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Anti-Allergic Potential of Herbs and Herbal Natural Products - Activities and

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26 Recent Patents on Endocrine, Metabolic & Immune Drug Discovery 2013, 7, 26-56

Anti-Allergic Potential of Herbs and Herbal Natural Products -

Activities and Patents

Betania B. Cota1, *, Caryne M. Bertollo1 and Djalma M. de Oliveira2

1
Laboratório de Química de Produtos Naturais, Centro de Pesquisas René Rachou - CPqRR-FIOCRUZ, Avenida
Augusto de Lima, 1715, Barro Preto, Belo Horizonte, Minas Gerais, Brazil; 2Departamento de Química e Exatas,
Universidade Estadual do Sudoeste da Bahia, Campus Jequié, Jequié, Bahia, Brazil

Received: June 20, 2012; Accepted: July 20, 2012; Revised: August 30, 2012

Abstract: The increase of allergic diseases has accompanied the global population growth and the major challenge is to
reduce morbidity. The currently available treatments present limitations regarding efficacy and safety. Hence, patients
with chronic allergic conditions seek alternatives to achieve better control of symptoms. Many natural products have been
identified as potential anti-allergic agents. In addition, plant formulations have demonstrated, in general, to be safe in
clinical trials and demonstrate additional effects along with Western medicines such as synergism and modulation of the
immune system. It is known that plants represent a source of new therapeutic agents and some of them have shown
mechanisms of action similar to synthetic agents. However, in general, herbs and their combination are patented mainly
by Asian countries to be used in food and drinks or cosmetics and dietary supplements and the anti-allergic mechanisms
of action are not yet fully elucidated. In this review, we highlight relevant patent and studies with cultivated plants, plant
formulations, and secondary metabolites that have been evaluated with respect to its anti-allergic potential.
Keywords: Anti-allergic, complementary alternative medicine, natural product, patent, plant.

INTRODUCTION primary health care approach. The spending on traditional

The prevalence of allergic diseases has increased in the
last three decades [1]. Although, allopathic medicines such
as corticosteroids, anti-histaminic drugs, mast cell stabilizers
and leukotriene inhibitors are available; these drugs are not
always able to improve the quality of life of patients. As a
result, many patients with chronic allergic conditions, such
as asthma, seek complementary alternative medicine (CAM)
in order to achieve better control of symptoms [2,3].
Generally, CAM is a set of healing resources that in-
cludes herbs that are used in traditional medicine. Plants rep-
resent the most ancient therapy for treating diseases that is
used worldwide [4]. However, the contribution of the herbal
medicines is not recognized by many modern health systems
in several countries. In general, allopathic medicines are the
most accepted by the scientific community and are consid-
ered a highly specialized and techno-centric approach of
treating diseases. On the other hand, herbs are found on the
market as herbal medicinal products, food supplements, and
as raw dry or fresh material [5,6].
Although less prescribed by physicians, traditional medi-
cine is used for primary care by 70-95% of citizens in the
majority of developing countries. In 2008, the global market
was estimated to be US$ 83 billion annually [7]. In Asian
countries such as China, South Korea, Thailand and Viet-
nam, traditional medicine based on herbals has been the
*Address correspondence to this author at the Laboratório de Química de
Produtos Naturais, Centro de Pesquisas René Rachou, Fundação Oswaldo
Cruz, Full address: Av. Augusto de Lima, 1715, Belo Horizonte, MG,
30190-002, Brazil; Tel: +55 31 33497791/ 7845; Fax: +55 31 32953115;
E-mail: betania@cpqrr.fiocruz.br
medicines in China and Japan represent, respectively, values
of $ 14 billion USD (2005) and over $ 1 billion USD (2006).
In European nations, sales of herbal medicines were esti-
mated to be $ 5 billion USD in 2003 [7]. In turn, in the
United States (US) 17.7% of adults reported having used
herbs or supplements in a National Health Interview Survey
conducted in 2007 [8].
Despite the limited data about the efficacy and safety of
herbal medicines in the treatment of allergic conditions [9]
there is a globally increasing interest in the use of CAM,
including medicinal herbs. In a 2009, cross sectional study
carried out in the United Arab Emirates (UAE), 7.4% of the
participants used herbal remedies as a type of alternative
medicine and 1.9% used alternative medicine for the treat-
ment of allergic diseases [10]. In the US, there is a high
prevalence of use of complementary and alternative medi-
cine (50 to 61%) by patients with dermatological diseases
(dermatitis or psoriasis). The data analysis from 2,043 adults
reporting skin problems in 2007 showed that herbal supple-
ments were used by 870 subjects in the last 12 months and
from the various categories of CAM modalities used for skin
problems, herbal supplements represented 32.7% (n = 8/28)
[11]. Moreover, the Asthma Call Back Survey from 2006 to
2008 in the US, revealed that among children with poorly
controlled asthma, the use of CAM was estimated to be 34%,
whereas herbal products represented 12.8% of CAM therapy
[12].
In this review, we focus on general results about anti-
allergic herbs and natural products identified recently and
highlight some considerations about clinical trials with
herbal formulations. In addition, we discuss herein the cur-

2212-3334/13 $100.00+.00 © 2013 Bentham Science Publishers

Anti-Allergic Natural Products Recent Patents on Endocrine, Metabolic & Immune Drug Discovery 2013, Vol. 7, No. 1
rently known mechanisms of action of herbs and isolated
natural products for treating asthma and allergy.
MECHANISMS FOR THE EFFECTIVENESS OF
HERBAL PRODUCTS ON ALLERGIC CONDITIONS
Allergy is defined as a disease following a response by
the immune system to an innocuous antigen. The balance
between responsiveness and non-responsiveness (tolerance)
of the immune system for host protection is impaired and
leads to immunologic diseases such as allergy, hypersensitiv-
ity, and inflammation. Clinical manifestations of allergic
reactions can be divided in “early phase” and “late phase”,
which are characterized as mast cell and basophil-dependent
and allergic inflammation, respectively [13,14].
The immediate hypersensitivity response is mainly medi-
ated by mast cells and basophils. Mast cells are highly spe-
cialized cells and together with IgE are critical players in the
defense against certain bacterial, parasitic and viral infec-
tions [15,16]. The mast cells degranulation is triggered by
activation of the high affinity immunoglobulin E receptor
(FcRI) when antigens cross-link immunoglobulin E (IgE)
bound to those receptors that are constitutively expressed on
the mast cells surface. Mast cells can be also activated by
receptor-binding agonists (IgE, Ig light chain, complement,
microbial products, cytokines, chemokines), physical activa-
tors (temperature, pressure), toll-like receptor (TLR) activa-
tion and cell-cell contact (OX40/OX40L, CD40/CD40L,
TCR/MHCII) [17-20].
The “early phase” of the allergic reaction occurs few
minutes later after degranulation and the synthesis of lipid
mediators by mast cell and/or basophils activated by aller-
gens. The degranulation effect in mast cells is triggered by
the activation of tyrosine kinases (Lyn, SyK, Lat), which
induce the activation of phospholipase C (PLC) and Ca2+
mobilization, or by the activation of the Ras-Raf-Map kinase
(MAPK) cascade or by PI3K/Akt/IKK/IB and NF-B sig-
naling pathways that lead to the expression of transcription
factors. Calcium mobilization is required for arachidonic
acid synthesis, production of lipid mediators, and exocytotic
processes in the degranulation effect. Ca2+ antagonists can
disrupt ion influx with the attenuation of degranulation and
inhibitors of signaling pathways can block the phosphoryla-
tion that activates transcription of cytokines [21,22]. Mast
cells produce histamine, proteases, tryptase, serotonin, lipid-
derived mediators (prostaglandins and leukotrienes) and
store -hexosaminidase in the secretory granules [18,19].
Histamine induces vasodilatation and increases vascular
permeability; leukotrienes (LTs) C4 and B4 stimulate smooth
muscle contraction and enhance transudation and edema;
prostaglandins enhance local vasodilatation, attraction and
activation of neutrophils, macrophages and mast cells and,
tryptase promotes fibroblast collagen synthesis [23, 24]. In
the “early phase” there is also eosinophil recruitment medi-
ated by platelet activating factor (PAF) and the release of the
granulocyte macrophage-colony stimulating factor (GM-
CSF) from mast cells [17].
Secondary exposure to allergens leads to the activation of
the IgE-sensitized antigen presenting cells (APCs), which in
turn promote antigen-specific immunoglobulins, such as IgE
by B lymphocytes maintaining mast-cell and APC sensitiza-
27
tion. The presence of interleukin (IL)-12 and interferon-
(IFN-) can differentiate T cells into TH1 (T- helper) effector
cells, whereas IL-4 induces TH2 T-cell differentiation. TH1
cells secrete the cytokines IFN- and tumor necrosis factor- 
(TNF-) and TH2 cells lead to the expression of cytokines
(IL-4, -5, -6, and -13) that stimulate B cells activation and
their differentiation into plasma cells and, consequently, the
antigen-specific immunoglobulins secretion. The “late
phase” reactions are also associated with chemokine produc-
tion and the release of mediators that recruit eosinophils,
mast cells, basophils and TH2 lymphocytes to the site of the
allergic inflammation contributing to a chronic allergic in-
flammation, smooth muscle contraction, mucus hypersecre-
tion, edema and triggering tissue damage [13-15, 25]. The
TH2 cell polarization and maintenance are mediated by the
activation of STAT6 followed by the activation of GATA-3
and the overexpression of these transcription factors are
found in atopic asthma. Some chemokine-chemokine recep-
tors (CKRs) regulate the chemotaxis of TH2 cells and its
ligands can regulate chemotaxis and, consequently the ac-
cumulation of TH2 cells and the inflammatory responses
[15].
The control of the immune responses to both self and
non-self antigens in humans is also modulated by the sub-
population of CD4 T cells termed T regulatory (Treg) cells.
The transcription factor forkhead box P3 (FoxP3+) is crucial
for the development of natural Treg cells and a deficiency of
these cells may result in severe food allergies and atopic
dermatitis. Food allergy IgE mediated is prevalent in atopic
individuals and can manifest by cutaneous and gastrointesti-
nal symptoms. The gut is exposed to a variety of antigens
and remains insensitive to almost all antigens due to the im-
munosuppressive function in the gastrointestinal system by
Treg cells [25-27].
In general, anti-allergic actions from natural products are
identified by assays, such as -hexosaminidase release using
rat basophilic leukemia (RBL)-2H3 cells, a continuous mast
cell model obtained from the dilution technique after treat-
ment with a carcinogen drug (-chloroethylamine) [28]. -
Hexosaminidase is released concomitantly with histamine.
Therefore, it is important to characterize whether the com-
pound is able to inhibit -hexosaminidase release or activity
of the -hexosaminidase [18,20]. Passante et al. [29] showed
that lipopolysaccharide (Escherichia coli 0111:B4) is not
able to stimulate the release of cytokines (IL-13 and TNF-
)
in RBL-2H3 cells, an effect that can be explained by the lack
of CD14 expression in this cell line. According to Passante
et al. [29], assays using RBL-2H3 cells are reliable for
studying only the IgE-mediated degranulation of secretory
cells because these cells share some characteristics of baso-
phils rather than those of mast cells.
Each herb produces a variety of compounds from differ-
ent biosynthetic pathways that affect several targets and their
combination can result in synergistic effect based on multi-
target mechanisms of action. Mast cell stabilizers are the
drugs that are more frequently identified as active constitu-
ents from herbs and herbal natural products but they can af-
fect several steps of allergic response Fig. (1). Herbal medi-
cines and small molecules can stimulate either innate or
adaptive immunity by the activation of T or B cells, by the
28 Recent Patents on Endocrine, Metabolic & Immune Drug Discovery 2013, Vol. 7, No. 1 Cota et al.

Antigen
MAST CELL

Antigen
APC GPCR
Cytokine receptor
FceRI
Naive T cell n Action sites of herbal products
G protein

8
LYN

9 PLCβ MAP3K 13
CD4+ SYK
12

FoxP3 RAS PI3K PLCγ p38 c-Jun IKK2

IL-12 IL-4
14
Treg Antibody production RAF Akt 2+
Ca PKC NF-kB
17
2 10

MEK 1\2
GATA
TH1 1 TH2 B cell Plasma cell
IL-4,IL-5,IL-10 ERK 1\2
IL-13
IFN-γ, IL-2, Glucocorticoid
TNF-β cPLA 2
receptor

3 Arachidonic acid
IL-4, IL-5 IL-4, IL-9 IL-4, IL-5 cascade
IgE

FceRI
COX LOX
5 7
Degranulation
Ag
Cytokine gene 15
IL-9, IL-13 expression
Basophil Eosinophil Mast cell
4
11

IL-4, IL-13
Mucus production
16
6

Prostaglandins Leukotrienes Cytokines Histamine

Chemokines Tryptase
Thromboxanes β-Hexominidase

Action sites of some herbal medicines, edible plants and natural products

Ailanthus excelsa: 4,15 Daphne gnidium: 1, 5, 6 Gomisins C, G, N: 7 Lithospermum erythrorhizon: 1 Rice: 16

Amomum compactum: 3, 4, 11 Diosgenin: 2 Guarana: 16 Mangostin: 12 Schinzandrols A,B: 7
Apple: 4, 11, 16 Echinodorus grandiflorus: 3,11 Hardy kiwi: 3, 11 Matricaria recutita: 16 Schinzandrins A, C: 7
Aubergine: 1, 16 Eggplant: 11 Hesperidin: 5, 13, 17 Nobiletin: 5, 13, 17 Selidinin: 12
Burdock: 7, 16 Emodine: 1, 5, 6, 7, 9, 12 Humulene: 1, 5, 6 Nootkatone: 7 Sinomenine: 6, 7
Camellia japonica: 3, 8, 11, 14, 15 Eupatilin: 1, 17 Inula japonica: 3, 11 Oat: 11 Syzygium cumini: 15
Caryophyllene Oxide: 7 Naringin: 5, 13, 17 Isatis tinctoria: 4 Oryza sativa: 1 Teucrium japonicum: 1, 3, 10, 17
Clitoria ternatea: 15 FAHF-2: 1, 3 Isokaempferide: 1 Panax ginseng: 1, 10 Tomato: 4
Coffee: 1, 3, 16 Garlic: 16 Jaceosidin: 1, 17 Phlomis umbrosa: 1, 11 Trans-caryophyllene: 1, 5, 6
Cydonia oblonga: 3 Gencydo®: 2 Lindera obtusiloba: 1, 10 Rehmaninia glutinosa: 11 Valence: 7,8

Fig. (1). Schematic representation of molecular mechanisms involved in allergy which are influenced by herbal medicines and natural prod-
ucts. The forms of octagons represent the targets in which the extracts, formulas and natural products can act. Components of herbal medi-
cines and natural products inhibit a variety of transduction pathways involved in the “early and late phases” of the immune response. The
“early response” occurs within minutes after allergen exposure and primarily involves histamine, heparin,
-hexominidase, leukotrienes and
prostaglandin mediators. First exposure to allergen lead to activation of TH2 cells and stimulation of IgE class switching in B cells. The
crosslinkage of IgE to high-affinity Fc receptor expressed on mast cells, basophils and eosinophils initiates the degranulation response. Mast
cells can be also directly activated by peptides, chemokines, complement-derived anaphylatoxins, by Fc
RI molecules without bound IgE and
chemical crosslinkage of IgE. The “late response” occurs hours later and involves mainly cytokines and chemokines. The mediators released
increase endothelial cell permeability and smooth-muscle contraction (histamine, heparin, serotonin, leukotrienes, prostaglandins, and
bradykinin). They also recruit inflammatory cells and are responsible for bronquial mucus secretion (proteases), platelet aggregation, de-
granulation and chemotaxis and activation of leukocytes (platelet- activating factor).
Anti-Allergic Natural Products Recent Patents on Endocrine, Metabolic & Immune Drug Discovery 2013, Vol. 7, No. 1
modulation of expression of co-stimulatory ligands on the
surface of the APCs, inhibition of TH2 cell differentiation
and modulation of cytokine-regulated genes, CKRs and
ligands of TH2 cells. In addition, the TH2 signal transduction
pathways can be modulated and the identification of agonists
or antagonists of histamine receptors, inhibitors of CysLT, 5-
LOX, COX and prostaglandin D2 synthase (HPGD2) en-
zymes can be further explored. The enhancement of the TH1
response is the main approach in drug discovery for anti-
allergic agents, but we have to consider the immunostasis
effect and, consequently, the Th2 functions of the mainte-
nance of humoral immunity and upregulation of antibody
production [15, 23, 30].
THE POTENTIAL OF FOOD PLANTS
Studies with Edible Plants
Agricultural plants are mainly nutrition sources and re-
cent studies have demonstrated that their secondary bioactive
metabolites can act as pharmaceutical compounds. Several
crops have been evaluated regarding its anti-allergic poten-
tial. Tewtrakul et al. [31] evaluated the effects of some food
plants from Thailand that showed in vitro potential as dietary
supplements. The extracts [(95% ethanol (EtOH), 50%
EtOH, H2O (W), and hot H2O (HW)] were tested in an assay
using antigen-induced
-hexosaminidase release as a marker
of the degranulation of RBL-2H3 cells. The IC50 values ob-
tained for those extracts ranged from 7.5 to 62.1μgmL-1. It is
noteworthy that mango seed (50% EtOH, IC50 = 7.5μgmL-1),
banana (W, IC50 = 13.5μgmL-1), okra (W, IC50 =
13.6μgmL1), jampadah skin (HW, IC50 = 13.8μgmL-1), tama-
rind seed coat (HW, IC50 = 14.2μgmL-1), and jampadah flesh
(W, IC50 = 14.6μgmL-1) were the most active extracts [31].
Eating plants with a high content of tannins, alkaloids,
terpenes and phenolics compounds may benefit herbivores as
a long-term healthcare habit to resist and treat diseases
[32,33]. Table 1 summarizes some edible plants with anti-
allergic activity within in vitro and in vivo models. In gen-
eral, the studies to investigate the anti-allergic effects were
performed by short-term administration of extracts and not
by the direct ingestion of plant material. Nevertheless, there
is a great difference in bioavailability of bioactive com-
pounds considering plant material intake or extracts admini-
stration. This difference is due to the variability in the ab-
sorption profile of the components present in the mixture
and, therefore, the interpretations of these studies must be
made with caution [34].
In the studies mentioned in Table 1 [35-49], the extracts
tested may affect both early and lathe-phases of allergic con-
ditions. Eggplant (Solanum melongena), burdock (Arctium
lappa), and rice (Oryza sativa) inhibit the release of media-
tors such as histamine [37,44-47] and in vivo guarana (Pau-
linia cupana) suppresses cutaneous anaphylactic reaction
[45]. Coffee (Coffea arabica) intake does not suppress the
release of histamine from mast cells. However, coffee sup-
presses IgE production conferring a prophylactic effect
against allergic reactions [48].
In addition, topical administration but not oral admini-
stration of extract from burdock is able to inhibit acute
mouse ear swelling by 50% in an in vivo cow’s milk allergic
29
model confirming its popular use in Brazil and Asia due to
an anti-inflammatory effect. The extract was identified to-
gether with 98 extracts from a high throughput screening of
10,000 herbal extracts using a
-hexosaminidase release as-
say in RBL-2H3 cells. The study also compared the activity
of eight extracts from A. lappa prepared by different
methods and derived from various suppliers on the release of

-hexosaminidase in RBL-2H3 cells. Only the extract pro-
vided by PhytoMyco Research Corporation (PMRC) showed
comparable activity to the extract dissolved in EtOH 20%.
Constituents from the PMRC extract were able to inhibit the
degranulation and cys-leukotriene release in vitro without
affecting the viability and metabolic activity of PBMCs in
the same dose suggesting the low toxicity of burdock [37,48,
49].
In a recent study, a water-soluble extract prepared from
the edible fruits of Actinidia arguta (Hardy Kiwi) was admi-
nistrated to 90 asymptomatic subjects with atopy and ele-
vated levels of serum total IgE. Subjects took two tablets of
250mg of powdered hot-water extract twice a day for 8
weeks. The treatment reduced total serum IgE, eosinophilic
cation protein (ECP), eotaxin and eosinophil counts in the
peripheral blood and no serious adverse events were reported
[50]. The results from this clinical trial are in accordance
with the property of A. arguta to suppress dermatitis in dogs
[51], prevent food allergy and ameliorate allergic diarrhea by
oral administration in the murine OVA-induced allergic diar-
rhea model [35]. Furthermore, an in vitro study demonstrated
that the extract downregulates the expression of IgE and sev-
eral key cytokines (IL-5, and IL-13) while up-regulating im-
portant markers of regulatory T cells such as FoxP3+, TGF-

1, and IL-10, [35]. To date, extracts from black rice [52],
apple [53] and, A. arguta have been patented [54].
Edible Plants in Food Allergy
Food allergy is an adverse immune response to food al-
lergens. It is a common allergic disorder and a pediatric
health problem in Western countries. The prevalence of food
allergy in Europe and North America ranges from 6% to 8%
in children up to the age of 3 years. Currently, there is con-
siderable variation and no agreed treatment pathways for
food allergy care [55]. Food plants with anti-allergic poten-
tial might be a helpful tool.
Many food supplements may reduce the sensitization to a
specific allergen and/or reduce the severity of allergic reac-
tions. A nutritional composition can prevent allergies by
reducing the risk of sensitization of patients to allergens by
reducing the levels of allergen-specific IgE antibodies (pri-
mary prevention) or modulating the occurrence or intensity
of the allergic symptoms in patients already sensitized (sec-
ondary prevention). The modulation of immune system de-
pends on the maturity of various components of the gut bar-
rier and previous exposition to allergens. Thus, this kind of
intervention can be advantageous in some groups of patients
such as children and elderly people because they do not tol-
erate some medicines and the only treatment in food allergy
is the strict avoidance of allergic food components [56].
Dietary interventions may promote the immune tolerance
and prevent the immune diseases. Recently, the protective
30 Recent Patents on Endocrine, Metabolic & Immune Drug Discovery 2013, Vol. 7, No. 1 Cota et al.

Table 1. In vitro and In vivo Studies and Clinical Evidence of Antiallergic Effects of Edible Plants. Plant Species and Common
Names, Allergic Markers and Biological Response Evaluated.

Common Assay
Food Plant Allergic Markers Evaluated Response Other Aspects Reference
Name Type

Actinidia arguta (Sie- [35]

bold & Zucc.) Planch. ex Hardy kiwi  IgE, IL-5, IL-13
Miq

Allium sativum L. Garlic  Histamine [36]

Arctium lappa Linne Burdock  -HEX, LT  Basophils degranulation [37]

Avena sativa L. Oat  PGF-1
, IL-2 [38]

In vitro
Malus pumila cv. Fuji Apple  Histamine  Mast cells degranulation [39-43]

 -HEX, histamine, [44]

Oryza sativa L. Rice
TNF-
, IL-1, IL-6

Paulinia cupana Kunth Guarana  -HEX [45]

Eggplant,  Histamine and [46]

Solanum melongena L.
aubergine TNF-

Purple-fruited [47]
Solanum trilobatum L.  IL-1
and
IL-8
pea eggplant

Gene expression

Actinidia arguta (Sie- Hardy kiwi  IL-5, eotaxin,  Airway hyperresponsivness
Heme oxygenase-1, [35]
bold & Zucc.) Planch. MCP-1, TARC and Foxp3+, TGF-1, and IL-
ex Miq IgE 10 T reg

 Eosinophil peroxi-  Ear swelling, systemic ana- [36]

Allium sativum L. Garlic
dase activity phylaxis, rat paw edema

Arctium lappa Linne Burdock  Ear swelling [37]

 IL-2 and IgE
IL- [48]

Coffea arabica L. Coffee
In vivo

12

 T-helper type-2 associ- [39-43]

 Symptoms of food allergy,
Malus pumila cv. Fuji Apple  Cytokine secretion ated and pro-inflammatory
intestinal mast cell protease
genes

Paulinia cupana Kunth Guarana  PCA reaction in mice [45]

Eggplant,
PCA and anaphylatic reaction [46]

Solanum melongena L.
aubergine in mice

Purple-fruited Stabilization of mast [47]

Solanum trilobatum L.
pea eggplant cells

Pathological condition

Lycopersicon esculen- Tomato  IgE, Eosinophil  Sneezing, rhinorrhea and Allergic rhinitis [49]
tum Miller nasal obstruction

 Inflammation, lichenification, [39-43]

Clinical

Malus pumila cv. Fuji Apple  Eosinophil cracking, itching, sleep distur- Atopy
bance

 Sneezing attacks, nasal dis- [44]

Oryza sativa L. Rice charge, swelling of the nasal Allergic rhinitis
turbinate
Anti-Allergic Natural Products Recent Patents on Endocrine, Metabolic & Immune Drug Discovery 2013, Vol. 7, No. 1
effect against allergic conditions of Lyc-O-Mato® (LycoRed
Natural Products Industries Ltd, Israel), which is a supple-
ment to be taken in doses of 4 mg or 8 mg/kg per day (0.16
mg lycopene + 0.006 mg -carotene + 0.05 mg vitamin E),
was demonstrated in BALB/c mice. The treatment with Lyc-
O-Mato® reduced eosinophilic infiltrates in the bronchoal-
veolar lavage fluid, lung tissue and blood. It also reduced the
number of mucus-secreting cells in the airways and sup-
pressed the OVA-specific release of the IL-4 and IL-5 [57].
Another study showed that diet supplementation with vita-
min E (5mg /100g of diet) plus -carotene (50mg/100g of
diet) suppresses both the antigen-specific IgG1 and total IgE
levels in BALB/c mice [58]. A diet containing only -
carotene (20mg/kg bw) for 1 month in BALB/c mice showed
the same previous results and increased CD4+ and CD8+ T
cells, IgG2a levels and cytokines (IFN- , IL-12 and IL-2)
in the spleen cells [59]. However, the IFN- and IL-12 levels
only increased in the DO11.10 mice group fed with both  -
carotene (0.05mg/100g) and
-tocopherol (0.005g of its ace-
tate) as a supplement. When vitamin E was supplemented as
-tocopherol (100mg/kg) for 4 days, it provided a broad pro-
tection spectrum in induced inflammation in allergic Brown
Norway rats. This treatment inhibited eosinophil recruitment,
PGE2, LTB4, CysLT, nasal expression of cytokines (IL-4, -5,
-13 and IFN-) and overproduction of mucus in induced al-
lergic rhinitis and asthma models [60].
Secondary Metabolites From Edible Plants
Several researchers have suggested that the changes (in-
crease or decrease) of antioxidant intake including vitamins
E, C, D, carotenoids, selenium, polyphenols, polyunsaturated
fatty acids, in the last three decades, are responsible for the
increase in asthma and in allergic diseases. The antioxidant
foods consumption such as polyphenolic compounds Fig. (2)
has been associated with a reduced likelihood of asthma and
wheezing symptoms [61]. According to Singh et al. [62], the
presence of polyphenols in the daily diet confer them a
safety profile and justifies their recognition as anti-allergic
agents. It is known that polyphenols can form insoluble
R1
R2
HO O HO
R3
O R4
OH O O
Flavonoid R1 R2 R3 R4
Quercetin OH OH H H
Kaempferol H OH H H
Isoquecitin OH OH H  -D-glucopiranosy l
Rutin OH OH H
-L -rh amn opiranosyl-(1
My ricetin 3- O -rutinoside OH OH OH
-L -rh amn opiranosyl-(1
Fig. (2). Antioxidant flavonoids and tannins common in fruits and vegetables.(*)
(*) USDA Database for the Flavonoid Content of Selected Foods - Release 3/2011.
31
complexes with allergenic proteins changing their structure
or rendering it less bioavailable. These effects can lead to
inefficient antigen presentation by specialized cells such as
dendritic cells and inhibits T cell proliferation and cytokine
production. Thus, these compounds can modulate different
phases of the allergy, inhibit airway inflammation and tissue
eosinophilia, prevent food allergy and to manage staphylo-
coccal infection in atopic eczema [62].
Flavonoids are a class of natural product that is most ex-
tensively found in food associated with anti-allergic activity
[63, 64]. On the other hand, saponins which are frequently
found in several food plants such as soybeans, peas, spinach,
quinoa, licorice, ginseng, capsicum peppers, eggplant and
yam, present glucorticoid-like activity and have huge bio-
logic potential [65]. The triterpene saponin named as com-
pound K Fig. (3A) is a protopanaxadiol ginsenoside metabo-
lite of ginseng which competes with dexamethasone (Dex)
for binding to glucocorticoid receptor (GR). This compound
represses TLR4-dependent inflammatory response genes, the
secretion of pro-inflammatory cytokines by macrophages
and also protects septic mice against hyperresponsiveness
and death [66]. Avicin D Fig. (3B) is another triterpenoid
saponin from Acacia victoriae that competes with Dex for
binding to the GR and induces nuclear translocation of this
receptor, decreasing the expression of GC-dependent meta-
bolic proteins such as PEPCK and FASN besides inhibiting
NF-B transcription [67].
CONCERNS ABOUT SUPPLEMENTS BASED ON
EDIBLE PLANTS
Nearly, 500-1,000 plants and/or plant parts are used in
plant food supplements in Europe, China and South Africa
[68]. According to Global Industry Analysts (GIA), it is es-
timated that the worldwide market of herbal supplements and
remedies will reach $93.15 billion USD by the year 2015
[69]. Allan and Devereux [61] emphasize that studies about
supplements to complement conventional treatment also
need to prove their effects in associations with other nutri-
OH
O
OH
OH OH
HO O
OH
OH
OH O
P rocyanidin B2
6)- O -  -D-glucop iran osyl
6)- O -  -D-glucop iran osyl
32 Recent Patents on Endocrine, Metabolic & Immune Drug Discovery 2013, Vol. 7, No. 1
CH2 OH
O O
OH
OH
OH
OH
HO
O
Xyl-Fuc-NAG
(A) Compound K
Fig. (3). Saponins with glucorticoid-like activity isolated from plants.
ents and foods. Some parameters have to be improved in
scientific research for eliminating complex social and behav-
ioral factors. Therefore, investigations about metabolites
generation in humans, levels of active ingredients, route of
administration, dose needed, the type of intervention (pre-
vention vs. treatment), the stage of the human life span to be
used, the impact on immune cells in different anatomical
sites (gut vs. blood), occurrences of allergic manifestations
and interactions with commensal bacteria have to be well
designed.
The labels of herbal dietary supplements cannot state that
those supplements prevent, treat, or cure diseases or condi-
tions without specific approval from the FDA or other regu-
latory agencies. However, they can claim vague health bene-
fits and does not necessarily have to cure, treat, or prevent
illness. Although the safety and efficacy of several herbs is
not well established, dietary supplements can be produced
and marketed without providing FDA documentation as re-
quired for pharmaceutical drugs [70]. Some herbal dietary
supplements may contain high levels of contaminants (arse-
nic, lead, mercury, chlorpyrifos, HCB, etc.) and interact with
prescription drugs. The FDA does not set contaminant resi-
due limits or establish rules for interaction studies with other
prescription drugs, supplements, or foods, albeit it receives
approximately 4,000 such claim submissions per year [70,
71].
CLINICAL TRIAL WITH PLANT FORMULATIONS
Chinese based formulations
Traditional Chinese medicine (TCM) has existed for over
2,000 years as part of Chinese culture maintained for ap-
proximately 1/7 of the world population. TCM, since the
1950s under a decree of the Mao Tsetung government is re-
sponsible for half of the medical assistance service in pri-
mary care done in the Chinese health system. TCM medical
Cota et al.
O
O
O
O OH
O OH
OH
Glu-Rha-Glu
H O
Ara
O
O
(B) Avicin D HO
H O
experts provide diagnoses and treatments based on tradi-
tional and dualistic principles known as Yin-Yang. They
develop a holistic view of the patients with the aim to restore
a natural balance to their metabolism. TCM practice varies
from the use of Chinese herbs, acupuncture, bone-setting,
moxibustion, exercises, breathing techniques, and diets.
TCM develops an important role in primary care to enhance
the quality of life and health of the elderly people especially
those with chronic diseases. However, in recent years, TCM
has been gaining increasing popularity in Western popula-
tions and Chinese herbs are commonly perceived to be free
from side effects and are used widely by the public for self-
medication [72]. The principles guided by Yin-Yang phi-
losophy are also followed in other Asian countries, and their
herbal medicine is known under different names such as Ko-
rean medicine, Kampo Japan, and traditional Vietnamese
medicine. In general, this kind of intervention is practiced
with formulations containing several medicinal plants and,
although these combinations have been used in anthroposo-
phical medicine, their mechanism of action in allergic dis-
eases is unknown.
The infiltrating cells observed in the “late phase” of al-
lergic reactions such as asthma, atopic dermatitis and allergic
rhinitis, result in the recruitment and activation of leukocytes
with a high proportion of lymphocytes and eosinophils.
Atopic dermatitis (AD) is a chronic, refractory skin disease
that requires long-term application of topical steroids that
can cause skin atrophy and telangiectasia in some patients.
Tacrolimus is also used in the treatment of AD but it causes
the sensation of skin burning or irritation after application.
Therefore, effective and safe therapeutic alternatives are re-
quired. The effect of hot water extract from the traditional
herbal (Kampo) medicine known as Hochu-ekki-to was
tested in 37 patients with atopic dermatitis. Hochu-ekki-to
contains Ginseng radix (4.0 g), Atractylodis rhizoma (4.0 g),
Astragali radix (4.0 g), Angelicae radix (3.0 g), Zizyphi fruc-
tus (2.0 g), Bupleuri radix (2.0 g), Glycyrrhizae radix (1.5 g),
Anti-Allergic Natural Products Recent Patents on Endocrine, Metabolic & Immune Drug Discovery 2013, Vol. 7, No. 1
Zingiberis rhizome (0.5 g), Cimicifugae rhizome (1.0 g) and
Aurantii nobilis Pericarpium (2.0 g). It was orally adminis-
trated twice daily for 24 weeks since this formulation re-
quires a longer time of administration to show effectiveness.
Indeed, in this study, the significant clinical benefits ap-
peared at the 24th week. Hochu-ekki-to administration re-
duced the dosage of topical steroids and/ tacrolimus and the
aggravated rates. Moreover, 19% of patients in the treated
group were devoid of skin eruption after the 24-weeks. In
addition, adverse effects related to skin were not reported by
patients [73]. Previous studies in mice orally administered
with Hochu-ekki-to suggest that the improvement of dermati-
tis can be due to the induction of INF-
production from in-
traepithelial lymphocytes. Evidence has suggested that AD
patients have a variety of defects in the innate immune sys-
tem leading them to be susceptible to many pathogens, such
as bacterial, viral, and fungal infections of the skin and Ho-
chu-ekki-to have shown to augment the resistance against
bacterial infections [74,75].
The advantage of herbal preparations over traditional
medicines can be provided by a persisting beneficial effect.
In a randomized double-blind trial, patients with moderate to
severe asthma received oral ASHMITM capsules (n= 46) or
prednisone (n= 46) for 4 weeks. ASHMI TM is composed of 2
herbs and 1 fungus, (Sophora flavescens, Glycyrrhiza
uralensis and Ganoderma lucidum) and is derived from a
TCM 14-herb formula. Clinical symptom scores, use of 2-
bronchodilators, serum IgE levels, and TH2 cytokine levels
were reduced but serum IFN- and cortisol levels were sig-
nificantly increased in the ASHMITM group [76]. The persist-
ing benefits 8 weeks after therapy with ASHMITM had been
discontinued, suggests that a high IFN- level was responsi-
ble for the suppression of airway allergy and to reducing
systemic TH2 cytokines [77]. In addition, the high dose of
ASHMI TM (1,800 mg twice a day) did not increase the TNF-

, IL-1 and IL-6 levels and was well tolerated by patients
(n= 4/12, 33%) [78].
Concerning the control of generalized symptoms in the
“early phase” of the allergic diseases, herbal products with a
wider range of activities may be more effective and have
potential for treating allergic conditions such as food aller-
gies [79]. In these types of allergies, there is an excessive
activation of the mast cells and basophils by IgE, thereby
leading to an extreme inflammatory response. The therapy of
food allergy with Chinese herbs has been considered as the
promising food allergen-nonspecific therapy [80]. Food Al-
lergy Herbal Formula-2 (FAHF-2) is a Chinese extract of 9
herbs that protects animals from anaphylactic symptoms in a
murine model of peanut allergy [81, 82]. The anaphylactic
shock is a severe reaction induced by food and is caused by
the release of large amounts of mediators (histamine, prosta-
glandins, leukotrienes) from mast cells and basophiles lead-
ing to systemic vasodilatation and edema of bronchial mu-
cosa. The treatment of patients with food allergy with 3.3 g
(6 tablets) of FAHF-2 three times a day for 6 months re-
duced CD63 basophile percentages in the blood. In addition,
there was a trend toward a reduction in the percentages of
eosinophil and basophil cells. The protective effect of
FAHF-2 was correlated with the reduction on the basophil
CD63 expression, a protein located inside the granule mem-
brane that is considered a marker of degranulation in anaphy-
33
laxis. It promotes the fusion between granules and plasma
membrane, followed by the release of inflammatory media-
tors such as histamine and tryptase. Clinical protection has
also been associated with increased levels of IFN- and re-
duction in TH2 cytokine, and mainly with the increase of
serum IgE levels. These effects correlate with the reduction
of mast cells and basophils when FAHF-2 is used. In this
study, long-term treatment with FAHF-2 reduced both T/B
lymphocytes and effectors cells and demonstrated to be safe
by oral administration [83].
European Based Formulations
Pantescal® (Bionap, Italy) is a mixture of plant extracts
from Capparis spinosa, Olea europaea, Panax Ginseng and
Ribes nigrum used to relieve allergic symptoms. It is found
in different food supplements available on the European and
USA markets, but on the Italian market 1 g of Pantescal® is
an ingredient of a food supplement sold as a sachet formula-
tion known as Xineall™. Although anti-allergic activities
have already been described for the secondary compounds or
for plant species of Pantescal®, the mechanism of action is
unknown [84-86]. Patients (n= 35/60) diagnosed with mod-
erate asthma in association with rhinitis, received a supple-
mentation of 2 sachets/day of Xineall™. After 10 days, Pan-
tescal® was able to reduce allergen-induced biomarkers such
as sulphidoleukotrienes (43.3%) and CD63 expression
(64.8%). This clinical trial demonstrated the membrane-
stabilizing effect of Pantescal® which could prevent baso-
phil/mast cell degranulation and reduce the responsiveness
of the cells involved in allergic processes toward aeroaller-
gens. In this study, the reduction of the release of sulphi-
doleukotrienes was considered a secondary effect to the cell
stabilization and a result from the decrease of availability of
membrane lipids for synthesis of these inflammatory media-
tors derived from arachidonic acid [87].
In relation to allergic rhinitis, the usual treatment of pa-
tients is performed with antihistamines and/or local corticos-
teroids. Antihistamines are able to reduce the symptoms, but
they do not possess any immunotherapeutic potency to in-
hibit inflammation in the “late phase” of allergic reactions
[88]. Gencydo® (Weleda AG, Germany) is an alternative
anti-allergic therapy used in Europe that contains lemon
juice (Citrus limon) and an aqueous extract from the fruit of
quince (Cydonia oblonga). A recent clinical trial was carried
out to compare the efficacy and safety of two routes of ad-
ministration. Patients (n = 23) aged 18 to 60 and suffering
from seasonal allergic rhinitis (SAR) for at least two years
received Citrus/Cydonia compositum 1% subcutaneous in-
jections (n = 11) twice per week or the Gencydo® nasal spray
(1-2 sprays in each nostril; n = 11) four times a day for five
weeks. Analyses of the mononuclear cells (PBMC) obtained
from peripheral blood samples at day 1 of allergen-specific
stimulation showed that both routes of administration stimu-
late the monocyte compartment (innate immune system) into
a more immunoregulatory phenotype. The treatment en-
hances IL-10 production while reducing the inflammation
marker TNF-
. In turn, analyses at day 7 showed a decrease
in the activity of both monocytes and Treg (decrease of IL-
10) demonstrating a reduction in the activation of immune
system. The treatment with Citrus/Cydonia (ampoules) sig-
nificantly reduces SAR symptom severity and presents supe-
34 Recent Patents on Endocrine, Metabolic & Immune Drug Discovery 2013, Vol. 7, No. 1
rior clinical efficacy than Gencydo® as nasal spray. After
subcutaneous administration, Gencydo® reduces chronic
inflammation and demonstrates profound effects in innate
immune response. Authors believe that the decreased in the
activity of the Treg can be responsible for the observed relief
of symptoms. They also state that Citrus/Cydonia composi-
tum may be regarded as a curative type of treatment because
its ability to regulate the activity of the immune system of
SAR patients permanently [89].
In an in vitro study, Gencydo® inhibited the degranula-
tion and histamine release from basophils and mast cells, the
production of inflammatory cytokines by mast cells (IL-8,
TNF-
, GM-CSF), the IgE-mediated release of GM-CSF
and decreased eotaxin release from human bronchial epithe-
lial cells. In allergic response, eosinophils are especially at-
tracted to the site of allergen exposure by eotaxin. Gencydo®
was also able to reduce the attraction of eosinophils, but it
did not promote the apoptosis of these cells. These character-
istics within in vivo and in vitro can be advantageous com-
pared to antihistamines because they affect both “early and
late phases” of allergic reactions [90].
CONCERNS ABOUT CLINICAL TRIALS
Several studies about CAM clinical trials have demon-
strated that the reported information is poor in quality, result-
ing in difficulties in the assessment of internal and external
validity and reproducibility. Although herbal medicine trials
are somewhat better reported compared with homeopathy
and acupuncture trials, they do not report details of the inter-
vention in randomized clinical trials. Gagnier et al. [91]
demonstrated that herbal clinical trials fail in reporting more
than 60% of the information required for this type of study.
From 406 randomized clinical trials evaluated, only 38% of
the information suggested in the checklist based on Consoli-
dated Standards of Reporting Trials Statement was found.
CAM trials, in many cases, do not describe the generation of
the random sequence, method of authentication of the raw
material, where the voucher specimen is kept, and descrip-
tion of any special testing/purity testing. In this study, only
the year of publication was found as a significant predictor
(11 predictors), because clinical trials that were published in
more recent years comprise more items [91].
In addition, HPLC-MS profiling of preparations and
markers of species are rarely characterized to ensure the pre-
cise dose for effectiveness, quality and consistency [78]. The
treatment schedules adopted in clinical trials with herbal
formulations are very different, can vary from 1 to 24 weeks,
and in most of clinical trials the efficacy of slow-acting for-
mulations cannot be demonstrated [73,78]. In these studies,
the identification of the probable active compounds is not
one of the goals and the hormonal effects that can be attrib-
uted to their own components or contamination are not asso-
ciated with results and adverse effects [92]. Furthermore,
there is insufficient clinical information available about the
use of herbal medicines for long periods. Thus, liver and
renal damages, carcinogenic effects, and interactions with
other prescription drugs are not accessed [93].
Cota et al.
CURRENT STATUS ABOUT THE STUDIES WITH
HERBS
Herbal medicines have gained increasing popularity due
to the side effects resulting from Western drug treatments or
because they may improve conventional medical treatments.
This kind of intervention has represented a large percentage
of pharmaceutical sales in the U.S., Europe [69] and in
China. In the last country where the use of traditional medi-
cine is spread among people a project called herbalome was
created to analyze the complex components and investigate
pharmacological effects aiming to establish a resource li-
brary [94]. The increasing importance of herbal products to
the global market led to the International Regulatory Coop-
eration for Herbal Medicines to support the creation of one
database and network for sharing information and expertise
by technical documents [7].
Several plants used for asthma in Ayurveda have shown
antiasthmatic activity in in vitro and in vivo models [95].
Recently, a study demonstrated that the species used in Thai
traditional medicine to treat allergy diseases are active in the
-hexosaminidase release assay with RBL-2H3 cells and
some of them such as Kaempferia parviflora (EtOH, IC50 =
10.9 μgmL-1) and Zingiber cassumunar (EtOH, IC50 = 12
μgmL-1) are more active than ketotifen fumarate (IC50 = 20.2
μgmL-1) [96]. A great proportion of plants reported with
anti-allergic properties in the last five years is from South
Korea traditional medicine (Table 2) and these studies have
proven that their popular indications are in accordance with
the results found in models of asthma, anaphylaxis, pruritis
and dermatitis.
According to [97] approximately 50% of severe asthma
exacerbations are eosinophilic in nature and the most prom-
ising approaches under investigation are those that reduce
airway eosinophils in patients with severe refractory asthma
and a persisting airway eosinophilia. Eosinophils are multi-
functional cells sources of various inflammatory and regula-
tory cytokines. They accumulate in the blood, organs, and
tissues in allergic and parasitic diseases and this accumula-
tion is correlated with a negative prognostic indicator. Sev-
eral plants such as Ailanthus excels, Angelica dahurica,
Clitoria ternatea, Echinodorus grandiflorus, Inula japonica,
Isatis tinctoria and Syzygium cumini are able to reduce the
total number of inflammatory cells or eosinophils in bron-
choalveolar lavage in asthma models with mice or rats. Al-
though long-term treatment with inhaled corticosteroids has
improved quality of life and contributed to a reduction in
deaths of asthmatic patients, approximately 5-10% of pa-
tients with severe disease fail to respond to conventional
treatment. The recent trend in asthma therapy is to target
several biomarkers simultaneously and the combinations of
drugs represent a huge potential of intervention [98]. Thus,
the herbs containing a great number of chemical constituents
could modulate, through specific and non-specific ap-
proaches, several components of the immune system [30].
Asthmatic patients often have atopic eczema lesions,
which is a chronic inflammatory skin disorder characterized
by eczematous skin lesions and pruritus. Itch in atopic ec-
zema/dermatitis can be mediated by neuropeptides, interleu-
Anti-Allergic Natural Products Recent Patents on Endocrine, Metabolic & Immune Drug Discovery 2013, Vol. 7, No. 1
kins, proteases, and cytokines by direct binding to itch recep-
tors or indirectly via histamine release [99]. Aristolochia
bracteolate, Cydonia oblonga, Matricaria recutita, Rehman-
nia glutinosa extracts are able to alleviate dermatitis in the
mice model. In atopic eczema/dermatitis syndrome about 70-
85% of patients have high serum IgE levels and the disease
is IgE-mediated [100, 101]. Almost half of the species listed
in Table 2 inhibits histamine release and some of them can
reduce the serum IgE level. Anaphylaxis (acute allergic re-
sponse) is also triggered in response to allergen exposure
following formation of IgE to specific portions of the aller-
gen from activated B cells and IgE binding to FcRI recep-
tors located on the surface of mast cells and basophils. Sev-
eral polar extracts (Acanthopanax senticosus, Bauhinia
variegate, Lindera obtusiloba, Matricaria recutita, Phlomis
umbrosa, Teucrium japonicum) inhibit immediate-type hy-
persensitivity in systemic allergic model (anaphylaxis) with
mice. Intraperitoneally administration of L. obtusiloba (100
mg/kg bw) inhibit the mortality of mice completely while the
majority of other species were orally administered and sup-
pressed about 50% of the induced fatal shock.
From 23 species Table 2 [95, 102-123], 9 inhibit TH2-
derived cytokines mainly IL-4, IL-5 and TNF-
(Amomum
compactum, Angelica dahurica, Camellia japonica, Inula
japonica, Isatis tinctoria Lithospermum erythrorhizon,
Panax ginseng, Rehmannia glutinosa, Syzygium cumini).
The modulation of cytokines can be useful as a therapeutic
strategy for allergic inflammatory diseases. The increase of
endogenous expression of anti-inflammatory cytokines (IL-
10 and IL-12) or the decrease of expression of inflammatory
cytokines (IL-4 and IL-13) through immunomodulatory
pathways can be more effective than their direct administra-
tion [98].
The potential of plants is the immense rich diversity of
secondary metabolites that provide them the ability to act in
multiple pathways including the blockage of mast cell de-
granulation, Th2 activation and IgE, prostaglandin and leu-
kotrienes production. In studies focused on accessing prob-
able kinase pathway as mechanism of action, Camellia ja-
ponica, Lithospermum erythrorhizon, Lindera obtusiloba
and Panax ginseng appear promising as inhibitors of IKK2
or MAPK pathways that are implicated in corticosteroid
function. The leaf extract of C. japonica was identified from
a screening of 100 Korean plant extracts as the most potent
inhibitor of degranulation of RBL-2H3 mast cells. It also
inhibited Syk kinase phosphorylation and the three major
MAP kinases, Erk1/2, p38 and JNK. Syk is involved in trig-
gering mast cell degranulation through the FcRI, in B and T
lymphocyte antigen receptor signaling and in eosinophil sur-
vival. The activation of Erk1/2, p38, and JNK pathways in-
creases the expression of inflammatory cytokines, chemoki-
nes and the recruitment and activation of infiltrating and
resident cell types [98,102].
However, the efficacy of the extracts is related to their
composition. The qualitative and quantitative chemical pro-
files of the extracts are influenced by collection, extraction
method, plant part and stored conditions. In general, con-
stituents found in aqueous or ethanolic extracts are compara-
ble to those present in the teas and infusions, but it is rare to
35
find comparison in the works between the pharmacological
effects of extracts obtained using different solvents, methods
and parts of the plant. Preliminary phytochemical screening
to observe the presence of classes of natural products is not
performed in the majority of scientific studies, although we
can find a HPLC profile of one standard mixture of previ-
ously isolated compounds of species/genus [103] or quantifi-
cation of ubiquitous secondary metabolites in the nature that
the anti-allergic properties were already described [104].
POTENTIAL ANTI-ALLERGIC OF SECONDARY
METABOLITES FROM PLANTS
Systematic studies of plants have resulted in the knowl-
edge of the single chemical entities that are the active com-
ponents. Anti-allergic natural products have different mo-
lecular sizes, belong to several classes of chemical skeletons
(flavonoids, triterpenes, alkaloids, xanthones, stilbenes, etc.),
and have a molecular weight ranging from 200 to 1500 kDa.
Although many natural products have been identified as anti-
allergic agents their mechanisms of action were not fully
elucidated. Over the past 30 years (1981-2010), only 17 new
chemical entities were approved for the treatment of aller-
gies. Natural products (n = 1), natural product botanical (n =
1) and substances derived from a natural product (n = 4) rep-
resented an inexpressive contribution as a source of new
drugs in this therapeutic area demonstrating that they still
have considerable potential in drug discovery. The secondary
metabolites may influence multiples pathways of allergic
responses and show immunomodulatory properties resulting
in benefits to human health [124].
Among all classes of natural products, antiallergic activ-
ity of flavonoids is well described in the literature although
there is not a large number of samples and systematic pre-
liminary screening with these natural products in the last five
years. Some natural products with anti-allergic properties
and their mechanisms of action are summarized in Table 3
[125-154]. In phytochemistry studies with isolation of sev-
eral compounds from the same biosynthetic pathway, struc-
ture-activity relationships can be suggested. Schizandrins
Fig. (4A) and gomisins Fig. (4B) isolated, respectively, from
Schisandra fructus and Magnolia flos are good examples.
These compounds demonstrated inhibitory activity on 5-
LOX-catalysed leukotriene production. 5-LOX inhibitory
activity was modified by the presence of 8-hydroxyl group
or 12,13-methylenedioxy group in the basic skeleton [125].
The acyl group at the 22-position of the aglycon part of sa-
sanquasaponins Fig. (5) isolated from the flower buds of
Camellia sasanqua was essential for the potent inhibitory
activity on the release of
-hexosaminidase from RBL-2H3
cells. Antiallergic potency can also be influenced by the
presence of a single sugar in the structure. Aglycon (1.25
mg/kg, p.o.) of cucurbitacin E 2-O-
-D-glucopyranoside is
significantly more active than glycosilated compound (200
mg/kg, p.o) and equivalent for that of a reference compound,
tranilast on passive cutaneous anaphylaxis (PCA) reaction in
mice [126]. Structure-activity relationships studies may iden-
tify pharmacophores that are responsible for immune re-
sponse and enable the rational design of molecules with im-
munomodulating properties.
36 Recent Patents on Endocrine, Metabolic & Immune Drug Discovery 2013, Vol. 7, No. 1 Cota et al.

Table 2. In vitro and In vivo Evaluation of Antiallergic Potential of Plants Extracts. Species, Family, Plant Part Studied, Type of
Extract and Assay, and Effective Dose Values Used in Experimental Models.

Species Family Plant Part Extract Assay Type Effective Dose Experimental Model (Stimuly) Reference

Goat;
the tracheal contraction [105]

Ex vivo 100
gmL-1
(induced by histamine)

100, 200, 400 Mice;
leukocytosis and eosino-

Ailanthus excelsa mg/kg (p.o.) philia (induced by milk)
Simaroubaceae Leaf MeOH
Roxb.
200, 400mg/kg
In vivo Rat;
the paw edema
(p.o.)

Rat;
the mast cell degranula-

400mg/kg (p.o.)
tion (clonidine)

Mice;
the infiltrating eosino- [106]

Amomum compac- 100, 200mg/kg phils; the mucus production; IL-
Zingiberaceae Seed H2O: EtOH In vivo
tum Sol. Ex Maton (p.o.) 4, IL-5 and IgE level (induced by
OVA)

Mice;
the eosinophilia, IL-4, [103]

Angelica dahurica 50, 100mg/kg IL-5, TNF-
, IgE levels and the
Umbelliferae Root H2O: EtOH In vivo
Bentham et Hooker (p.o.) mucus production (induced by
OVA)

Rat;
histamine and the serum [107]

nitrate levels (induced by com-
pound 48/80)

Mice;
anaphylaxis, rhinitis,

400mg/kg (p.o.)
pruritus and dermatitis (induced
Aristolochia by compound 48/80)
Aristolochiaceae Whole plant CHCl3 In vivo
bracteolate Lamk.
Mice;
rhinitis (toluidine diiso-
cyanate)

Rat;
nitrate levels in the perito-

500mg/kg (p.o.) neal fluid and in the BALF (in-
duced by compound 48/80)

Mice; the mortality in anaphylac- [108]

Bauhinia variegata
Caesalpiniaceae Stem bark EtOH In vivo 400mg/kg tic reaction (induced by com-
L.
pound 48/80)

Mice;
the tracheal contractions [109]

Dichrostachys (induced by CCh, serotonin-
cinerea (L.) Wight Fabaceae Root bark EtOH: H2O Ex vivo 1mgmL-1 KBS-KCl) dependent on epithe-
et Arn. lium and K+ channels, namely Kv
and BKCa channels

100-1000mg/kg Mice;
the PCA reaction (in- [102]

In vivo
(p.o.) duced by IgE)

RBL-2H3 cells;
the degranula-

In vitro ~50mgmL-1 (IC50)
tion process

RBL-2H3 cells;
the TNF-
and

In vitro 10-100
gmL-1
Camellia japonica IL-4 secretion
Theaceae Leaf EtOH
L.
RBL-2H3 cells;
the
-1 phosphorylation of Syk kinase,
In vitro 10-100
gmL
p38, Er
1/2, JNK, LAT, Akt and
MAP kinases

BMMCs;
the phosphorylation

In vitro 0.3-10
gmL-1
of Lyn kinase
Anti-Allergic Natural Products Recent Patents on Endocrine, Metabolic & Immune Drug Discovery 2013, Vol. 7, No. 1 37

(Table 2) Contd….

Species Family Plant Part Extract Assay Type Effective Dose Experimental Model (Stimuly) Reference

RBL-2H3 cells;
the -HEX [110]

100
gmL-1
release
In vitro
RBL-2H3 cells;
the mRNA
200
gmL-1 expression of IgE (FcRI)
Cydonia oblonga
Rosaceae Fruit H 2O subunit
Miller

Diet supplemented NC/Nga mice;
serum IgE level

In vivo
with 5% of extract and
dermatitis

100-150mg/kg Mice;
leucocytosis and eosino- [95]

(i.p.) philia (induced by milk)

Clitoria ternatea L. Fabaceae Root EtOH In vivo Mice;
degranulation of mast

100mg/kg (i.p.)
cells (induced by egg albumin)

100mg/kg (i.p.) Rat;
PCA reaction

100-500mg/kg Mice;
the systemic anaphylaxis [111]

In vivo
(p.o.) (induced by compound 48/80)
Dictamnus dasy-
Rutaceae Root bark H2O: EtOH Mice;
the scratching behavior
carpus Turcz
and
the vascular permeability
In vivo 500mg/kg (p.o.)
(induced by compound 48/80,
histamine, serotonin)

Peritoneal macrophages;
ex- [104]

-1 pression of COX-2, iNOS, IL-1,
Daphne gnidium L. Thymelaeaceae Leaf EtAc In vitro 25-100
gmL
TNF-
; synthesis (induced by
LPS) of NO and PGE2

Lung tissue from mice;
the [112]

total number of cells and eosino-
Echinodorus
phils in BALF,
eosinophil
grandiflorus Alismataceae Leaf H 2O In vivo 23mg/kg (p.o.)
peroxidase activity,
the IgE
(Cham. & Schltdl.)
level,
the levels of CCL11, IL-
Micheli.
4 and IL-13

Cultured splenocytes of OVA- [113]

Ex vivo 50-400mg/kg (p.o.) induced mice;
the levels of IL-
4, IL-5, IL-13 in supernatant

Inula japonica Mice;
the eosinophils and TH2

Compositae Flowers H2O: EtOH cytokines in BALF,
the airway
Thunb
200, 400mg/kg hyper-responsiveness,
the
In vivo
(p.o.) mucus hypersecretion (induced
by OVA) and
the serum IgE
level (induced by methacholine)

Mice;
the airway hyperrespon- [114]

30, 100
g (itn.) siveness (induced by OVA and
methacholine)

Mice;
the eosinophil peroxi-

Supercriti- dase activity,
the levels of IL-4,
Isatis tinctoria L. Brassicaceae Leaf In vivo 30
g (itn.)
cal CO2 IL-5 and RANTES (induced by
OVA)

Mice;
the eosinophil recruit-

10, 30, 100
g (itn.) ment, inflammation and produc-
tion of mucus in BALF
38 Recent Patents on Endocrine, Metabolic & Immune Drug Discovery 2013, Vol. 7, No. 1 Cota et al.

(Table 2) Contd….

Species Family Plant Part Extract Assay Type Effective Dose Experimental Model (Stimuly) Reference

HMC-1 cell;
the histamine [115]

release,
intracellular Ca2+,

gene expression of TNF-
and
In vitro 1-100
gmL-1 IL-6 and
degradation of IB
,
(induced by PMACI)

Lindera obtusiloba RBL-2H3 and RPMC;
hista-

Lauraceae Whole plant H2O
Blume mine release (anti-DNP IgE)

Mice;
the systemic allergic

reaction,
serum histamine
In vivo 1-100mg/kg (i.p.) (induced by compound 48/80)
and
the local allergic reactions
(induced by IgE)

Rat mast cell;
the release of [116]

In vitro 1mgmL-1 histamine (induced by compound
Lithospermum 48/80)
erythrorhizon
Borraginaceae Root H 2O HMC-1 cell;
the expression of
Siebold. et Zuc-
In vitro 0.01 and 1mgmL-1 IL-6, IL-8 and TNF-
(induced
carinii
by PMACI)

In vivo 65.9mg/kg (p.o.) Rat;
PCA

Rat;
mortality,
the scratching [117]

incidences and
the mast cell
In vivo 100mg/kg (p.o.)
degranulation (induced by com-
Matricaria recutita pound 48/80)
Asteraceae Capitulas MeOH
L.
Rat blood;
the histamine con-
Ex vivo 300mg/kg (p.o.) tent (induced by compound
48/80)

Mice; the allergic asthma (in- [118]

duced by OVA),
inflammatory
cell infiltration in the peribron-
Panax ginseng
Araliaceae Whole plant H2O In vivo 20mg/kg (i.p.) chial and perivascular areas and
C.A. Mayer

the expression of EMBP,
Muc5ac, CD40, CD40L, IL-1,
IL-4, IL-5, and TNF-

RPMCs;
the release of hista- [119]

mine (induced by compound
48/80 and anti- DNP IgE)
In vitro 1mgmL-1
HMC-1 cell;
the IL-1 and
TNF-
levels (induced by
Phlomis umbrosa PMACI)
Labiatae Root H 2O
Turcz
Mice;
the systemic anaphylaxis
(induced by compound 48/80)
0.001 - 1 g/kg (i.p.
In vivo Mice;
the histamine level and
and p.o.)
the local allergic reaction (in-
duced by anti- DNP IgE)
Anti-Allergic Natural Products Recent Patents on Endocrine, Metabolic & Immune Drug Discovery 2013, Vol. 7, No. 1 39

(Table 2) Contd….

Species Family Plant Part Extract Assay Type Effective Dose Experimental Model (Stimuly) Reference

NC/Nga mice;
the atopic der- [120]

matitis,
the ear thicknesses,

the serum histamine level,
the
thickening of the epider-
mis/dermis,
dermal infiltration
Rehmannia gluti-
Scrophulariaceae Root H2O: EtOH In vivo 400
g (topic) by inflammatory cells, and
the
nosa L.
mRNA expression of IL-4, TNF-

, VCAM-1, ICAM-1 and the
production of TARC, MDC,
RANTES levels in the ear lesions
(induced by mite allergen)

RPMC;
the mast cell degranu- [121]

In vitro 1μgmL-1 lation (induced by compound
48/80)

Mice; the allergic paw edema

Syzygium cumini 25-100mg/kg (p.o.) (induced by compound 48/80,
Myrtaceae Leaf H 2O
(L.) histamine and serotonin )
In vivo Mice;
the eosinophil accumula-
tion in allergic pleurisy,
the IL-
100mg/kg (p.o.)
5 and CCL11/eotaxin levels in
pleural lavage fluid

RPMC; mast cell stabilizing [122]

Sphaeranthus 100-300mg/kg
Asteraceae Whole plant EtOH In vitro activity (induced by sheep serum
indicus Kurz (p.o.)
and compound 48/80)

RPMC;
the release of hista- [123]

mine and
intracellular Ca2+
(induced by compound 48/80)
In vitro 0.01-1mgmL-1 HMC-1 cell;
TNF-
expres-
sion and
nuclear translocation
Teucrium japoni- of p65 NF-B (induced by
Labiatae Whole plant H 2O PMACI)
cum Houtt
Mice;
the systemic anaphylaxis
100mg/kg i.p. and
the histamine release (in-
In vivo duced by compound 48/80)

Mice;
the PCA reaction (in-

1-1000mg/kg i.p
duced by IgE)

In nature, we can find many natural products with simple
chemical structures that show a beneficial potential in the
treatment of allergic diseases. Cyperus rotundus L.
(Cyperaceae) is a Chinese traditional medicine used as an
antinociceptive and anti-inflammatory drug in China, Japan,
and Korea [145]. Monoterpenes and sesquiterpenes were
identified as the major constituents from the ethanolic extract
of the C. rotundus rhizomes. The sesquiterpenes valencene,
nootkatone and caryophyllene
-oxide inhibited the leukot-
riene production and -hexosaminidase release from RBL-
2H3 cells. From the isolated sesquiterpenes, only valencene
can block the degranulation reaction of -hexosaminidase
release via the inhibition of Lyn activation, an important step
for Ca2+ mobilization and for the delayed-type hypersensitiv-
ity reaction in mice. Structurally related to caryophyllene
-
oxide, (-)-trans-caryophyllene (50 mg/kg, p.o.) is able to
reduced the release of TNF-
, the production of PGE2 and,
inducible iNOS and COX-2 expression in the paws of car-
rageenan-treated rats. Trans-caryophyllene and
-humulene
are the bioactive components from Cordia verbenaceae
(Boraginaceae), a native plant of the Brazilian coasts used to
treat arthritis, wounds and contusions. The association be-
tween a Brazilian research group with Aché pharmaceutical
industry led to the development of the first phytomedicine
(Acheflan) in Brazil. These sesquiterpenes are also able to
inhibit the “acute and late phases” on rat paw edema induced
by carrageenan after a single oral administration. Thus,
based on their long-lasting profile for the anti-inflammatory
actions, inhibition of cytokines and PGE2 production, authors
suggest that these natural products have a potential for the
treatment of allergy or related conditions such as asthma
[144].
40 Recent Patents on Endocrine, Metabolic & Immune Drug Discovery 2013, Vol. 7, No. 1 Cota et al.

OCH3 O
12 O 12
H3CO
13 13
OH H
H3 CO H3CO

H3CO H3 CO

H OH
O -Benzoyl
H3CO H3 CO

OCH3 OCH3

(A) Schisandrol A (B) Gomisin C

Fig. (4). Natural products with 5-LOX-inhibitory activity. Schizandrol (A) and Gomisin G (B) isolated, respectively, from Schisandra
fructus and Magnolia flos.

O
22
O
CH2 OH
OH
COOH
OH
O O
CH2OH O
HO O
OH H
HO
H CH2OH
O
O O
HO O OH
HO H
OH
H
HO OH
Sasanquasaponin I

Fig. (5). Sasanquasaponin with anti-allergic properties. Sasanquasaponin I inhibits the release of -hexosaminidase from RBL-2H3 cells.
Table 3. Antiallergic Effects of Natural Products Isolated from Plant Extracts. Class of Natural Products by Biosynthetic Origin,
Species Source, Active Natural Product Isolated, and Concentration or Dose Values Used in Experimental Models.

Concentra-
Class Species Natural Product Experimental Model Reference
tion/Dose

Sinomenium acu- Sinomenine 20
M (IC50) BMMC,
the production of IL-6, PGD 2, LTC4, - [127]
Alkaloid tum Rehd. et Wils HEX, and COX-2 protein (PMA plus A23187)
(Wako, Osaka)

Anthraqui- Reynoutria ellip- Emodin 50mg/kg p.o. Mast cells,
the production of serum histamine, [22]
none tica (Koidz.) PGD2, LTC4 (induced by IgE/Ag)
Migo
50mg/kg p.o. Mice,
the PCA and PSA reactions

20
M (IC50) IgE/Ag-activated BMMCs,
the degranulation

process (-HEX release) and the Ca2+ influx

20
M (IC50) IgE/Ag-activated BMMCs,
the COX-2 expres-

sion and the production of TNF-
and IL-6

20
M (IC50) IgE/Ag-activated HMC-1 cells,
the phosphoryla-

tion of PI3K/At/NF- B pathways and the phos-
phorylation of Syk, LAT and PLC1-Ca2+ pathways

Benzophenone Garcinia 7-Epiclusianone 2.3
M (IC50) Guinea pig ileum,
the contractions (induced by [128,129]
brasiliensis Mart. OVA)
Anti-Allergic Natural Products Recent Patents on Endocrine, Metabolic & Immune Drug Discovery 2013, Vol. 7, No. 1 41

(Table 3) Contd…..

Concentra-
Class Species Natural Product Experimental Model Reference
tion/Dose

3.7
M (IC50) Guinea pig ileum,  the contractions (induced by

histamine)

1.1
M (IC50) Guinea pig ileum,  the contractions (induced by

acetylcholine)

3.8
M (IC50) Guinea pig ileum,  the release of histamin

1-100
M Guinea pig tracheal ring,  the contractions (in-

duced by OVA, histamine, 5-hydroxytryptamine
and carbachol), and  the tracheal ring contractions
(induced by Ca2+)

1-100
M Guinea pig tracheal rings,
the tissue content of

cGMP

100mg/kg, p.o. BALB/c mice,  the methacholine-induced airway

obstruction

Gossypin 27mg/kg i.p. Balb/c mice,  systemic anaphylaxis reactions [130]

(ED50) (induced by compound 48/80)

25mg/kg sc. Balb/c mice,  pruritis reactions (induced by com-

(ED50) pound 48/80)
Hibiscus vitifolius
Bioflavonoid 26mg/kg i.p. Mast cells from Sprague-Dawely rats,
the protec-
Linn
(ED50) tion of cell degranulation

10-60mg/kg i.p Sprague-Dawely rats,  the release of histamine,

NO in serum, BAL and peritoneal fluid (induced by
compound 48/80)

Rhododendron Anthopogochromane 114
M (IC50 ) RPMCs,  the release of histamine (induced by [131]
Chromane compound 48/80)
anthopogonoides
derivative
Maximowicz Anthopogochromene A 63
M (IC50)

Selinidin >100
gmL-1 BMMCs, no cytotoxic effect [132]

50
gmL -1
IgE-sensitized BMMCs,  the release of -HEX
Coumarin Angelica keiskei and  the production of LTC4, and TNF-

derivative Koidzumi
50
gmL-1 IgE-sensitized BMMCs,  the tyrosine phosphory-
lation of FcRI -chain, PLC1, p38 MAPK and
IB-

Eupatilin and Jaceosidin 3.4
M (IC50) IgE-sensitized RBL-2H3 cells,  the release of - [20]
HEX

50mg/kg p.o. ICR and Balb/c mice, respectively,  the PCA

reaction (induced by IgE) and  the scratching
Artemisia princeps behaviors (induced by compound 48/80)
Pampan
20
M IgE-sensitized RBL-2H3 cells,  the expression of
IL-4 and TNF-

Flavonoid
20
M IgE-sensitized RBL-2H3 cells,  the activation of
NF-B

Nobiletin, Naringin, Hes- 12.5-50
gmL-1 RAW 264.7 macrophages,  the expression of IL-6 [133]
peridin and TNF-
(induced by LPS)
Citrus aurantium
L. 12.5-50
gmL-1 RAW 264.7 macrophages,  the induction of NF-
B and MAPK, and  the induction of COX-2 and
iNOS protein (induced by LPS)
42 Recent Patents on Endocrine, Metabolic & Immune Drug Discovery 2013, Vol. 7, No. 1 Cota et al.

(Table 3) Contd…..

Concentra-
Class Species Natural Product Experimental Model Reference
tion/Dose

Quercetin 10mg/kg p.o. BALB/c mice (model of asthma),
the eosinophil [134]
counts in the blood, BALF and lung parenchyma

Isoquercitrin 15mg/kg, p.o. BALB/c mice (model of asthma),
the eosinophil

Dimorphandra
counts in the blood and BALF and neutrophil in the
mollis
blood

15mg/kg, p.o. BALB/c mice (model of asthma),
the IL-5 levels

in lung homogenates

Fisetin, Morin, Apigenin, 40
M M12 cells,
the STAT6 phosphorylation (induced [135]
Luteolin and Butein by IL4)

Kaempferol 10-40
M A1.1, 32D, HL-60, U937 cells,
the STAT6 phos-
phorylation (induced by IL4)

10-40
M PBMC,
the specific induction of CD23 expres-

Sigma Chemical sion (induced by IL4)
Co (citrus fruits) 20 and 40
M 32D, Src8, and NIH3T3 cells,
the STAT6 phos-
phorylation activity of JAK3-expressing cells

20 and 40
M M12 cells,
the JAK1 and JAK3 phosphorylation

(induced by IL4)

10-40
M 32D cells,
the JAK3-dependent but not -

independent cytokines (induced by IL-2 and IL-3)

Kaempferol glycoside 3-O- 30 and 90mg/kg BALB/c mice,
the total leukocyte and eosinophil [136]
[-D-glycopiranosil- sc. counts in BAL
(1
6)-
-L-
30 and 90mg/kg BALB/c mice,
the production of IL-5 and IL-13
ramnopiranosil]-7-O-
-L-
sc. in BAL fluid
ramnopiranosil-kaempferol
Solanun asperum 30 and 90mg/kg BALB/c mice,
the total number of cells express-
Rich. sc. ing CD4+ or B220 present in the BAL fluid

30 and 90mg/kg BALB/c mice,
the MHCII and CD40 expression

sc. on CD11b+/CD11c+ cells in the BAL

30 and 90mg/kg BALB/c mice,
the airway hyperresponsiveness

sc. and the airway mucus production

5-Hydroxy-3,7,3’,4’- 8.0 and 12.7
M RBL-2H3 cells,
the release of -HEX [31]
Tetramethoxyflavone (IC50)

5-Hydroxy-7- 20.6 and 16.2
M RBL-2H3 cells,
the release of -HEX (inhibition
Methoxyflavone (IC50) of Ca2+ influx to the cells via CRAC channels)
(induced by ionomycin)
5-Hydroxy-7,4’- 26.0 and 44.2
M
Dimethoxyflavone (IC50)
Flavone Kaempferia parvi-
flora Wall. Ex. 5-Hydroxy-3,7,4’- 49.9
M (IC50) RBL-2H3 cells,
the release of -HEX
derivative Baker Trimethoxyflavone

5-Hydroxy- 3,7- 66.5
M (IC50)

Dimethoxyflavone

3,5,7-Trimethoxyflavone 37.5
M (IC50)

3,5,7,4’- 38.4
M (IC50)

Tetramethoxyflavone
Anti-Allergic Natural Products Recent Patents on Endocrine, Metabolic & Immune Drug Discovery 2013, Vol. 7, No. 1 43

(Table 3) Contd…..

Concentra-
Class Species Natural Product Experimental Model Reference
tion/Dose

Gomisin C 4.1
M (IC50) RBL-1 cells,  the 5-LOX products [125]

Magnolia ovobata
Gomisin G 7.4
M (IC50)
Thunb.
Gomisin N 6.6
M (IC50)

Eudesmin 10.69
gmL- Aortic from Wistar rats,  the contractions (induced [137]
1
Piper truncatum- (ED50) by phenylephrine)
Vell. 35.0
gmL-1 Aortic from Wistar rats, induces endothelium-
(ED50) denuded preparations

Lignan Schizandrin 39.7 and 73.1
M RBL-1 cells,  the 5-LOX products [125]
(IC50)

39.7 and 73.1
M RAW 264.7 cells,  the NO production

Schizandra (IC50)
chinensis (Turcz.) Schizandrin A 34.1
M (IC50) RBL-1 cells,  the 5-LOX products
Baill.
Schizandrin C 36.8
M (IC50)

Schisandrol A 7.6
M (IC50)

Schisandrol B 20.1
M (IC50)

Rhinacanthin-C 6.9, 0.7 and RBL-2H3 cells,  the release of -HEX [138]
7.0
M (IC50)

Naphthoqui- Rhinacanthus Rhinacanthin-D 8.9, 3.8 and RBL-2H3 cells,  the release of TNF-

none derivative nasutus (L.) Kurz 5.4
M (IC50)

Rhinacanthin-N 6.4, 10.3 and RBL-2H3 cells,  the gene expression of IL-4
12.0
M (IC50)

Hexahydrocurcumin, 6- 1-200
M RBL-2H3 cells,  the release of -HEX [139]

Phenolic Zingiber officinale Dehydrogingerdione,10-
derivative Roscoe Gingerol, 6-Shogaol and 6-
Gingerol

Diosgenin 100 and BALB/c mice,  CD 3+, GATA3+ and FoxP3 + cells [140]
200mg/kg, p.o. (induced by OVA)
Dioscorea oppo-
Sapogenin BALB/c mice,  the expression of IL-4 (induced by
site Thunb.
OVA)

FoxP3+ cells,
the expression of IL-10

Camellia sasan- Sasanquasaponins I, II and 3
M RBL-2H3 cells,  the release of -HEX [141]
qua Thunb. III

Foliatheasaponins II 3 and 6
M RBL-2H3 cells,  the release of -HEX [142,143]

Saponin Foliatheasaponins III 6
M

Camellia sinensis
(L.) O. Kuntze Floratheasaponins A, B, C 3 and 6
M
and Floratheasaponins F

Floratheasaponins D and E 1 and 3
M

-Humulene and (
)- 50mg/kg, p.o. Swiss mice,  the paw edema (induced by bradyki- [144]
Cordia verbena- Trans-caryophyllene nin, PAF and histamine)
Sesquiterpene
cea D.C. 50mg/kg, p.o. Wistar rat,  the paw edema (induced by car-
rageenan)
44 Recent Patents on Endocrine, Metabolic & Immune Drug Discovery 2013, Vol. 7, No. 1 Cota et al.

(Table 3) Contd…..

Concentra-
Class Species Natural Product Experimental Model Reference
tion/Dose

-Humulene 50mg/kg, p.o. Wistar rat,
the expression of iNOS and COX-2
and
the production of IL-1, TNF-
, PGE2

(
)-Trans-caryophyllene 50mg/kg, p.o. Wistar rat,
the expression of iNOS and COX-2
and
the production of TNF-, PGE2

Valencene, Caryophyllene 100
M IgE-sensitized RBL-2H3 cells,
the degranulation [145]

-oxide and Nootkatone process (-HEX release)

100
M RBL-1 cells,
the 5-LOX products

Cyperus rotundus
L. 50-300mg/kg, ICR mice,
the delayed-type IV hypersensitivity
p.o. reaction

Valencene 10, 50, 100
M RBL-2H3 cells,
the Lyn activation (induced by
IgE)

Withanolide-A 0.1-100ngmL-1 Splenocytes from BALB/c mice,
the expression [146]

Steroidal lac- Withania somnif- of IFN-, IL-2 and decreases IL-4 level
tone era (L.) Dunal 0.1-10ngmL-1 Splenocytes from BALB/c mice, restores dex-
amethasone induced suppression of IFN- and IL-2

6
-Acetoxygedunin, 7- 50
gmL-1 Splenocytes from C57BL/6 mice,
the prolifera- [147]

Deacetoxy-7-oxogedunin, tion and IFN- production (anti-CD3 induced)
Andirobin, Gedunin,
C57BL/6 mice,
the splenocyte adhesion to
Carapa guianensis Methyl angolensate
endothelial cells
Aubl.
Splenocyte from C57BL/6 mice,
the production
Triterpene
of IL-2, IFN-,, CCL5 and, CCL11 and NFB
protein levels (induced by OVA)

Citrullus colo- Cucurbitacin E 2-O--D- 200mg/kg, p.o. ddY mice,
the ear PCA reaction [126]
cynthis (L.) glucopyranoside
Schrad. Cucurbitacin E 2.5mg/kg, p.o

, - and -Mangostin 20
M RBL-2H3 cells,
the release of histamine and
[148]
degranulation by activation of FcRI (induced by
IgE)
Garcinia man-
Xanthone
gostana 20
M RBL-2H3 cells,
the Ca2+ influx (induced by IgE)

20
M RBL-2H3 cells,
the activation of Syk and PLC

proteins kinases C pathway (induced by IgE)

Miscellaneous

Amburoside A 25 and 50mg/kg Wistar rats and Swiss mice,
the paw edema (in- [149]
Phenol gluco- Amburana cearen- i.p. duced by carrageenan, PGE2, histamine and sero-
side and flavon- sis (Allemão) A.C. tonin)
oid Sm. Isokaempferide 12.5, 25 and Neutrophils,
the TNF-
release (induced by LPS)
50mg/kg i.p.

Longusol B 96
M (IC50) RBL-2H3 cells,
the release of -HEX [150]

Luteolin 3.0
M (IC50)

Flavonoid and Resveratrol 17
M (IC50)

Cyperus longus L.
stilbene Piceatannol 24
M (IC50)

Cassigarols E 84
M (IC50)

Cassigarols G 84
M (IC50)

Anti-Allergic Natural Products Recent Patents on Endocrine, Metabolic & Immune Drug Discovery 2013, Vol. 7, No. 1 45

(Table 3) Contd…..

Concentra-
Class Species Natural Product Experimental Model Reference
tion/Dose

Flavonoid, Hypericum per- Pseudohypericin 0.08
M RAW 264.7 and peritoneal macrophages,
the [151]
naphthodian- foratum L. production of PGE2 , NO, TNF- and IL-1 (in-
Quercetin 10
M
throne, phloro- duced by LPS)
glucinol Amentoflavone 0.03
M

Chlorogenic acid 0.58
M

Uliginosin A 0.04-2.6
M

1,3-Hydroxybakuchiol 49
M (IC50) RBL-2H3 cells,
the release of -HEX [152]

Meroterpenes
Psoralea corylifo-
,2-Hydroxybakuchiol
3
69
M (IC50)
and prenyl
lia L. Bavachin 58
M (IC50)
flavanone
Psoralidin 100
M (IC50 )

Spirost-5-ene-3,12-diol 22.4
M (IC50) RBL-1 cells,
the LTC4 release [153]

N-trans-feruloyltyramine 16.6
M (IC50)

12 (R)-3-(4-hydroxy-3- 22.6
M (IC50)

Alkaloid, cin-
methoxyphenyl)-N-[2-(4-
namic acid ester, Solanum nigrum
hydroxyphenyl)-2
steroid deriva- L.
methoxyethyl]acrylamide
tive (spirostan)
13 (E)-ethyl caffeate 2.2
M (IC50)

Ethyl 4-hydroxy-3- 10.3
M (IC50)

methoxycinnamate

Luteolin 7-O--D- - Mast cell of rat abdomen,
the release of -HEX [154]
glucopyranoside, 8- (induced by compound 48/80)
epidesacylcynaropicrin--
- RBL-2H3 cells,
the release of -HEX (induced
Phenylpro- D-glucopyranoside, Glu-
by antigen 2,4-dinitrophenyl-OVA)
panoid deriva- cozalzanin C
Youngia japonica
tive, flavonoid
(L.) D.C. Chicoric acid, 2- Caffeoyl, - Mast cell of rat abdomen,
the release of -HEX
and sesquiter-
3-p-hydroxycinnamoyl (induced by compound 48/80)
pene
(S,S)-tartaric acid

Crepisides D, I and Gro- - RBL-2H3 cells,
the release of -HEX (induced

sheimin by antigen 2,4-dinitrophenyl-OVA)

(-)Not provided by the study.

Natural products are able to suppress and regulate targets these natural products on both “early phase” and “late phase”
simultaneously and they can be effective on both acute and reactions. In addition, the substitution with octadienoic acid
chronic phases of allergic reactions. Silibinin Fig. (6) is a (rhinacanthin-C) or benzodioxo carboxylic acid ester (rhi-
flavanone found as major component of milk thistle ex- nacanthin-D) in the basic skeleton, results in higher activity
tracted from Silybum marianum. It attenuates the production on the inhibition of production of TNF- and IL-4 [157].
of antigen-specific IgE in mice and inhibits the release of H
histamine trigged by IgE and IL-6 cytokine from rat perito- O
OH
neal mast cells (RPMC), contributing to the reduction of
acute response. This flavanone suppresses the IL-4 produc- HO O OCH3
O
tion by splenocytes and the release of TNF-, modulating H
balance from the TH2 to TH1 direction and, consequently it OH OH
reduces the inflammation in “late phase” of allergic reaction OH O
[155,156]. Rhinacanthin-C, D and N Fig. (7) are naphtho-
quinone derivatives isolated from Rhinacanthus nasutus ex- Silibinin
tract as constituents responsible for the anti-allergic effect.
They inhibit the release of -hexominidase, TNF- and IL-4 Fig. (6). Flavanone with anti-allergic properties. Silibilin attenu-
from RBL-2H3 cells, effects that support the potential of ates acute response and inflammation in late phase allergic reaction.
46 Recent Patents on Endocrine, Metabolic & Immune Drug Discovery 2013, Vol. 7, No. 1 Cota et al.

Rhinacanthin-C R =

O O

O
Rhinacanthin-D R =

OH OR O

O O OH

Rhinacanthin-N R =

OCH3

Fig. (7). Naphthoquinone derivatives with anti-allergic effect. Rhinacanthin-C, D and N inhibit the release of -hexominidase, TNF-
and
IL-4 from RBL-2H3 cells.

In the inflammatory sites associated with food allergy a
suppressive effect can maintain the immune homeostasis.
Diosgenin Fig. (8) is a steroidal sapogenin found in rhizomes
of Dioscorea opposita, a Chinese yam used as food supple-
ment in Asian countries. This secondary metabolite attenu-
ates the intestinal expression of IL-4 and GATA3 in BALB/c
mice with food allergy. Overexpression of GATA-3 is asso-
ciated with allergic asthma by the activation of a TH2 re-
sponse. It also increases the number of FoxP3+IL-10+ cells
and suppresses the number of GATA3+ cells. The factor
FoxP3+ is crucial for the development of Treg cells and IL-
10 and TGF-, are inhibitory cytokines secreted by these
cells that downregulate the expression of the TH2 cells.
Diosgenin increases the IL-10 production by FoxP3+ cells in
the duodenum suggesting it to be responsible for an antial-
lergic effect [140,158].
O
O was developed to patent analysis using Scifinder Scholar

HO
Diosgenin
Fig. (8). Steroidal sapogenin with antiinflammatory properties.
Diosgenin attenuates intestinal expression of inflammatory markers
associated with food allergy.
According to our literature research, some natural prod-
ucts can be more active [126,141,143] or show IC50 values
ranging in the same proportion of positive controls
[138,157]. Azelastine, ketotifen fumarate, tranilast and diso-
dium cromoglycate are the positive controls more frequently
used in the -hexosaminidase release assays and their IC50
values can range twofold. Indeed, there are in vivo studies
that have tested positive controls and natural products by
different routes of administration [20,144]. The effects, po-
tencies, and efficacies must be compared with some caution
since they can differ in absorption, distribution, metabolism,
excretion and, consequently, these parameters can influence
the mechanism of action. In general, the studies evaluated
the preventive effect of natural products by their administra-
tion before sensitization and challenge, while the curative
effect that is determined when the drugs are given after chal-
lenge, is not frequently accessed. Furthermore, it is desirable
that anti-allergic drugs show a long-acting effect and, the
evaluation of the persistent activity of natural products after
treatment is another effect that should be measured. Moreo-
ver, changes in eosinophil or other leukocyte populations
and histopathology abnormalities are also other parameters
that are not usually determined in the anti-allergic studies to
monitor the toxicity of compounds.
ABSTRACTS SEARCH CRITERIA
Search terms for the capture of articles were based on
keywords that included anti-allergic, allergy, food, plant,
herbal and natural product. These terms were used in combi-
nation with the words “extract”, “compounds”, “treatment”,
“asthma”, “dermatitis”, and “rhinitis”. The search strategy
with key words "anti-allergic plant" and refined by “patent”
subject. We also applied the same combination of keywords
in a range from 2007 to 2011 and used the subject “plant
extract”. The next approach was to refine the search using
keywords such as “alkaloid”, “catechin”, “ flavonoid”,
“coumarin”, “curcuminoid”, “diterpene”, “phenanthrene”,
“phenolic”, “stilbene”, “sapogenin”, “saponin”, “terpene”,
“triterpene”, “xanthone”, “tryptase”, “mast cell”, “lipoxy-
genase”, “hyaluronidase”, “prostaglandin inhibitor”, “cy-
clooxygenase”, “COX”, “LOX”, “eosinophil”, “degranula-
tion”, “chemokine receptor”, “histamine”, “hexosamini-
dase”, “arachidonic”, “leukotriene”, “immunoglobulin”,
“IgA”, “IgG”, “IgM”, “anaphylaxis”, “antiallergic”, “anti-
pruritic”, “asthma”, “atopic”, “dermatitis”, “eczema”, “im-
mediate hypersensitivity”, “itch”, “pruritus”, “rhinitis”, “ur-
ticaria”, “beverage”, “cosmetic”, “drink”, “food”, “supple-
ment” and “tea”.
PATENT REVIEW COVERAGE
According to the World Intellectual Property [159] Orga-
nization [146], in 2009 the US, Japan, and China filled about
60% of the total patent applications. Between 2008 and
Anti-Allergic Natural Products Recent Patents on Endocrine, Metabolic & Immune Drug Discovery 2013, Vol. 7, No. 1 47

2009, of the top three offices, Japan witnessed a 10.8 % drop

in the number of applications received. Meanwhile the U.S.
remained almost unchanged and China had an increase in
patent applications by about 8.5%. The advances of science
and technology in China for the last 20 years have resulted in
the increase of patent protection. From a total of 789 patents
about anti-allergic therapies that have been granted in China
from 1988 to 2008, 167 (21%) are about traditional Chinese
medicines. The anti-allergic patents issued in China focused
on main drugs the mechanisms of action of which are an-
tagonisms of histamine receptors (n = 137) followed by the
inhibition of leukotriene synthesis (n = 32) and antagonism
of chemokine receptors (n = 13). In addition, bronchial
asthma (n = 340) and allergic rhinitis (n= 268) are the main
target diseases [160] in these Chinese patents. (A)


A survey in SciFinder database shows that 184 patents
about antiallergic plants were granted from 1980 to 2011. In
this survey, 2006 was the year with more applications (n
=18) followed by 2010 (n = 17), 2009 (n = 15), 1998 (n =
13), 2007 (n = 11), 2008 (n = 10), 2005 (n = 10), 2003 (n =
10) and 2002 (n = 10). Patents using herbs as anti-allergic
agents are predominantly required by Asian authors from
Republic of Korea, Japan and China. According to Sci-
Finder
database, 4 Japanese companies (Ichimaru Pharcos
Inc., Japan, Kao Corp., Narisu Cosmetic Co Ltd.) are among
the top five organizations in terms of numbers of patents.
When we analyzed the number of patents granted in the last
five years Fig. (9), 2010 demonstrated 29.0% of the inven-
tions about plants with antiallergic activity. Sixty patents are
related to the use of antiallergic plant extracts as food and
beverages and 67 are claimed to be used for cosmetics and
dietary supplements. The claims include anti-allergic (aller-
gic asthma, rhinitis) and anti-inflammatory actions for the (B)
treatment of anaphylaxis conditions and atopic diseases Fig. Fig. (10). Number of occurrences of patents using keywords (A) of
(10A). During 2007-2011 (n = 38), the inventions were diseases symptoms and (B) compositions claims in anti-allergic
claimed to be used mainly as cosmetic followed by food Fig. patents found by Scifinder
software (search keywords: anti-
(10B). allergic plant; refined terms: extract).

targets as antihistamines, chemokine receptor antagonists,

Fig. (9). Analysis of the percentage of inventions about anti-allergic
plants in the last five years (search keywords: anti-allergic plant;
refined terms: extract).
It must also be considered that the biological effects
showed by a composition in in vitro assays are not the same
that are observed in vivo assays. The toxicity of components
is an aspect that is not frequently considered. In addition,
few patents have described the discovery of agents based on
and thromboxane A2 inhibitors. Although several studies are
available, the decrease of levels of IgE as anti-allergic action,
the increase of IgA levels by herbs and natural products are
rarely investigated. Serum IgA has anti-inflammatory action
and maintain the integrity of immune responses by down-
regulating IgG-mediated phagocytosis, chemotaxis, bacteri-
cidal activity, and cytokine release and its selective defi-
ciency has been associated with the increase of allergic
manifestations [161,162]. Considering this approach, Ishi-
zuka et al. [163] identified several plant extracts (Anthriscus
cerefolium, Calendula officinalis Sambucus nigra, Althaea
officinalis, Hordeum vulgare, Silybum marianum, Urtica
dioica, Adenophora triphylla, Citrus Sinensis, Passiflora
coerulea, and Psoralea corylifolia) that are able to promote
IgA secretion.
Between 181 patents applications (1980-2011) that have
claimed to have anti-allergic agents, 26 have cited secondary
natural products as active constituents. In a SciFinder
data-
base survey, from 2007 to 2011, flavonoid (n= 5) followed
by catechin (n= 3), phenolic (n= 3), alkaloid (n= 2),
48 Recent Patents on Endocrine, Metabolic & Immune Drug Discovery 2013, Vol. 7, No. 1
Table 4. Patents of Antiallergic Plants Granted in the Last Five Years. Main Claims, Plant Source, Effective Natural Products,
Patent Number and Target of Action.
Main Species/ Source
Claims
Antiallergic Ficus carica L.
Effect
Morinda citrifolia L.
Daemonorops draco
(Willd.) Blume
Salacia spp. (S. reticulata
Bark or
S. oblonga Wall. ex Wight &
Arn.)
Perilla frutescens Britton
var. crispa, Aloe barbadensis
Mill., Houttuynia cordata
Thunb, Chrysanthemum
morifolium L.
Glycine max (L.) Merr
Solanum lycocarpum St. Hil.
Fagonia bruguieri DC.
Cammellia sinensis (L.)
Kuntze
Not provided by the study
Poncirus trifoliata (L.) Raf.
Poncirus spp.
Calceolaria filicaulis,
Adesmia verrucosa Meyen,
Fuchsia magellanica Lam.
Allergic Guaiacum officinale L.,
Rhinitis Guaiacum sanctum L., or
Inhibitors Bulnesia sarmientoi Lorentz
ex Griseb., Rubus suavis-
simus S. Lee
Urtica dioica L.
Cota et al.
Effective Natural Products Patent Number Target References
Not provided by the study JP2011184310
The degranulation of [164]
mast cells
Not provided by the study KR2011029022
The secretion of
- [165]
HEX, TNF-
and IL-4
Flavonoid JP2010173939
The production of IgE [166]
(Dracoflavan B1, B2, C2)
Not provided by the study JP2010120905 (Type I allergy inhibitor) [167]
Not provided by the study KR2009131417
The production of IgE, [168]
IL-2 and IFN-
and re-
lease of histamine
Saponins and isoflavones JP2007197398
The production of IgE [169]
Steroidal saponins (solasonine, sola- JP2007197366 Not provided by the [170]
margine, 12-Hydroxysolasonine, study
robeneosides A and B)
Alkaloids, tannins, and flavonoids WO2007072100
Bronchoconstriction [171]
induced by histamine
Catechins (epicatechin-3-O-(3-O- WO2007080965 Unidentified [172]
methyl)gallate, epicatechin-3-O-(4-O-
methyl)gallate, epicatechin-3-O-(3,4-
O-dimethyl)gallate) (method)
Catechins, flavonoids and/or their JP2007186457 (Tryptase inhibitors) [173]
glycosides and/or tannins
Flavonoids and isoflavones US20100215672
The production of IgE [174]
and, the production and
release of histamine
(mast cell)
Not provided by the study US20100310690
The degranulation of [175]
eosinophil
(estrogen receptor modu-
lators)
Not provided by the study JP2011026268
The formation of [176]
CysLT (RBL-2H3 cells)
4-Methyl-7-ethoxy coumarin, 4- US20100009927
The activity of COX-1, [52]
shogaol, piper- COX-2, 5-LOX and
ine/cocluarine/laurifoline, 8- tryptase
dehydrogingerdione, si- (H1 antagonist)
nomenin/deoxyharringtonine, and
picrocrocin/carnosol
Anti-Allergic Natural Products Recent Patents on Endocrine, Metabolic & Immune Drug Discovery 2013, Vol. 7, No. 1 49

(Table 4) Contd….

Main Species/ Source Effective Natural Products Patent Number Target References
Claims

Cinnamon spp. Not provided by the study IN2008MU00009 Not provided by the [177]
study

Salacia spp. Catechin, flavonoid, xanthone glyco- JP2010077039 Not provided by the [178]
S. reticulata Bark or side (mangiferin) WO2010035675 study
S. chinensis L. or S. oblonga
Wall. ex Wight & Arn.

Curcuma longa L., Curcuma Curcumin, bisdemethoxycurcumin, WO2010109482
The release of hista- [179]
aromatica Salisb., Curcuma demethoxycurcumin EP2410999 mine and
-HEX
zedoaria (Christm.) Roscoe US20120010297
AU2011232745

Allergic Skin Coptis japonica Thunb., Not provided by the study KR2011040024
The activity of lipoxy- [180]
Diseases Scutellaria baicalensis genase and hyaluronidase
Inhibitors Georgi, Phellodendron
amurense Rupr., Polygo-
natum sibiricum F. Delaro-
che, Astragalus mem-
branaceus (Fisch.) Bunge

Cnidium monnieri (L.) Coumarin or osthole CN1994342 Not provided by the [181]
Cusson ex Juss. study

Rubiaceae uncaria Willd. Not provided by the study JP2007230977
The formation of GM- [182]
DC, Ilex paraguariensis A. CSF
St.-Hil., Perilla frutescens
Britton var. crispa, Cnidium
officinale Makino, Opuntia
streptacantha Lem., Jusitia
gendarussa Burm F.

Treat or Nigella sativa L., Eupato- Quinone (thymoquinone) EP2263664
The plasma levels of [183]
Prevent Food rium ayapana Vent., IgE and MMCP-1 in the
Allergy Satureja montana L., Thy- mice;
mus (opioid receptor agonist)

Inflammation Oryza sativa L. 12-Shogaol, curcumene, tryptamine, US20090285919
The activity of COX-1, [184]
Conditions fatty acids (hydroxyoctadecatrienoic COX-2 and 5-LOX
acid), alcohol long chain (octadeca-
trienol), etc.

coumarin (n = 1) and curcuminoid (n = 1) are the natural
products classes that have been most cited in patents. Some
examples of patents granted in the last five years are summa-
rized in Table 4 [164-184].
Hygienic tissue paper containing polyphenol (cathecin
derivatives) from plant extracts [185] and an anti-allergen
solid material that contains plant tissue for use in the vacuum
cleaner bag or in the dust-collection cup are examples of
curious patents [186]. Plant extracts that are suppressors of
the expression of c-Kit are claimed as anti-allergic agents. c-
Kit is a subclass of receptor tyrosine kinase superfamily,
activated by stem cell factor that can be predominantly found
on mast cells. c-Kit activates MAP-kinases Erk1 and 2,
JAK/STAT pathway, phospholipase C , tyrosise phospha-
tases and kinases and, some transcription factors [187-189].
In patent documents, we can find that the compositions
can contain at least one of the ingredients that is one plant
derived and the herbs can be interchanged by another from
the same genus. Combinations of compositions that includes
at least luteolin (Perilla), Cinnamon zeylanicum, Malphighia
glabra, Bidens pilosa and alternatively other three species
(Aframomum, Rosmarinic acid, and Tinospora) are claimed
to present anti-allergic activity. The compositions are de-
scribed as able to prevent, inhibit, and/or mitigate allergic
responses by downregulating the production of IgE antibod-
ies or its interaction with its receptors on cells. Also, these
compositions may inhibit histamine, PGD2 or LTC4 release.
Although the synergic effect is not always achieved in all
combinations (5, 4 and 3 ingredients), the change of each
individual ingredient can result in a specific mechanism and
efficacy. In general, the amount of daily subject dosage of
50 Recent Patents on Endocrine, Metabolic & Immune Drug Discovery 2013, Vol. 7, No. 1
each ingredient has high variation (from 25 mg to 650 mg) in
the embodiments. The efficacy of the one composition
(Blend: equal parts of Cinnamon, Acerola and Picao) was
tested in 20 human subjects in three doses (450 mg per dose)
a day for two days before a nasal allergen challenge. The
scores about nasal symptoms, pruritus-rhinorrhea-
conjunctivitis and sneeze counting were better reduced in the
Blend group in the delayed phase (2-8 h) compared to pla-
cebo and comparable to Claritin®. Prostaglandin D2 levels in
nasal fluid from the subjects of the Blend group were also
reduced showing that this formula can act in the late-phase
reaction [190].
Food allergy is prevalent in the first years of life and one
of the strategies is to modulate the immune system by dietary
interventions [191]. Nutritional compositions based on apple
extract (Pomactiv HFV) that is rich in polyphenols were de-
veloped especially for infants and/or young children for the
prevention of allergies. The consumption of 1% of apple
extract (Pomactiv HFV) by mice during the last week before
allergen challenge (secondary prevention) reduced the symp-
toms of food allergy but not when the apple extract was ad-
ministrated during the sensitization phase (primary preven-
tion). Mouse mast cell protease 1 serum levels and the ex-
pression of various genes (IL-5, -13, CCL11, GATA3) in
ileum and Ileal Peyer’s Patch were also reduced in mice
compared to non-treated control. The reduction of the ex-
pression of genes that are markers for Th2 response corrobo-
rates with the results obtained from in vivo assays confirm-
ing the use of nutritional compositions for the secondary
prevention of food allergies [43,53].
Although there are extensive studies about Nettle (Urtica
dioica L., Urticaceae) demonstrating beneficial properties for
the treatment of allergies (e.g., allergic rhinitis), Alzheimer's
disease, joint and muscle pain in arthritis and inflammatory
conditions, 8 extracts of this species were patented to contain
compounds that are active in in vitro against endpoints re-
lated to seasonal allergies and associated inflammation, such
as COX (IC50 1-500 μgmL-1), LOX (IC50 1-1000 μgmL-1),
HPDGS (IC50 1-1000 μgmL-1), tryptase (IC50 1-500 μgmL-1),
and H1 receptor (IC50 1-1000 μgmL-1). The key bioactives
(6-azacytosine, levulinic acid, threonine, niacinamide, DL-
methyl-m-tyrosine, 4-methyl-7-ethoxy coumarin, vitamin
B5, isopropyl-
-D thiogalactopyranoside, osthole, phos-
phatidylcholine, 4-shogaol, piperine/cocluarine/laurifoline, 8
dehydrogingerdione, sinomenin/deoxyharringtonine, and
picrocrocin/carnosol) were identified from serum and urine
samples of 5 healthy individuals after the administration of
two 100 mg doses of nettle extract. The identification of key
bioactives was performed using Direct Analysis in Real
Time TOF mass spectrometry. The study also determined the
time which the levels of the bioactives increased and per-
sisted in the serum and urine. In addition, it was reported
recently that sinomenin, an alkaloid identified between the
bioactives in nettle extract, has an inhibitory effect in the
production of IL-6, PGD2, LTC4,
-hexosaminidase, and
COX-2 protein [52,127].
CURRENT & FUTURE DEVELOPMENTS
Allergic diseases affect many people worldwide thereby
creating negative impacts on human health. The inability of
Cota et al.
Western medicine to offer a complete cure and relieve the
symptoms of these diseases has resulted in the use of alterna-
tive approaches such as herbal medicines, supplements, and
natural products. In general, the use of dietary supplements
or herbal medicines tends to increase in the world due to the
aging of the population, environmental pollution, and bad
dietary habits. In its turn, the alternative therapy of allergic
diseases is mainly based on improved versions of old drugs
or their plant combinations that were discovered in the last
century. These drugs are able to relieve the symptoms but
cannot cure the patient. Indeed, allergic diseases have shown
to be more complex and heterogeneous than previously
imagined. New insights about phenotypic clusters of allergic
patients and genomic and proteomic advances will allow for
the identification of novel markers to complement screening
studies and drug discovery. The description of phenotypes of
the patients will help to drive and optimize the medical treat-
ments and, therefore, the herbs and herbal products could be
used more rationally.
The scientific literature has shown that herbal medicines
may affect several pathways involved in allergic diseases by
specific and non-specific mechanisms of action. They pre-
vent allergic disease, modulate the chronic phase, and offer
persistent effects. However, the quality and quantities of
bioactive compounds found in the herbs and the route of
administration have an influence on the profiles and selectiv-
ity of this type of therapy. This suggests that the preparations
must be standardized and well-characterized. Although sev-
eral clinical trials have demonstrated that some herbs and
plant combinations are safe immunomodulators agents that
are able to relieve the symptoms of allergies, the great part of
the results are inconclusive, requiring the improvement of
quality of the studies. The discovery of bioactive compounds
in the anti-allergic preparations will provide more elaborated
studies to determine their mechanisms of action and synergic
effects, and optimize the combinations to find more effective
and safe treatments that could result in the increase of the
interest in patenting new medicines.
The in vitro and in vivo models that are used to discover
anti-allergic agents have identified several herbs and their
natural products as a source of new medicines. The restore of
the Th1/Th2 balance has been the principal goal of the stud-
ies reported in this review. The majority of the mentioned
herbs are from the traditional medicine of Asian countries,
especially Korea and China, but their bioactive compounds
have not yet been identified. The cultivated plant used in the
diet has also shown beneficial effects that are useful in the
prevention of allergic conditions. In addition, some natural
products have similar pharmacological potential to the first
line drugs, but the route of administration, dosage schedule,
and adjuvant effects, preventive or curative effect, remain to
be determined.
CONFLICT OF INTEREST
The authors declare no conflict of interest.
ACKNOWLEDGEMENTS
We are grateful to Fundação Oswaldo Cruz (FIOCRUZ),
Fundação de Amparo Pesquisa Estado de Minas Gerais
Anti-Allergic Natural Products Recent Patents on Endocrine, Metabolic & Immune Drug Discovery 2013, Vol. 7, No. 1 51

(FAPEMIG) and Conselho Nacional de Desenvolvimento HEX = Hexosaminidase

Científico e Tecnológico (CNPq) for support.
H2O = Water
ABBREVIATIONS HPDGS = Hematopoietic prostaglandin D syn-
thase
AD = Atopic dermatitis
HPGD2 = Prostaglandin D2 synthase
Akt = AKT8 virus oncogene cellular ho-
molog 5-HT = 5-Hydroxytryptamine
APCs = Antigen presenting cells HMC-1 = Human mast cell line
B220 = Insulin receptor protein kinase IFN = Interferon
BALF = Bronchoalveolar lavage fluid Ig = Immunoglobulin
BMCMCs = Bone marrow-derived cultured mast I B = Inhibitor of NF-B
cells IKK = I
B kinase
CCh = Carbachol IL = Interleukin
CCL = Chemokine (C-C motif) ligand I.P. = Intraperitoneal injection
CD3+ = T-cell surface glycoprotein CD3 ITN. = Intranasal
CD4+ = T-cell surface glycoprotein CD4 JAK3 = Janus Kinase 3
CD40 = Tumor necrosis factor receptor super- JNK = Jun N-terminal kinase
family member 5 (CD40L receptor)
LOX = Lipoxygenase
CD40L = CD40 ligand
LPS = Lipopolysaccharide
CD63 = Melanoma-associated antigen ME491
LT = Leukotriene
CD8+ =
T-cell surface glycoprotein CD8
Lyn = A src family tyrosine-protein kinase
CKRs = Chemokine-chemokine receptors
MAP = Mitogen activated protein
cGMP = Cyclic guanosine monophosphate
MAPK = Mitogen activated protein kinase
CO2 = Carbon dioxide
MCP-1 = Monocyte chemotactic protein-1
COX = Cyclooxygenase
MeOH = Methanol
cPLA2 = Cytoplasmic phospholipase A2
MHC = Major histocompatibility complex
CRAC channels = Ca2+ release-activated Ca2+ channels
MMCP-1 = Mast cell protease
CysLt = Cysteinyl leukotriene
NF-
B = Nuclear transcription factor-
B
Dex = Dexamethasone
NO = Nitric oxide
DNP = Dinitrophenyl
NOS = Nitric oxide synthase
GR = Glucocorticoid receptor
OVA = Ovalbumin
ERK = Extracellular signal-regulated kinase
OX40 = Tumor necrosis factor receptor super-
EtOH = Ethanol family CD134
FASN = Fatty acid synthase OX40L = Ligand for CD134 expressed on sub-
Fc
RI = High affinity IgE receptor type of dendritic cells
FDA = Food and Drug Administration p38 = p38 Mitogen-activated protein kinase
FoxP3+ = Forkhead box P3 protein PAF = Platelet activating factor
GATA = Globin transcription factor PBMCs = Peripheral blood mononuclear cells
GATA3+ cells = Trans-acting T-cell-specific transcrip- PCA = Passive cutaneous anaphylaxis
tion factor expressed by GATA3 gene PEPCK = Phosphoenolpyruvate carboxykinase
in human cells enzyme
GC = Glucocorticoids PG = Prostaglandin
GM-CSF = Granulocyte macrophage colony- PGF = Placental growth factor
stimulating factor
PI-3K = Phospatidylinostol-3-phosphate kinase
H1 = Histamine H1 receptor
PL = Phospholipase
52 Recent Patents on Endocrine, Metabolic & Immune Drug Discovery 2013, Vol. 7, No. 1 Cota et al.

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