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Copyright: © 2015 Vijay K. Kapoor et al.
http://dx.doi.org/10.19104/jamr.2015.107
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Review Article
Journal of Alternative Medical Research
Open Access
Herb -Drug Interactions –An Update on Synergistic Interactions
Vijay K. Kapoor* and Sonia Singla
G.H.G. Khalsa College of Pharmacy, Gurusar Sadhar (Ludhiana), India
Received Date: July 24, 2015, Accepted Date: August 24, 2015, Published Date: September 03, 2015.
*Corresponding author: Vijay Kumar Kapoor, G.H.G. Khalsa College of Pharmacy, Gurusar Sadhar (Ludhiana) 141104, India, Tel: 987-245-189-51; E-mail:
[email protected]
Abstract
Herbal drugs are bestowed with a number of properties due to
which they are used in healthcare since ancient times. Several of them
are reported to enhance immunity and natural resistance to disease and
have recuperative power of the body. Such drugs are being consumed
along with modern allopathic drugs particularly by geriatric patients.
In recent years a number of herb-drug interactions have been reported
some of which are serious in nature; for example consumption of
Gingko biloba along with anticoagulant warfarin may result in excessive
bleeding or concomitant use of St. John wort and antidepressant drugs
may result in serotonin syndrome. Through pharmacodynamics and
pharmacokinetic processes the herb-drug interaction often results in
potentiation of action of the drug by synergistic mechanism. Several
such synergistic reports on herb-drug interactions in the area of
antimicrobials, antineoplastics, antidiabetics, cardiovascular actives,
antihepatotoxics, CNS actives etc are discussed.
Keywords: Herb-drug interaction; Pharmacodynamics and pharmacokinetic effect; Plant secondary metabolite-drug interaction;
Herb-drug synergistic interactions
Introduction
Herbs and other botanically derived drugs have been used in
variety of diseases from antiquity. Ayurveda, the Indian science of
healthcare, is one of the oldest systems of medicine and its herbal
medicines have been in vogue right from the vedic period at around
600 BC. The use of complementary and alternative medicine (CAM)
has increased in recent years. A number of herbal products in
the form of dietary supplements are being consumed along with
modern allopathic drugs [1,2]. This is particularly true for geriatric
patients who consume a number of medications simultaneously.
The consumption of herbal drugs is often associated with a general
belief that these drugs are relatively safe and without side effects.
There are a number of potential drug interactions which are often
unpredictable. There may be herb-herb interactions resulting
in synergistic effect or antagonistic effect. Fundamentally, the
drug action is due to a number of chemical compounds present
in medicament, which are metabolized in the body (liver) though
a number of enzyme system. Cytochrome P450 (CYP) and its
isoforms such as CYPIA1/2, CYP2B6, CYP2C8/9/19, CYP2D6,
CYP2E1, CYP3A4/5 and CYP4A, are involved in biotransformation
of xenobiotics and endobiotics. The role is also played by a number
of transporters, such as P-glycoprotein (P-gp).
The herb-drug interactions can either be pharmacodynamic or
pharmacokinetic in nature. In the former case the constituents of
herbal product have either synergistic or antagonistic activity in
relation to a modern drug. In pharmacokinetic interactions herb
drug interactions may involve inhibition of drug metabolizing
enzymes and/or drug transporters resulting in increased levels of
one or both the drugs. A well known example in this regard is of
interaction of garlic with warfarin resulting in excessive bleeding.
Conversely, herb drug interaction may result in induction of the
J Alt Med Res
enzyme systems leading to under dosing of the patient by the drug.
A number of excellent reviews have appeared recently highlighting
such interactions [1,3-15]. The present communication gives an
account of recent updates on herb drug interactions which are
discussed under the heads of herb-herb interactions and synergistic
herb-drug interactions.
Herb-Drug Interactions
Some of the most common globally consumed herbs are St John
wort (Hypericum perforatum), ginseng (Panax ginseng), ginkgo
(Gingko biloba), milk thisle (Silybum marianum), garlic (Allium
sativum), danshan (Salvia miltiorrhiza), Echinacea (Echinacea
angustifolia), saw palmetto (Serinoa repens), Glycyrrhiza
(Glycyrrhiza glabra), psyllium (Plantago ovate), ginger (Zinziber
officinale), momordica (Momordica charantia), guar gum (Cyamopsis
tetragonolobus) tamarind (Tamarindus indica), turmeric (Curcuma
longa) are the general items of dietary supplements. Interactions of
these herbs are often reported with modern drugs.
St. John wort: St. John wort is marketed as the extract of
flowering tops or aerial parts of Hypericum perforatum. It is used
frequently for self medication, in the treatment of depression.
Hypericin (1) and hyperforin (2) are the two major constituents,
the latter being potent inhibitor of serotonin, norepinephrine and
dopamine reuptake. Being a popular herbal drug maximum number
of interations of St. John′s wort with modern drugs have been
reported [3,16] .The herb is reported to interact with cyclosporine,
tacrolimus, indinavir, navirapine, irinotecan, imatnib mesylate,
alprazolam, midazolam, quazepam, amitryptylline, digoxin,
fenoxfexadine, methadone, simvastatin, omeprazole, theophylline,
verapamil and warfarin. Use of St. John′s wort with serotonin
reuptake inhibitors like nefazodone, paroxetine, and venlaxafine
may result in synergistic interaction causing serotonin syndrome.
There is a report that St. John′s wort does not interfere with the
antiandrogenic properties of oral contraceptives [17]. An update on
clinical drug interactions with St.John′s wort is given [18]. These
interactions are due to induction of CYP3A4 and P-gp.
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Milk Thistle: Milk thistle is that dried ripe fruit of Silybum
marianum, devoid of the pappus. The fruit contains the active
principle silymarin, a mixture of flavolignans which include the
isomers silibinin, silicristin and silidanin. Silibinin (3) is the major
constituent. Milk thistle is used as standardized extract mainly
for the gastrointestinal and hepatobiliary disorders. The drug
is marketed in U.S as a dietary supplement as hepatoprotective.
Silybinin significantly inhibits cytochrome P450 isoform 3A4 and
UDP glucuronosyl transferase isoform 1A1 in vitro.
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Ginko biloba: The drug consists of whole or fragmented dried
leaf of Ginko biloba. The extract of leaves is used in cerebrovascular
and peripheral vascular disorders. Terpenoid molecules isolated
from Ginko biloba are also called as ginkgolides which have plateletactivating factor antagonist properties. A mixture of ginkgoides A,
B, C is used for asthma, and other inflammatory disorders. Serious
interactions of Ginko biloba with anticoagulants such as warfarin
have been reported. It also interacts with aspirin, ibuprofen,
trazadone, valproate and thiazide diuretics [1,3]. Excellent reviews
on the interaction of Ginkgo biloba with drugs have appeared
[19,20].
Ginseng: Ginseng is the dried root of Panax ginseng, popularly
known as Asian ginseng. Other species include Panax quinquefolius
(American ginseng) and P. pseudoginseng. Ginseng contains complex
mixtures of saponins termed ginsenosides or panaxosides. Ginseng
is reported to enhance the natural immunity, improving mental and
physical performance [21,22]. Ginseng[1,3] interacts with warfarin,
phenelzine and digoxin.
Garlic: Garlic is fresh or dried compound bulbs of Allium
sativium. It contains alliin (4), allicin (5), diallyl sulphide and
ajoene. Traditionally garlic used in diets has reportedly expectorant,
diaphoretic, disinfectant and diuretic properties. Other effects
ascribed to garlic are antimicrobial, antihypertensive, lipid
lowering, fibrinolytic and antiplatelet.
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It has been widely promoted for use in the treatment of
hyperlipidaemia. Garlic is reported to interact with warfarin, and
the patients using warfarin are cautioned against consuming large
quantities of garlic due to possible risk of increased bleeding. Garlic
is also reported to cause decrease in plasma levels of saquinivir
[3] In vitro interactions of water-soluble garlic components with
cytochrome P450 [23] and drug interaction of garlic in humans are
reported [24].
Saw Palmetto: Saw palmetto is the dried ripe fruit of Serenoa
repens. Various steroidal compounds, with anti-androgenic and
estrogenic activities, are its constituents. Saw palmetto is used for
the treatment of benign prostatic hyperplasia. Interactions between
saw palmetto and prescription drugs have been reviewed [25].
Echinacea: Echinacea consist of dried rhizome and roots of
Echinacea angustifolia, E.pallida or E. purpurea. It is widely used
in herbal preparations to treat and prevent upper respiratory
tract infections such as common cold. It is used for prophylaxis of
bacterial and viral infections.
Glycyrrhiza: Commonly known as liquorice glycyrrhiza is the
dried rhizome and roots of Glycyrrhiza glabra. It contains a saponin
glycyrrhizinic acid whose hydrolytic product is glycyrrhetinic
acid (6). Glycyrrhetinic acid is inhibitor of cortisol metabolism
resulting in its increased concentration in the body. Liquorice has
demulcent, expectorant, ulcer-healing and mild antiinflammatory
properties besides being flavouring and sweetening agent. It has
mineralocorticoid properties and its excessive use may cause severe
hypokalemia. Liquorice is reported to interact with prednisolone,
resulting in its increased plasma concentration. Contraindications
with hydrocortisone and oral contraceptives are also reported.
Interaction of glycyrrhizin with angiotension- converting enzyme
inhibitor enalapril has been reported [26].
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Guar Gum: Guar gum is a gum obtained from the ground
endosperms of Cyamopsis tetragonolobus. The gum consists
of a high molecular weight hydrocolloidal polysaccharide, a
galactomannan, which is composed of D-galactose and D-mannose
units combined through glycosidic linkages. Guar gum is used as
an adjunct with diet in the treatment of diabetes mellitus. As an
example of a soluble fibre, guar gum is also used as a dietary adjunct
in hypercholesterolaemia. Guar gum may retard the absorption of
other drugs.
Psyllium: Psylluim or ispaghula is the cleaned, dried ripe seed
of Plantago ovata, or of P. psylluim or of P.indica. It is used as psyllium
Citation: Kapoor VK, Singla S (2015) Herb -Drug Interactions –An Update on Synergistic Interactions. J Alt Med Res 1(1):
http://dx.doi.org/10.19104/jamr.2015.107.
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husk which is cleaned dried seed coat (epidermis) of seeds of
Plantago species, or psyllum seed which is whole seed of Plantago
species. The seed and husk are used as the bulk laxatives. They
absorb water in the gastrointestinal tract to form a mucilaginous
mass which increases the volume of faeces and promote peristalsis.
It is also given as adjunct in lipid-lowering diet. Interaction between
ispaghula husk and lithium salts has been reported [27] in which
there is decreased lithium concentration.
Tamarind: Tamarined is the fruit of Tamarindus indica freed
from the brittle outer part of the pericarp. It is used as a food item
and also used as laxative. It contains tartaric, citric and malic acid
and their salts. Tamarind interacts with aspirin where it increases
its bioavailability.
Bitter gourd (Biter melon): Bitter melon is the fruit of
Momordica charantia which is consumed as a vegetable particularly
by diabetics as it is reported to decrease glucose concentrations in
blood [28]. The fruit interacts with chlorpropamide causing less
glycuria [29].
Ginger: Ginger is the dried rhizome of Zingiber officinale, which
is commonly used dietary item with a characteristic aromatic
odour. It is used for the prophylaxes of motion sickness and nausea
and vomiting in pregnancy. It contains 1.5% of volatile oil. Although
the evidence for an interaction between ginger and warfarin
inconclusive, patients taking warfarin and other anticoagulants are
advised against consuming large quantities of ginger [3].
Synergistic Interactions
The synergistic interactions can be between herb and herb,
between herb and a drug, between the plant secondary metabolite
and the drug, and between plant secondary metabolite and a
secondary metabolite. In the present communication, the synergistic
interactions have been discussed based on pharmacological
activities.
Anticoagulant Synergistic Interaction
Warfarin (7) is one of the most widely used anticoagulant.
It exerts its anticoagulant activity by depressing the vitamin-K
dependent clotting factor II (prothrombin), factor VII, IX, X. It also
inhibits activation of vitamin K-dependent regulatory proteins
C and S. Warfarin is marketed as a racemic mixture of R- and Senantiomers. S-Warfarin is five times more active than R- isomer.
There are a number of reports on herb-warfarin interaction.
Herbs can influence the pharmacokinetic of warfarin either by
decreasing the absorption from the gastrointestinal tract, or by
affecting its metabolic clearance. The enzyme responsible for
warfarin metabolism is CYP2C9. It is reported [30] herbal extracts
and isolated components inhibit CYP2C9 activity in human liver
microsomes.
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The herbs which are reported [3] to interact with warfarin
synergistically are Salvia miltiorrhiza (danshan), Anglica sinensis
(dong quai), Allium sativum (garlic), Zingiber officinale (ginger),
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Ginko biloba, Panax quinquefolium (American ginseng), Panax
ginseng (Asian ginseng), Camellia sinensis (green tea), Seronoa
repens (saw palmetto), Hypericum perforatum (St. John wort).
Patients on warfarin therapy should be advised concurrent use of
these herbs due to the possible risk of increased bleeding.
A case of 70 year-old women who, being treated with warfarin,
was admitted to hospital with multiple internal haemorrhage after
having use Matricaria chamomella products [31]. Interactions
of warfarin with foods, herbs and other dietary supplements has
appeared [32].
Antimicrobial Synergistic Interaction
Herb-Drug: There have been reports where an herbal drug
or its extract given along with an antibiotic has enhanced the
antibacterial effect of the latter. Synergistic effect of grape (Vitis
vinifera) seed extract with amphotericin B against disseminated
candidiasis due to Candida albicans has been reported which
indicated the combination can reduce more than 75% of
amphotericin dose [33]. A synergistic combination for multi drug
resistant Salmonella enterica serover typhi of aqueous fruit solution
of Cassia fistula and amoxicillin has been reported [34]. Synergistic
activity of methanolic extract of Thespesia populnea flowers with
oxytetracycline was observed with highest synergism rate against
Shigella boydii [35]. A n-hexane fraction of Smallanthus sonchifolius
showed more effective antimicrobial activity against methicillinresistant Staphylococcus aureus strains under light. Synergistic
effect of the fraction with ampicillin or oxacillin was observed
[36]. A synergistic antimicrobial effect of garlic (Allium sativum)
with ciprofloxacin in chronic bacterial prostatitis rat models has
been reported [37]. Synergism between the extracts of Eugenia
uniflora and E. jambolanum and gentamicin was demonstrated for
antimicrobial activity against two stains of Escherichia coli [38]. In a
vector control programme study extracts of Eugenia jambolana and
Solidago canadenesis showed synergistic effect with the chemical
insecticide deltamethrin against dengue vector Aldes aegypti
[39]. Proven scientifically to have antiplasmodial effects, leaves of
Azadirachta indica showed potentiated reduction of parasitemia
and increased cure rate when given in combination with artesunic
acid [40]. The leaf extracts of Ocimum sanctum was reported to
enhance in vitro antibacterial activity of chloramphenicol and
trimethoprim against Salmonella enterica serovar typhi, showing
synergism [41]. The essential oil of Ocimum sanctum had antifungal
effect against various Candida isolates, and showed synergy with
established azole antimycotics flucanazole and ketoconazole [42].
Propolis, a honey bee product has been intensively investigated
for its antimicrobial activity. Recently, propolis has shown in vitro
synergism with antibiotics acting on bacterial DNA (ciprofloxacin,
norfloxacin) [43] and on ribosomes (chloramphenicol, tetracycline
and neomycin) [44] against Salmonella enterica serovar typhi.
A mention may be made here of a phyto-synergy between two
parts of the same plant. The hydrodistilled leaf essential oil and
extract of bark, root, leaf of Croton gratissimus were essential for
antimicrobial activity independently and in combination. The result
indicated greatest synergy in root and leaf combination against
Bacillus cereus, Candida albicans and Cryptococcus neoformans [45].
The methanolic extracts of resin of Ferula assafoetida, rhizome
of Zingiber officinale and root of Gylcyrrhiza glabra were studied
for antimicrobial efficacies independently and in combination
against a number of microorganisms. The result indicated a better
antimicrobial effect in combination extract than in individual
providing evidence of synergism [46].
Natural products, which are plant secondary metabolites
formed by enzymatically governed biosynthetic process, are
Citation: Kapoor VK, Singla S (2015) Herb -Drug Interactions –An Update on Synergistic Interactions. J Alt Med Res 1(1):
http://dx.doi.org/10.19104/jamr.2015.107.
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bestowed with various biological activities. There are many
reports on synergistic interactions between natural products
formed within the same plant, natural product with a natural
product from different sources, or natural product with drugs. A
classical example of natural products of the same source acting
synergistically is of berberine (8) with 5′-methoxyhydnocarpin (9).
Berberine, a hydrophobic alkaloid is a weak antibacterial agent but
a combination of berberine with 5′-methoxyhydrocarpin is a potent
antibacterial agent [47], both of which are produced by berberry
plants.
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combined with synthetic antifungal agents mancozeb and carboxin
against Fusasium verticilloides [61]. The synergistic effect was also
observed between scopoletin and other isolated constituents from
the same plant viz vanillin, 4-hydroxy-3-methoxycinnamaldehyde
and pinoresinol. Recently, synergistic antifungal effect of
ketoconazole combined with berberine, an alkaloid from
Berberis sp is reported [62]. Enhancement of fungicidal activity
of amphotericin B by allicin, a constituent of Allium sativum has
been observed [63]. The antifungal effects of the volatile oil from
Allium species against Trichophyton species and synergism of the
oil with the drug ketoconazole is already reported [64]. Essential
oils from different plants such as Thymus vulgaris [65], Agastache
rugosa [66] have shown synergistic interaction with ketoconazole
and amphotericin B, respectively. Enhanced antifugal activity of
ketoconazole by latex of Euphorbia characias against Candida
albicans also has been reported [67].
The volatile components of the essential oil of Lantana camara
[68] and L. montevidensis [69] have been reported to show
synergistic effects combined with aminoglycosides gentamicin and
amikacin. Synergism of gentamicin and norfloxacin with the volatile
compounds of Lippia microphylla has also been reported [70].
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Several of synergistic interactions of the secondary metabolites
of plants with antibiotics have been discussed [48]. The
antibacterial action of antibiotics has been enhanced synergistically
by natural products such as corilagin from Arctostaphylos uvarvsi [49], baicalin from Scutellaria amoena [50,51], carnosol and
carnosic acid from Salvia officinalis [52]. Recently, phlorotannins
from Eisenia bicyclis [53], curcumin from Curcuma longa [54],
eugenol from Eugenia aromatic [55] have been reported to exhibit
synergistic with antibiotics.
Helvolic acid, a metabolite obtained from a strain Aspergillus
sp 136 showed synergistic effect with penicillin which was three
times that of clavulanic acid with penicillin [56]. Methylglyoxal,
a dicarbonyl natural compound obtainable from Manuka honey
produced from Manuka flowers in New Zealand [57], has exhibited
distinct and statistically significant synergism with piperacillin
against Pseudomonas aeruginosa [58].
18β-Glycyrrhetinic acid, a major component of Glycyrrhiza
uralensis has potent antimycobacterial properties against drug
susceptible and drug-resistant Mycobacterium bovis. Recently
it has been reported to exhibit synergistic effects with frist-line
drugs like isoniazed, rifampicin and streptomycin against clinical
M. bovis isolates [59]. Earlier a naphthoquinone 7-methyljuglone
isolated from the roots of Euclea natalensis showed synergism with
isoniazid or rifampicin against M. tuberculosis [60].
Antifungal synergistic effects of a number of natural products
with drugs have been reported. A hydroxycoumarin scopoletin
isolated from Melia azedarach has shown synergistic effects when
Herb−Herb/Drug: Many of the herbs and herbal preparations
are used by cancer patients for their ability to stimulate immunity
and improve the quality of life. Mistletoe (Viscum album), Curcuma
longa, garlic (Allium sativum) are the prominent ones. Besides
possessing antiproliferative activity such herb are reported to
potentiate the anticancer effect of other herbs or drugs. Antrodia
camphora extract, when combined with antitumor agents show
adjuvant antiproliferative effects on hepatoma cells (in vitro) and
on xenografted cell in tumor-implanted nude mice (in vivo) [71].
Mistletoe extracts have cytotoxic effect on Jurkat cells; the activity
is attributed to lectins present in the herb. It has been reported
that the extract in combination with doxorubicin exert synergistic
cytotoxic and apoptosis-inducing effects on Jurkat cells [72].
Mistletoe lectin-1 is reported to augment antiproliferative effects
of the peroxisome proliferator-activated receptor gamma (PPAR
gamma) agonist rosiglitazone on human malignat melanoma cells
[73]. Garlic, a herb, and naltrexone, an opioid receptor antagonist,
both have immumomodulatory and antitumor effects. Recently,
it has been shown that aged garlic extract has synergistic effects
with naltrexone on inhibition of tumor growth and increment of
survival time when tested on experimentally induced fibrosarcoma
tumor in BAL B/C mice [74]. The leaves of Azadirachta indica are
reported to have immunostimulatory activity. It has been shown
that pretreatment of mice with the extract of the herb reduced the
extent of leucopenia and neutropenia in normal and tumor-bearing
cyclophosphamide treated mice [75].
Curcumin (10), the active constituent of turmeric (Curcuma
longa) is a potential anticancer agent. It has been shown to
reduce viability of the highly malignant, metastatic rat mammary
gland cell line ENUI564 in culture and reduce metastasis of these
cells injected into nude mice [76]. Curcumin has been proven to
induce tumor apoptosis and inhibit tumor proliferation, invasion,
angiogenesis, and metastasis via modulating numerous targets
in various types of cancer cells [77]. There are recent reports
of curcumin showing synergistic anticancer activity with other
natural products or drugs. Curcumin in combination with catechins,
the polyphenolic compounds of green tea (Camellia sinensis) can
synergistically inhibit the proliferation of HCT 15, HCT 116 of
human colon adenocarcinoma and human larynx carcinoma Hep
G-2 cells efficiently through induction of apoptosis [78]. Curcumin
in combination with resveratrol (11) is reported to inhibit the
Citation: Kapoor VK, Singla S (2015) Herb -Drug Interactions –An Update on Synergistic Interactions. J Alt Med Res 1(1):
http://dx.doi.org/10.19104/jamr.2015.107.
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proliferation of Hepa 1-6 hepatocellular carcinoma cells in a dose
and time-dependent manner [79]. The data suggest that curcumin
and resveratrol is a promising combination in treating liver
cancer. Synergistic anticancer effects of curcumin with two dietary
components docohexaenoic acid and an omega-3 fatty acid present
in cold-water fish have been shown in an in vivo model of DMBAinduced mammary tumorigenesis in mice [80].
O
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cyclamin synergistically enhances the growth inhibitory effect
of 5-fluorouracil, cisplatin, and epirubicin on Bel-7402, but not
on HL-7702 cells [87]. Furanodiene, a terpenoid isolated from
Rhizoma curcumae, a well-known Chinese medicinal herb is
reported to have anti-proliferative activities in several cell lines.
Recently, it was found that combined treatment of furanodiene with
paclitaxel showed synergetic anti-proliferative activities in 95-D
lung cancer cells [88]. It is reported that the cytotoxic effect of a
1,4-naphthoquinone namely 5-methoxy-3,4-dihydroxanthomegnin
isolated from Paepalanthus latipes gets potentiated by ascorbic acid
[89].
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Dietary supplements are known to offer nontoxic therapeutic
management as well as chemopreventive intervention for slowgrowing prostate cancers. It has been suggested that the benefits of
such supplements are not ascribable to individual phytochemicals,
rather may be ascribed to synergistic interactions among them.
In a recent study [81], growth-inhibiting and apoptosis-inducing
properties of ginger (Zingiber officinale) extract in in vivo and
in vitro prostate cancer models was demonstrated. Further it
was shown that binary combination of ginger phytochemicals
(such as 6-, 8-, 10-gingerols and 6-shogoal) synergistically inhibit
proliferation of prostate cancer cells. Combining ginger extract
with 6-gingerol particularly showed more significant result.
Angelica sinensis is a chinese medicinal herb used in conjunction
in cancer chemotherapy. It contains three phthalides namely
n-butylidenephthalide, senkyunolide A and Z-ligustilide. All the
three components showed cytotoxic and antiproliferative effects
on colon cancer cells. However, the phthalides in combination with
other ingredients in Angelica sinensis extract displayed significant
synergy leading to stronger anti-tumor effect [82].
There are several reports where a secondary metabolite from
a plant has exhibited synergistic interaction with anticancer drugs.
Emodin (12), which is a constituent of Rhamnus frangula and
Cascara sagrada, has shown synergistic growth inhibitory effect
with 3′-azido-3′-deoxythymidine (AZT) on adriamycin-resistant
human chronic myelogenous leukemia (K562/ADM) cells [83]. The
flavolignan hydrocarpin, which is a constituent of Berberis species
has been reported to potentiate the effect of anticancer alkaloid
vincristine in a sensitive and p-gp-expressing acute lymphoblastic
leukemia cell line [84]. Withaferin A (13), a bioactive compound
isolated from Withania somnifera, in combination with cisplatin is
reported to offer more efficacious therapy for ovarian cancer [85].
Nobiletin from Citrus depressa when given along with a combination
of paclitaxel and carboplatin generated a synergistic inhibitory effect
against the proliferation of the human non-small-cell lung carcinoma
cell lines A549 and H460 [86]. Of the two chemotherapeutic drugs,
paclitaxel was responsible for the synergistic effect. Cyclamin,
a 13,28-epoxyoleanane type triterpenoid saponin from Ardisia
japonica is a potent chemosensitizer. A low cytotoxic level of
CH3
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OH
Hypoglycaemic Activity
Diabetes mellitus, characterized by hyperglycaemia, is a
disorder of carbohydrate metabolism due to diminished secretion
of insulin. Quite a few herbal drugs are tradionally used for their
hypoglycaemic effect; prominent ones are bitter gourd (Momordica
charantia), methi (Trigonella foenum-graecum) and guar gum.
Synergistic antidiabetic activity of Vernonia amygdalina and
Azadirachta indica has been repoted in streptozotocin induced
diabetic rat [90]. A Chinese herbal formulation NF3 comprisesing of
Astragali radix and Rehmanniae radix in the ration of 2:1 has been
found effective in enhancing diabetic wound heating in rats. The
effect was found to be due to herb-herb synergism [91].
Cases of synergism due to herb-drug interaction are also
reported. Alluim sativum shows a synergistic effect with
glibenclamide a sulphonylurea, the hypoglycaemic effect of
combination being greater than either of the drug given alone in
streptozotocin-induced diabetic rats [92]. Pleurotus pulmonarius
is reported to show potent synergistic antihyperglycaemic effect
in combination with glyburide in alloxan-induced diabetic mice
[93]. Interaction of Momordica charantia, a traditionally used herb
Citation: Kapoor VK, Singla S (2015) Herb -Drug Interactions –An Update on Synergistic Interactions. J Alt Med Res 1(1):
http://dx.doi.org/10.19104/jamr.2015.107.
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ISSN: 2470-1017
for diabetes, with rosiglitazone, a PPAR-γ-agonist was studied
in rats. It was found that hypoglycaemic effect with combination
was significantly more than either of the drugs given alone [94].
Potentiation of other hypoglycaemic drugs glibenclamide and
metformin by Momordica charantia has erlier been documented
[95].
Curcumin (10) the major phenolic compound of Curcuma longa,
has been reported to possess antihyperglycaemic activity in animal
models. Interestingly, the co-treatment of insulin and curcumin has
been reported to produce a mutual synergistic activation of muscle
cell glucose metabolism [96]. Additive interaction of baicalin (14),
a flavone from Scutellaria baicalensis with berberine for glucose
uptake in 3T3-L1 adipocytes and HepG2 hepatocytes has recently
been reported [97].
HO
O
HO
OH
O
(14)
Cardiovascular Activity
Garlic (Allium sativum) is used traditionally as a complementary
therapy for a number of disorders. The cardioprotective
effects of garlic have been reviewed [98]. Its hypolipidemic
and antihypertensive effects have been well documented. The
interaction of garlic with conventional cardioactive drugs has been
studied. The hypolipedemic effects of garlic was reported to be
augmented by captopril in rats [99]. Captopril is also reported to
have synergistic interaction with garlic and its main constituent
S-allylcysteine sulphoxide as antihypertensive and cardioprotective
[100]. The pharmacokinetic and pharmacodynamic interactions
of hydrochlorothiazide with garlic homogenates were studied in
rats. The study showed that garlic increases the bioavailability
and half life of hydrochlorothiazide, and also causes a substantial
fall in excretion of potassium [101]. It was shown that garlic in
moderate doses with hydrochlorothiazide possesses synergistic
cardioprotective and antihypertensive properties against fructose
and isoproterenol-induced toxicities in rats [102]. Aged garlic, an
alternative to garlic, is less irritating and does not induce toxic
changes observed with garlic. Recently, it was shown that aged
garlic extract and its constituent S-allylcysteine in combination with
atenolol combated more effectively the myocardial dysfunction
during isoproterenol-induced cardiotoxicity in rats [103].
Ginger is another traditional herb known to possess
hypolipedemic, antioxidant and hepatoprotective properties. The
combined effect of ginger extract and atorvastatin were investigated
on lipid profile and atorvastatin-induced hepatic toxicity in rats.
It was concluded that combined regimens containing garlic
extract and low doses of statins could be advantageous in treating
hypercholesterolemic patients which are susceptible to liver
function abnormalities [104].
Decoctions of Hibiscus sabdariffa are used traditionally for its
diuretic and antihypertensive potentials. In a study of herb drug
interaction it was observed in rats and rabbits that co-administration
of Hibiscus sabdariffa extract with hydrochlorothiazide caused
a significant increase in volume of urine excreted and resulted
in decrease in the pH of urine and concentration of sodium,
bicarbonate and chloride ions [105].
Antioxidant and Hepatoprotective Activity
A number of herbs have antioxidant property due to which
they are consumed as a protective against various diseases. Garlic
and curcuma are the two prominent examples. Several reports
on herb-herb synergistic interaction have appeared. Six herbs
namely Paeonia lactiflora, Atractylodes macrocephala, Angelica
sinensis, Astragalus membranaceus, Glycyrrhiza uralensis and
Rheum officinale were combined in pairs in eight traditional
Chinese medicine. These were investigated in vitro by assessing
the DPPH radical scavenging abilities. The results showed that
all eight pairs combination had a significantly larger scavenging
capacity than would be expected from the theoretical sum of the
respective constituent herbs (p less than 0.05), showing synergistic
antioxidant activity [106]. The synergistic effects were attributed
to the flavonoid content of the herbs. In an experimental model of
irritable bowel syndrome a mixture of Aloe vera and Matricaria
recutita showed more effectiveness than M. recutita alone [107].
Synergistic effect of tincture of Crataegus and Mangifera indica on
hyperlipidemic and antioxidant status was reported in atherogenic
rats [108]. The effect was attributed to the synergism between
flavonoids present in Crataegus and the polyphenols of M. indica
Synergism is also shown by pure chemical entity of natural
origin during interaction with herb or other natural product.
L-Arginine is repoted to augument the antioxidant effect of garlic
against acetic acid-induced ulcerative colitis in rats [109]. The effect
might be mainly attributed to the nitric oxide donating propery of
L-arginine. The flavonoids luteolin (15) is one of the most potent
antioxidative plant metabolites and also has ultraviolet-absorbing
property. These effects of luteolin are reported to be synergistically
augmented by tocopherol and ubiquinone, which themselves
are antioxidants [110]. The antioxidant potential of curcumin is
reportedly enhanced by resveratrol, and this synergy is four-fold
greater than that of curcumin with the flavonol quercetin [111].
OH
HO
O
OH
OH
O
(15)
The herbaceous plant Portulaca oleracea is famous for its
hepatoprotective activity, presumably due to its antioxidant effect.
It is reported that the oral administration an extract of P.oleracea
in combination with lycopene significantly ameliorates carbon
tetrachloride hepatotoxicity in rats [112]. Phyllanthus amarus is
another hepatoprotective herb, the effect of which gets potentiated
synergistically by silymarin [113].
CNS Activity
Two Chinese herbs Paeoniae radix and Glycyrrhiza radix are
used traditionally for the treatment of pain. A synergistic interaction
between total glucosides of Poeniae radix and total flavonoids of
Glycyrrhiza radix has been observed using isobolographic analysis
[114]. Morphine is the major alkaloid obtained from Papaver
Citation: Kapoor VK, Singla S (2015) Herb -Drug Interactions –An Update on Synergistic Interactions. J Alt Med Res 1(1):
http://dx.doi.org/10.19104/jamr.2015.107.
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ISSN: 2470-1017
somniferum which has potent analgesic activity. The antinociceptive
effect of morphine is reported to be potentiated by silymarin
[115], and grapefruit juice [116]. The enhancement of morphine
antinociception by grapefruit is repoted to be due to increase in
intestinal absorption [116]. It is reported that antitussive activity
of arabinogalactan of Andrographis paniculata gets increased by
synergistic action with andrographolide, a constituent of the same
plant [117]. Bacopa monniera is traditionally used as a nootropic
agent. A synergistic activity of B. mooniera with rivastigmine in
reversing aluminium-induced memory loss and learning deficit
has been reported in rats [118]. Valerian (Valeriana officinalis) has
been used as an anxiolytic and sedative. Its anti-anxiety activity is
reported to be potentiated by liquorice (Glycyrrhiza glabra) [119].
The protective effects of curcumin, a phenolic compound from the
rhizome of Curcuma longa, against chronic unpredictable stressinduced cognitive impairment and oxidative damage in mice is
reported to be potentiated by piperine (16) a constituent of Piper
nigrum [120] and other species of Piper. The enhancement of the
effect is attributed to increased bioavailability of curcumin by
piperine. In a study the antidepressant effect of a new zinc (II) curcumin complex was attributed to synergism between curcumin
and zinc [121]. In a study carried out to compare the efficacy of
ginger (Zingiber officinale) added to ondansetron in preventing
post-operative nausea and vomiting after ambulatory surgery,
it was found that ginger ondansetron combination was superior
to plain ondansetron as antiemetic regimen for both related to
frequency and severity [122].
O
N
O
O
(16)
Miscellaneous Activities
There are reports on miscellaneous synergistic interactions
which can be listed. The anti-inflammatory and antiarthritic
properties of a siddha formulation “Kalpaamruthaa”, which consist of
extract of Semecarpus anacardium and Emblica officinalis, are better
then sole treatment with S. anacardium. It is attributed to combined
interactions of the phytochemicals such as flavonoids, tannins and
others present in the formulation [123]. A combination of Angelica
sinensis and Sophora flavescens radix is used in a Chinese traditional
medicine to treat a number of inflammatory conditions. Sodium
ferulate and oxymatrine are the active constituents of A. sinensis and
S. flavescens, respectively. A study reported that the combination of
sodium ferulate and oxymatrine could significantly inhibit oedema
in xylene-induced mouse ear oedema and carrageenan-induced
rat paw oedema, but no effect was found when each constituent
was used alone [124]. Synergistic effect of the Lepidium meyenii
and Fagara tessmannii on male sexual organs and hormone level
in rats`has been reported [125]. In traditional Chinese, Japanese
and Korean medicine a formulation Hachimi-jio-gam is used for
treating osteoporosis. The effect of this formulation in combination
with antiresorptive agent alendronate was studied in ovariectomyinduced bone loss in rats. It was found that combined treatment of
the formulaion and alendronate significantly improved trabecular
bone mass and bone microstructure, compared with either agent
alone [126].
Licochalone A, a constituent of Glycyrrhiza inflata root is
Vol. 1. Issue. 1. 4000107
reported to possess muscle relaxant activity. It is shown that
pretreatment with licochalone A enhanced the relaxanat effect of
forskolin, an adenylcyclase activator [127].
Conclusion
The concomitant use of a herbal medicine and an allopathic drug
as a therapeutic regimen in a particular disease is a matter of serious
consideration. The possible herb-drug interaction can reduce or
potentiate the action of the drug through either pharmacodynamic or
pharmacokinetic mechanism. The herb-drug interactions resulting
in potentiation through synergistic mechanism have been reported
in the categories of antimicrobials, antineoplastics, hypoglycaemics,
cardiovascular activity, antioxidants and antihepatotoxics, CNS
active drugs, and miscellaneous. The documented cases highlight
the importance of consideration of possible herb-drug interactions
before embarking on a combined therapy.
Acknowledgements
The authors are thankful to the Governing Council of G.H.G.
Khalsa Educational Institutions for the facilities provided.
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Corresponding author: Vijay Kumar Kapoor, G.H.G. Khalsa College of Pharmacy, Gurusar Sadhar (Ludhiana) 141104, India, Tel: 987-245-189-51;
E-mail: [email protected]
Received Date: July 24, 2015, Accepted Date: August 24, 2015, Published Date: September 03, 2015.
Copyright: © 2015 Vijay K. Kapoor et al. This is an open access article distributed under the Creative Commons Attribution License, which ermits
unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Citation: Kapoor VK, Singla S (2015) Herb -Drug Interactions –An Update on Synergistic Interactions. J Alt Med Res 1(1): http://dx.doi.org/10.19104/
jamr.2015.107.
Citation: Kapoor VK, Singla S (2015) Herb -Drug Interactions –An Update on Synergistic Interactions. J Alt Med Res 1(1):
http://dx.doi.org/10.19104/jamr.2015.107.
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