachone inhibited topoisomerase I-mediated DNA cleavage
The pathway involved in the formation of ROE involves induced by camptothecin, and that the incubation of ␤-lapachone
cellular reductases (i.e. NADH:cytochrome b5 reductase, and with topoisomerase I prior to the additon of the DNA substrate
NADPH:cytochrome P450 reductase) that reduce the quinone moi- strongly increased the inhibition observed.
ety to the unstable and highly reactive intermediate, semiquinone, A metabolic pathway that would activate the apoptotic activity
which is a superb free radical generator (Pink et al., 2000a). The of ␤-lapachone was proposed by Pink et al. (2000a). Since ␤-
generation of these free radicals initiate a redox cycle, which in lapachone is a naphtaquinone, Pink and co-workers hypothesized
turn results in the generation of superoxide anions. This superoxide that the enzyme which is involved in the detoxification or activation
6 J.R. Gómez Castellanos et al. / Journal of Ethnopharmacology 121 (2009) 1–13

of other naphtaquinones xenobiotics in the body, quinone oxi-
doreductase (NQO1) may be involved in the anticancer activity of
␤-lapachone.
It has been observed that NQO1 is over-expressed in certain
tumours, especially in breast, colon and lung cancer (Malkinson
et al., 1992). Therefore, it has been suggested that this enzyme
would be important for tumour-specific activity for a given drug,
like ␤-lapachone.
NQO1 catalyzes a two-electron reduction in quinones, using
NADH or NADPH as the electron donor. Unlike other reductases
that reduce ␤-lapachone to semiquinone-free-radical-generator
intermediate, NQO1 bypasses this intermediate and produces the
hydroquinone intermediate, which, for most quinones, is highly
stable. Since NQO1 is an ubiquitous enzyme in the body, its main
function ought to be the detoxification of the cell caused by natu-
rally occurring xenobiotics containing quinone moieties (Cadenas,
1995).
Contrary to other quinones, the hydroquinone resulting from
the reduction of ␤-lapachone seems to be unstable, and to have
a tendency to auto-oxidize itself back to ␤-lapachone, providing
renewed substrate for another round of NAD(P)H-mediated reduc-
tion. As this ‘futile cycle’ continues, the stock of NAD(P)H in the cells
diminishes, leading to a massive release of Ca2+ which depleted ATP
levels (Pink et al., 2000b; Tagliarino et al., 2001), causing stress on
the cell due to the inability to fulfil the processes needing these
co-factors, and activating apoptosis, through a pathway not fully
understood.
To further investigate the apoptotic pathway that ␤-lapachone
triggered, and, considering that the activation of a cysteine
protease, with characteristics consistent with the neutral calcium-

Fig. 3. Compounds isolated by Warashina et al. (2004, 2005, 2006).

 J.R. Gómez Castellanos et al. / Journal of Ethnopharmacology 121 (2009) 1–13 7

Fig. 3. (Continued )

dependant protease called calpain, and not caspases, nor p53, was
involved in the initiation of apoptosis (Planchon et al., 1995, 2001).
Tagliarino et al. (2001) examined alterations in Ca2+ homeosta-
sis using cells expressing NQO1; these cells, when exposed to
␤-lapachone showed an increasing in intracellular cytosolic Ca2+
levels, due to the depletion of NAD(P)H, from endoplasmic retic-
ulum Ca2+ stores. The use of chelating agents that block early
increases in Ca2+ levels arrested apoptosis, indicating a crucial role
of Ca2+ in the NQO1 apoptotic pathway.
In another study, Park et al. (2005b) reported the synergistic
effect of ionizing radiation (IR) and ␤-lapachone. In this study,
Park and co-workers observed that IR sensitizes cancer cells to
the actions of ␤-lapachone by means of a long-lasting elevation
of NQO1 levels in cancer cells. The basis for this research is that
previously, NQO1 was reported to be an IR-inducible transcript,
xip3 (Boothman et al., 1993, 1989), and, as mentioned, that NQO1
was reported to be over-expressed in tumour cells (Cresteil and
Jaiswel, 1991; Pardee et al., 2002; Begleiter and Fourie, 2004). Pro-
viding more information on the role of ␤-lapachone in IR therapy,
Boothman et al. (1987), reported that ␤-lapachone increased syn-
ergistically the dose enhancement ratios of several halogenated
pyrimidine radiosensitizers.
Even though Pink and co-workers reported substantial evidence
favouring the apoptosis via a non-ROS-producing pathway, Shiah
et al. (1999) have produced experimental evidence involving the
production of ROS. They treated HL-60 cells with ␤-lapachone and
observed an increased level of ROS, specially H2 O2 and O2 ; the ROS
pathway was confirmed with treatment of an antioxidant, vitamin
C, which arrested apoptosis. Further investigation into this line of
research yielded a possible route for the activation of apoptosis, that
c-Jun NH2 -terminal kinase (JNK), but not p38 mitogen-activated
protein kinase nor extracellular signal-regulated kinase 1/2 was the
protein activated and involved in the initiation of apoptosis due to
the overproduction of ROS.
8 J.R. Gómez Castellanos et al. / Journal of Ethnopharmacology 121 (2009) 1–13

Fig. 3. (Continued ).
 J.R. Gómez Castellanos et al. / Journal of Ethnopharmacology 121 (2009) 1–13
Although all these mechanisms offer good explanations for
the pharmacological activity of ␤-lapachone, there are some
inconsistencies. In the case of the inhibition of topoisomerase
I, the concentration needed for apoptosis is well below to that
needed for the inhibition (Planchon et al., 2001), implying that
other targets are also involved. In the case of NQO1, HL-60 and
MDA-MB-468 cell lines lacking NQO1 suffer ␤-lapachone-induced
apoptosis (Schuerch and Wehrli, 1978). Lastly, SW 480 cells have
NQO1 levels equivalent to those in NCM 460 cells, yet the later
shows resistance to ␤-lapachone-induced apoptosis (Li et al.,
2002).
Within cancer cells, the checkpoints in the cell cycle which
will normally safeguard genomic integrity during proliferation are
depressed. This permits cancer cells to avoid apoptosis that will
otherwise occur due to genetic damage (Hartwell and Weinert,
1989; Pardee, 1989; Volgstein et al., 2000; Zhou and Elledge, 2000).
Since the activation of the apoptotic pathway requires DNA dam-
age (which is caused by chemotherapeutics without selectivity of
cancer cells from normal cells), chemotherapeutics which initiate
apoptosis without interactions on DNA, like ␤-lapachone are of
major importance.
With these observations as a starting point, Li et al. (2002)
reported the selective induction of apoptosis, only in transformed
cells, by activating apoptosis checkpoints in the absence of DNA or
microtubule damage, preceded by the rapid and sustained increase
of regulator in checkpoint-mediated apoptosis, E2F1. E2F1 function
as a checkpoint in the G1 /S transition and S-phase, as well as an acti-
vator of apoptosis, as mediated by p53-dependent or independent
pathways (Nahle et al., 2002; Sears and Nevins, 2002; Trimarchi
and Lees, 2002). This experiment proved that ␤-lapachone induced
apoptosis in myeloma cells resistant to dexamethasone and con-
ventional therapies, as well as in MCF-7 human breast carcinoma
cell line and human colonic adenocarcinoma cells SW 480, but in
none of the non-transformed cell lines tested.
Similarly, Lee et al. (2005) described that the down-regulation
of cyclooxigenase-2 (COX-2), as well as that of human telomerase
reverse transcriptase (hTERT), in human prostate carcinoma DU145
cell line. Of the two known isoforms of cyclooxigenases, COX-2 –
which is expressed at low basal levels and can be rapidly induced
by tumour promoters, growth factors and inflammatory cytokines
– is the one that, when over-expressed, has been linked to tumori-
genesis. These findings suggest that COX-2 up-regulation is an
important process in carcinogenesis (Gately, 2003; Smith et al.,
2000). Some other reports, go as far as to demonstrate that the
over-expression of COX-2 is related to the inhibition of apopto-
sis (Stratton and Alberts, 2002; Umar et al., 2003). With these
results, Lee and co-workers provided yet another mechanism by
which ␤-lapachone may exert it anticancer activity, re-activating
the apoptotic pathways that would originally cleared the can-
cerous cells from the body through an increase of Bax/Bcl2 and
activation of caspase 3, while concomitantly causing a loss of
prostaglandin-E2 and telomerase activity by inhibition of COX-2
and hTERT expression.
In spite of all the above information, since no systematic clinical
studies on any preparation derived from Tabebuia impetiginosa have
been conducted so far, making an evaluation of its effectiveness is
impossible. Nevertheless, there has been clinical trials reporting
the effects of lapachol and ␤-lapachone independently.
7. Other pharmacological properties of Tabebuia
impetiginosa
Even though any ethnopharmacological uses of Tabebuia
impetiginosa have been recorded, the work done on establishing the
molecular basis of these mechanisms has not been done on all of
9
its traditional uses. Those which have been investigated thoroughly
are indicated next.
7.1. Antibacterial activity of Tabebuia impetiginosa
In an effort to identify new bioactive chemicals to help in the
treatment against harmful intestinal bacteria, Park et al. (2005a)
tested the extracts of the inner bark of Tabebuia impetiginosa
for its antibacterial activity against normal intestinal flora and
harmful bacteria; then, compared these extracts with widely used
antibiotics (chloramphenicol and tetracycline). They found that the
fractions obtained from the methanol extract showed weak to mod-
erate activity against intestinal bacteria Bifidobacterium longum,
Lactobacillus acidophilus and Lactobacillus casei in the paper disk
diffusion assay (10 mg/disk). Against the harmful bacteria Clostrid-
ium paraputrificum and Clostridium perfringes, the same assay
exhibited strong inhibitory activity, and moderate activity against
Escherichia coli. Spectroscopic analysis identified two compounds
thought to be responsible of this antibacterial activity, lapachol and
anthraquinone-2-carboxylic acid (1, 7). These compounds showed
no growth inhibition against Bifidobacterium adolescentis, Bifidobac-
terium bifidum, Bifidobacterium infantis, Lactobacillus acidophilius,
and Lactobacillus casei, and weak inhibition of Bifidobacterium
longum at 1000 ␮g/disk, while cloramphenicol and tetracycline per-
formed strongly on all bacteria (10 and 200 ␮g/disk). On the other
hand, anthraquinone-2-carboxylic acid showed a strong inhibitory
activity against Clostridium paraputrificum (1 ␮g/disk), and mod-
erate activity against Clostridium perfringes and Escherichia coli
(200 ␮g/disk), lapachol showed moderate activity against Clostrid-
ium paraputrificum (200 ␮g/disk), and moderate to weak activity
against Clostridium perfringes and Escherichia coli (1000 ␮g/disk),
while the comparator antibiotics were highly effective against
all harmful bacteria (chloramphenicol, 10 ␮g/disk; tetracycline,
0.1 ␮g/disk).
On a subsequent work Park et al. (2006) examined the
growth-inhibiting activity of the inner-bark extracts of Tabebuia
impetiginosa on Helicobacter pylori as a treatment against gastro-
duodenal diseases related to this pathogen. As with the previous
work, they found that the fractions obtained from the methanol
extract showed very strong activity against Helicobacter pylori
(fractions: hexane, 0.5 ␮g/disk; chloroform, 0.1 ␮g/disk; ethyl
acetate, 5.0 ␮g/disk). Lapachol, 2-(hydroxymethyl)anthraquinone
and anthraquinone-2-carboxylic acid were spectroscopically char-
acterized and deemed responsible of this activity (5, 7). In the
minimum inhibitory concentration (MIC) bioassay, all three com-
pounds from Tabebuia impetiginosa were more effective than
metronidazol (a 2 ␮g/ml, b 8 ␮g/ml and lapachol 4 ␮g/ml vs.
32 ␮g/ml), but far less effective than amoxicillin and tetracycline
(0.063 ␮g/ml and 0.5 ␮g/ml respectively).
7.2. Inhibitory effects of Tabebuia impetiginosa on platelet
aggregation and vascular smooth muscle cell (VSMC) proliferation
In search of new therapies against vascular diseases such
as thrombosis, atherosclerosis and restenosis, Son et al. (2006)
investigated the fractions from the methanol extract (chloroform
fraction) of Tabebuia impetiginosa against platelet aggregation and
VSMC, which are essential events in the pathogenesis of these
diseases. Tabebuia impetiginosa was capable of inhibiting platelet
aggregation and VSMC proliferation in vitro. The most probable
mechanism of the anti-platelet action is through the suppression
of arachidonic acid (AA) and collagen liberation, while the anti-
proliferative action on VSMC was attributed by the suppression of
phosphorylated extracellular signal regulated kinase (ERK1/2) and
mitogen activated protein kinase (MAPK) activation.
10 J.R. Gómez Castellanos et al. / Journal of Ethnopharmacology 121 (2009) 1–13
Fig. 4. Structure of the Vitamin K2 , Menaquinones. Bacteria-synthesized Vitamin K’s
side chain is formed by repeating 5-carbon units. These forms of Vitamin K are des-
ignated menaquinone-n (MK-n), where n stands for the number of 5-carbon units.
MK-n are collectively referred to as Vitamin K2 . MK-4 is not produced in significant
amounts by bacteria, but appears to be synthesized by animals (including humans)
from phylloquinone (Suttie, 1996).
7.3. Tabebuia impetiginosa compounds as antipsoriatic agents
Müller and co-workers have also reported the in vitro activ-
ity of eight of the most significant compounds of Tabebuia
impetiginosa against the growth of the human keratinocyte
cell line HaCaT. Lapachol, dehydro-␣-lapachone, ␣-lapachone,
␤-lapachone, naphto[2,3-b]furan-4,9-diones and dehydro-iso-␣-
lapachone. Of these compounds, ␤-lapachone displayed an
IC50 value of 0.7 ␮M, comparable to that of the antipsoriatic
drug anthralin; 2-acetyl-8-hydroxynaphtho[2,3-b]furan-4,9-dione
exhibited an IC50 value of 0.35 ␮M; the remainder of the com-
pounds presented IC50 values ranging from 0.5 to 3.0 ␮M. As with
anthralin, treatment of HaCaT cells with these compounds also
caused damage to the plasma membrane. The activity of these com-
pounds make them good candidates for further development in
psoriasis treatment (Müller et al., 1999).
8. Metabolism, pharmacokinetics and clinical trials of the
components of Red Lapacho
8.1. Vitamin K metabolism
As previously described (see Section 6), lapachol and ␤-
lapachone can be metabolised in the body by reductases, as other
exogenous naphtoquinones. The most important naphtoquinone
for the organism is Vitamin K. Vitamin K is a fat soluble vitamin
which essential for the functioning of several proteins involved in
blood clotting (Brody, 1999). There are two types of biosynthesized
Vitamin K: Vitamin K1 (phylloquinone) is synthesized in plants;
Vitamin K2 (menaquinones, MK-n, Fig. 4) is synthesized in bacteria
and animals, where -n represents the number of 5-carbon units in
the molecule (Shearer, 1995).
MK-4 appears to be the most important Vitamin K in humans,
and its seems to be a biosynthetic pathway for it in the human
body with phylloquine as the starting point (Booth and Suttie,
1998). Vitamin K exerts its biological action as a coenzyme for Vita-
min K-dependant carboxylase, which catalyzes the carboxylation
of glutamic acid into ␥-carboxyglutamic acid in the 7 Vitamin K-
dependant clotting factors: Factors II (prothrombin), VII, XI, X, and
proteins Z, C and S. The carboxylation of the glutamic acid residues
proteins is critical to the Ca2+ -binding properties of the clotting fac-
tors, which enables its activation (Suttie, 1996; Shearer, 1997; Furie
et al., 1999).
Most of the toxicity of Red Lapacho has been associated with
intervention in the biological cycle of Vitamin K in the body, with
perturbation in the clotting formation or inhibition properties of
Vitamin K.
8.2. Clinical trials and metabolism of lapachol and ˇ-lapachone
in mammals
According to Oswald (1993), the information gathered from tri-
als evaluating the action of whole plant extract versus the action
of the isolated constituents, proved that the potency of the later
declines as purification of the extract continues into more isolated
fractions or single compounds. This may point into the direction
of synergism, that is the potentiation of the individual potencies of
the compounds in the extract acting as a whole, as one of the most
important factors to take into account when evaluating Tabebuia
impetiginosa and its constituents.
The first compound from Tabebuia impetiginosa that was tested
in humans in clinical trials was lapachol. In this trial, twenty-one
patients with non-leukemic tumors or chronic myelocytic leukemia
were given lapachol at a dose range of 250–3750 mg daily for 5 days
and up to 3000 mg daily for 21 days; Block et al. (1974), reported
that lapachol did not have any effect on the clinical status of the
patients.
Though there is very little information on the metabolism of
Tabebuia impetiginosa as the ethnobotanical product (i.e. either
as a tea, decoction or the grounded bark), there has been some
research done on the complete and fully synthetic version of ␤-
lapachone (ARQ 501, ArQule, Inc.) Miao et al. (2008) and Savage et
al. (2008) identified that ␤-lapachone is extensively metabolized in
human (as well as in other mammals) in the red blood cells fraction.
Also, ARQ 501 has been tested clinically in phases I and II. Search-
ing into the clinical database ClinTrials.gov, three phase I trials
[NCT00075933 (Shapiro and Cunningham, 2008b), NCT00099190
(Cunningham, 2008), NCT00524524 (Shapiro, 2008a)], one phase
I/II trial [NCT00622063 (Senzer, 2008)], and three phase II tri-
als [NCT00102700 (ArQule, 2008a), NCT00310518 (ArQule, 2008b),
NCT00358930 (ArQule, 2008c)]. The specific cancer types on which
RQA 501 was tested included: (a) squamous cell head and neck
carcinoma, (b) pancreatic cancer, and (c) leiomyosarcoma.
9. Qualitative and quantitative analysis of Tabebuia
impetiginosa
9.1. Quality control issues of the plant material obtained from
Tabebuia impetiginosa
As with most ethnopharmacological agents which lack full
market authorisation and detailed quality control, Red Lapacho
products are generally not characterised phytochemically, bio-
chemically or pharmacologically (Mowrey, 2001). According to
Mowry, most of the biological material imported into the United
States from South American countries has not been properly iden-
tified, adulterated, or harvested incorrectly. Since gatherers are
unaware which parts of the plant contain the active ingredients,
and harvest all parts of the plant, shippers pay very little atten-
tion to protecting the goods from the hazards of transportation,
and importers very seldomly know what they are working with;
there are multiple steps which may result in poor-quality prod-
ucts.
In South America Red Lapacho is also widely used for tim-
ber (Taylor, 2005). The inner and outer bark used medicinally is
normally obtained from commercially available timber which is
stripped off at sawmills when the heartwood is milled into lum-
ber for construction material. When logged, just referred to as
Pau d’Arco and without flowers and leaves, adulterations with
one of the other hundred or so species of Tabebuia are likely, of
course, resulting in a considerably diminished quality and effec-
tiveness of the plant material. Quality control measures are urgently
needed.
 J.R. Gómez Castellanos et al. / Journal of Ethnopharmacology 121 (2009) 1–13
9.2. HPLC analysis of the components of Tabebuia impetiginosa
Some of the best reports on HPLC analysis of compounds
extracted from Tabebuia impetiginosa are provided by Steinert et
al. (1995) and Steinert and Rimpler (1996). Firstly, they reported
that the methanolic extract from Red Lapacho, in a reversed
phase stationary phase, eluted with a methanol–acetonitrile–
water–phosphoric acid (25:35:30:0.1, v/v/v/v) resulted nine differ-
ent compounds, included lapachol and dehydro-␣-lapachone, but
not ␤-lapachone, from Tabebuia impetiginosa in less than 15 min.
The second work reports a gradient elusion with methanol, water
and a mixture of methanol–water–phosphoric acid–methyl-tert-
butyl ether (65:30:0.1:5), with 75% mixture and 25% water for the
first 5 min, followed by 50% methanol and 50% mixture with lin-
ear increase and holding for 5 min, at a flow rate of 1.2 ml/min.
This work is of particular interest, since it includes the separa-
tion of the three isomers, lapachol, ␣-lapachone and ␤-lapachone,
which were only separated until then on a chiral stationary phase,
thanks to the use of an ether (methyl-tert-butyl ether) in the mobile
phase.
Park et al. (2004) report the analysis of the volatile compound
from Red Lapacho as well, though they are not of a particular phar-
macological interest.
10. Conclusions
Considerable research efforts have gone into providing scientific
evidence for the health claims of Tabebuia impetiginosa. However,
despite of all these efforts, little evidence for its therapeutic useful-
ness is available. Crucial for this is the lack of properly characterised
material for use in observational studies and problems associated
with a lack of quality assurance for the products during the whole
process from the crude drug to the final product.
This monograph also highlights the continuous role of local and
traditional information of supplying all sectors of the herbal drug
markets of the world. In this case the internet is one of the most
important sources for products of variable quality at best. While
there is considerable in vitro evidence, and empirical (incl. clini-
cal) evidence points to some health benefits, overall the evidence
is certainly still insufficient to include it in any form of mainstream
cancer therapy. More than forty years (Heinrich, 1998) the ini-
tial miraculous cures, the evidence remains scarce. Popular reports
about its miraculous effects have sparked a considerable interest in
the general public, and a more critical assessment of such claims in
the general media would certainly be warranted (Heinrich, 1998).
It is well known that in phytomedicines often a complex mixture of
compounds exerts more pronounced effects than individual com-
pounds (Heinrich et al., 2005). The role such complex mixtures and
the ‘ideal’ composition of an active extract needs to be investigated
first using a combination of in vitro (or in vivo animal) techniques
in combination with phytochemical or metabolomic techniques
(Verpoorte et al., 2005) and next potentially in controlled clinical
trials. This will be essential in the context of its traditional uses
(Jaeger, 2005) and is without doubt an essential research need in
South America (Calixto, 2005).
However, since it is a typical example of a drug people turn to as
a last resource, it will continuously be of interest. Based on a recog-
nition of its importance as a herbal drug one essential task of future
ethnopharmacological research will be to ascertain appropriate
quality control of products derived from Tabebuia impetiginosa.
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