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413266

Haniadka et al.Integrative Cancer Therapies


The Author(s) 2012

ICT11110.1177/1534735411413266

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Medicinal Plants as Antiemetics in


the Treatment of Cancer: A Review

Integrative Cancer Therapies


11(1) 1828
The Author(s) 2012
Reprints and permission: http://www.
sagepub.com/journalsPermissions.nav
DOI: 10.1177/1534735411413266
http://ict.sagepub.com

Raghavendra Haniadka, MBBS1, Sandhya Popouri, MBBS2,


Princy Louis Palatty, MBBS, MD1, Rajesh Arora, MSc, PhD, MBA3, and
Manjeshwar Shrinath Baliga, MSc, PhD1

Abstract
Chemotherapy- and radiotherapy-induced nausea and vomiting are the most common, intractable and unpleasant side effects
in patients undergoing treatment for cancer. 5-Hydroxytryptamine-3 (5-HT3) receptor antagonists plus dexamethasone
have significantly improved the control of acute nausea and vomiting, but delayed nausea and vomiting remains a significant
clinical problem. Combined neurokinin-1 receptor antagonists with 5-HT3 antagonists and steroids are observed to be
better in the control of both acute and delayed emesis. However, the use of these antiemetics is observed to possess
inherent side effects. The medicinal plants such as Scutellaria baicalensis, Korean red ginseng, American ginseng berry,
Ganoderma lucidum, Zingiber officinale, grape seed extract, and the oil of Mentha spicata are reported to be effective in the
treatment of nausea and vomiting mostly in preclinical studies. Of these, ginger has also been evaluated for its efficacy in
humans and the results have been contradictory. The current review for the first time summarizes the results related to
these properties. An attempt is also made to address the lacunae in these published studies and to emphasize aspects that
need further investigations for these plants to be of use in clinics in the future.
Keywords
chemotherapy, radiotherapy, nausea, vomiting, medicinal plants, anti-emetic

Introduction
Despite significant progress in the field of cancer treatment, effective management of chemotherapy- and radiationinduced nausea and vomiting, abbreviated as CINV and
RINV respectively, is still a major problem as nearly 70%
to 80% of patients are affected.1 These complications are
the most feared adverse effects of these cytotoxic treatment
modalities and may compel the patient to opt out of the therapy. Severe nausea and vomiting at times leads to the development of complications such as fluidelectrolyte imbalances,
weight loss, dehydration, anorexia, weakness, fractures,
esophageal tears, prerenal azotemia, wound dehiscence, or
decline in behavioral and mental status.1
These adverse effects may deteriorate patients physical
and mental status, self-care, and functional ability and may
lead toward withdrawal from the anticancer treatment regimen. This will invariably affect the treatment outcome and
survival of the patient.1,2 It also increases patients anxiety
and dissatisfaction with the hospital experience and may
contribute to future anticipatory nausea.3 Depending on the
severity and frequency, nausea and vomiting are graded as
represented in Table 1.

Depending on the time after administration of the chemotherapy/radiotherapy, nausea may be classified as acute
nausea, which occurs within 24 hours after chemotherapy
and can be subdivided into early acute (within 12 hours) and
late acute (12 to 24 hours); delayed nausea, which appears
more than 24 to 96 or 120 hours after treatment; anticipatory nausea, which occurs before a new cycle of chemotherapy in response to conditioned stimuli, such as the
smells, sights, and sound of the treatment room and breakthrough nausea and vomiting that occurs despite preventive
therapy.1-3,5
The major factors that determine the incidence and severity of CINV include the dose and type of chemotherapy
1

Father Muller Medical College, Mangalore, Karnataka, India


Sri Siddhartha Medical College, Tumkur, Karnataka, India
3
Office of the controller Research and Development (Life Sciences and
International Collaboration) DRDO headquarters, New Delhi, India
2

Corresponding Author:
Manjeshwar Shrinath Baliga, Research and Development, Father Muller
Medical College, Father Muller Road, Kankanady, Mangalore 575002,
Karnataka, India
Email: msbaliga@gmail.com

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Haniadka et al.
Table 1. Gradation of the Nausea,Vomiting, and Anorexia4
Grade
0
1
2
3
4

Nausea

Vomiting

Anorexia

None
Able to eat reasonable intake
Intake reduced significantly
Very poor intake

None
1 episode in 24 hours
2 episode in 24 hours
Up to 10 episodes in 24 hours
>10 episodes in 24 hours. Requires parenteral support

None
Mild
Moderate
Severe
Life threatening

administered, the treatment schedule, the use of combinations


of chemotherapeutic agents, and patients inherent characteristics. Chemotherapeutic agents such as carmustine,
cisplatin, cyclophosphamide (1500 mg2), dacarbazine,
mechlorethamine, and streptozocin are the highly
emetogenic and cause increased frequency of nausea and
vomiting.5
Comparatively, RINV is not as prevalent or severe as
CINV but can interrupt treatment schedule, can negatively
influence the efficacy of the treatment, and can affect the
quality of life.6 The pathophysiology of RINV is incompletely understood but is thought to be similar to that caused
by chemotherapy.6 Unlike chemotherapy, which is systemic
treatment; radiotherapy is delivered from an external source
and is localized.6 The severity of RINV depends on the site
of irradiation, the field size, and the dose per fraction.6,7
RINV is very high when the total body, proper abdominal,
and gastrointestinal regions are irradiated; moderate when
the upper abdomen, pelvic, and cranial parts are involved;
low when the lower thorax and craniospinal regions are
subjected; and minimal when breast and extremities are
irradiated.6,7
Increased risk of CINV and RINV are observed in
patients younger than 50 years, with history of light alcohol
use, and with history of vomiting during pregnancy-induced
nausea/vomiting. Additionally, patients who are dehydrated, debilitated, those who have an electrolyte imbalance, or those who have recently undergone surgery or
radiation therapy, are also at greater risk of experiencing
serious complications from CINV and RINV.1-3,5-7

Physiological and Biochemical


Basis for Nausea
Chronic nausea in the setting of cancer treatment is often
multifactorial in origin. Factors such as raised intracranial
pressure, metabolic abnormalities such as hypercalcemia,
hyponatremia, and uremia, dehydration, malignant bowel
obstruction, and gastroduodenal ulcers contribute to vomiting and nausea.8 Nausea also has a psychological basis,
which may either exacerbate or induce chronic nausea.8
Neurophysiologic studies have shown that both nausea and
vomiting are controlled and mediated by the central nervous system but by different mechanisms.4,9 Nausea is

mediated through the autonomic nervous system, whereas


vomiting results from the stimulation of a complex reflex
that is coordinated by a putative true vomiting center.4,10
The vomiting center is believed to receive convergent
afferent stimuli from several central neurologic pathways.
The sensory stimuli of smell, taste, psychological response,
and pain, led from the limbic system stimulate the chemoreceptor trigger zone (CTZ). Motion sickness occurs via
impulses from the labyrinthine apparatus of the inner ear.
Exogenous chemicals and endogenous substances that
accumulate during inflammation, ischemia, and irritation
stimulate vagal and spinal nerves from visceral and vasculature to cause vomiting and nausea.4,10
The cause of CINV has both components, that is, peripheral and central, which makes it difficult to treat. Serotonin
is produced by the enterochromaffin cells in the enteric nervous system, which accounts for 80% of the total body serotonin. Intestinal irritation or damage to the neoplasm leads
to release of 5HT that stimulates the 5HT3 receptors and
CTZ that ultimately stimulates the vomiting.4,10
The central pathway, on the other hand, is induced by substance P, which is abundantly present in the CTZ and stimulates the neurokinin-1 receptors as well as the gastrointestinal
vagal afferent nerve fiber. A multitude of receptors is effected
in CINV, namely, CB1 (canabinoid-1), D3 (dopamine-3), D2
(dopamine-2), H1 (histamine-1), M3, M5 (muscarinic-3 and -5),
and GABAB (gamma amino butyric acid-B). This is reflected
in the wide array of antiemetic drugs that are present. There
are more neurotransmitters and receptor systems in play
which are as yet unascertained. In CINV sometimes although
emesis is brought under control with drugs, nausea continues
unabated, reducing the quality of life.4,10

Conventional Antiemetic Agents


Used in Cancer Treatment
Antiemetic agents are the most commonly used interventional agents in the management of treatment-related nausea and vomiting. Conventionally, an antiemetic agent
should be effective against the nausea and vomiting produced by most chemotherapeutic drugs; have no interaction
with the cancer chemotherapeutic agents; be available as
oral, injectable, and suppository forms; possess minimal
side effects, especially euphoric reactions; be efficient and

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Integrative Cancer Therapies 11(1)

Table 2. Potency of Antiemetic Drugs4


Effective Against

Class of Antiemetics

Active against highly emetogenic chemotherapy


Active against mildly or moderately emetogenic
chemotherapy
Minimally active

5-HT3 receptor antagonists (eg, ondansetron); substituted benzamides (high


dose, eg, metoclopramide)
Phenothiazines (eg, chlorpromazine), corticosteroids (eg, decadron),
butyrophenones (eg, haloperidol), cannabinoids (eg, marinol)
Antihistamines (eg, meclizine), muscarinic receptor antagonists (eg, meclizine)

reproducible gastrointestinal absorption; have therapeutic


blood levels for 4 to 12 hours postadministration; be effective with repeated use; show low abuse potential; and have
reasonable cost.4
The basis for antiemetic therapy is the neurochemical
control of vomiting. Many antiemetics act by competitively
blocking receptors for these substances, thereby inhibiting
stimulation of peripheral nerves at the CTZ, and perhaps at
the vomiting center. Combination of antiemetic regimens
has become the standard care for the control of CINV.10
However, the choice is complicated as when selecting an
antiemetic the clinicians must opt for an agent that provides
optimal protection against nausea and vomiting while
avoiding drugdrug (antiemeticanticancer) interactions
and additional adverse events. The other factors that need to
be considered are the dose of antineoplastic agent used, the
combination of antineoplastic drugs, route of administration, and the treatment schedule.1,4
Regimens to prevent radiation- and chemotherapyinduced nausea and vomiting are guided by the emetogenic
potential of the drug dose and the combinatorial agents
used. Patients in a hospital setup receiving highly emetogenic potential chemotherapy, may require higher doses of
antiemetics, whereas those receiving highly emetogenic
chemotherapy on an outpatient basis may do best with sublingual or rectal antiemetic routes of delivery.1,4 Various
classes of antiemetics, their applications, and inherent side
effects are summarized in Tables 2 and 3.

Plants as Antiemetic Agents


Complementary therapies are widely used throughout the
world and according to a recent report almost 80% of the
global population relies on alternative therapies for their
health care.11 When compared with the conventionally used
drugs of modern medicine, these medications are clearly
underresearched. However, their wide acceptance makes it
imperative that scientific investigations are performed with
the plants commonly used in the various traditional systems
of medicine and have been practiced for centuries.11
Observations suggest that traditional knowledge and plants
have contributed to the development of antiemetic drugs in
the prevention of CINV and RINV and the development of

the cannabinoids dronabinol, nabilone, marinol, and cannabis from Cannabis sativa commonly known as marijuana
is the best example.4 Scientific studies carried out in the
past 2 decades have shown that some of the most important
medicinal plants, for xample, Scutellaria baicalensis,
Korean red ginseng, American ginseng berry, Ganoderma
lucidum, Zingiber officinale, and grape seed extract possess
antiemetic action against CINV and mint oil and ginger
against RINV. In the following sections, the antiemetic and
antinausea observations are addressed.

Ginseng
Among all medicinal plants, globally, ginseng is probably
the most famous and extensively investigated plant. The
generic name Panax derived from the Greek word Panakos
means a panacea, a virtue ascribed to it by the Chinese, who
consider it a sovereign remedy in almost all diseases.12
Ginseng is a slow-growing perennial plant and the fleshy
root bears resemblance to the human body. Because of
this morphological feature, they are also known as manroot.13,14 There are 11 species of ginseng, but the most
important and the well-studied species are the Panax ginseng (Asian, Korean, or Chinese ginseng) and Panax
quinquefolius (also called American, Canadian, or North
American ginseng).14,15 In the United States, where the
market for medicinal botanicals is US$3 billion (CA$4.3
billion) and growing, ginseng is the top-selling herb among
first-time herbal users and ranks third, surpassed only by
Echinacea and garlic.16
In the traditional Chinese system of medicine, ginseng is
referred to as the ultimate tonic to benefit the whole body
and has been used for more than 2000 years.15 Ginseng has
been used to improve the bodys resistance to stress, to
increase vitality, increase general well-being, immune function, libido, and athletic performance. Preclinical studies
suggest it to possess adaptogenic, anti-inflammatory, antineurological, hypoglycemic, antineoplastic, immunomodulatory, cardiovascular, central nervous system, endocrine,
and ergogenic effects.14 In traditional medicine, ginseng is
also used for the alleviation of emesis.15 Preclinical studies
have shown that the Korean red ginseng (P ginseng)17 and
the American ginseng berry (P quinquefolius)18 prevent

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Haniadka et al.
Table 3. Side Effects of Antiemetics Commonly Used in the Prevention of CINV and RINV
Class of Antiemetic
5-HT3 receptor antagonists
Phenothiazines

Antidopaminergic drugs

H1 antihistaminics

Corticosteroids
Muscarinic receptor
antagonists

Drugs
Ondansetron, tropisetron,
granisetron, dolasetron,
palonosetron, ramosetron
Prochlorperazine, promethazine,
thiethylperazine
Neuroleptics: Chlorpromazine,
Prochloropropazine
haloperidol, droperidol
Prokinetic drugs: Cisapride,
mosapride, tegaserod,
fluphenazine, domperidone
diphenidol
Substituted benzamides:
Metoclopramide,
trimethobenzamide
Dimenhydrinate, clizines,
cinnarizine, diphenhydramine,
promethazine, hydroxyzine,
meclizine, doxylamine
Dexamethasone,
betamethasone,
methylprednisolone
Scopolamine, dicyclomine
diphenidol

Benzodiazepines

Diazepam, lorazepam,
alprazolam

Cannabinoids

Dronabinol, nabilone, marinol

NK1 antogonists

Aperpitant
Casopitant
Fosaprepitant
Maropitant
Vestipitant

Adverse Effects
Diarrhea, headache, light-headedness, asthenia, abdominal
discomfort, rash and allergic reaction
Drowsiness, hypotension, impaired psychomotor activity,
agitation, insomnia, inversion of sleep, postural hypotension,
paroxysmal tachycardia, blurred vision, dry mouth,
constipation, paralytic illus, perspiration, hyperglycemia

Extrapyramidal effects, dystonias usually occuring acutely after


intravenous administration, Parkinsonian-like symptoms
tardive dyskinesia with chronic treatment, galactorrhea,
methemoglbinuri

Sedation, dizziness, tinnitus, blurred vision, euphoria,


uncoordination, constipation, dry mouth, dry cough.
Infrequent adverse effects include urinary retention,
palpitations, and hypotension
Pituitary adrenal suppression, suppression of HPA axis,
Cushings habitus, fragile skin, purple striae, easy bruising,
telangectsias, hirsutism, hyperglycemia, muscular weakness
Dry mouth, xerostomia, reddened skin, increased body
temperature, mydriasis, photophobia, loss of accommodation,
blurred vision, tachycardia, startled easily, urinary retention,
increased intraocular pressure, confusion, disorientation,
respiratory depression, memory problems
Vertigo, disorientation, amnesia, impairment of psychomotor
skills, weakness, blurring of vision, dry mouth, urinary
incontinence, irritability, nightmares
Tachycardia, vasodilatation, hypotension, euphoria, somnolence,
detachment, dizziness, anxiety, nervousness, panic, paranoid
reaction, thinking abnormalities. After abrupt withdrawal,
abstinence syndrome manifest by irritability, insomnia,
restlessness can occur
Asthenia, fatigue, anorexia, constipation, diarrhea, hiccups
Neutropenia, dehydration
Hypotension, purities, headache, flushing, erythrema
Drooling, drowsiness, diarrhea, appetite loss
Headache, fatigue, dry mouth

Abbreviations: CINV, chemotherapy-induced nausea and vomiting; RINV, radiotherapy-induced nausea and vomiting; HPA axis, hypothalamicpituitaryadrenal

cisplatin-induced nausea and vomiting in experimental animals. The following section addresses these aspects.

Korean Red Ginseng in the


Prevention of CINV
In Korea, depending on the type of processing, ginseng is classified into fresh ginseng (<4 years old), white ginseng (4-6 years
old and dried after peeling), and red ginseng (harvested when

6 years old, steamed, and dried).19 Red ginseng is not skinned


before it is steamed or otherwise heated and subsequently
dried.19 In the course of the steaming process, ginseng starch
is gelatinized, causing an increase in saponin content.
Traditionally, red ginseng has been used to restore and enhance
normal well-being, and it is often referred to as an adaptogenic.19
Kim et al17 evaluated the antiemetic effect of Korean red
ginseng total extract (aqueous) on cisplatin-induced nausea and
vomiting using ferrets. In the cisplatin control, intraperitoneal

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Integrative Cancer Therapies 11(1)

(i.p.) administration of cisplatin (7.5 mg/kg) induced both


nausea and vomiting. After a latency period of 1 hour, the
episodes of nausea and vomiting initiated and reached a
peak at 1.5 hours and persisted for 3 hours. Oral administration of the extract (0.3, 1.0, and 3.0 g/kg) reduced the cisplatin-induced nausea and vomiting in a concentration-dependent
manner. With increase in the dose of cisplatin to 10 mg/kg,
the nausea and vomiting were severe and the lower 2 doses
of 0.3 and 1.0 g/kg were ineffective, whereas the highest
dose of 3.0 g/kg exhibited significant antiemetic effects. In
the time-dependent effect studies, the authors also observed
that oral administration of 3.0 g/kg of the extract was effective only when administered 1 and 2 hours before cisplatin
(7.5 mg/kg, i.p.) and that a further increase to 4 hours before
cisplatin administration was not as effective as the other 2
earlier time points.17

American Ginseng Berry in


the Prevention of CINV
Studies have shown that pretreatment with ginseng berry
extracts (50, 100, and 150 mg/kg body weight) and the
phytochemical ginsenoside (2 and 5 mg/kg body weight) by
intraperitoneal route 30 minutes before cisplatin (3 mg/kg
body weight) resulted in a significant reduction in cisplatininduced pica (Pica means eating of nonnutritive substances
such as kaolin, a illness-response behavior in mice20 and
rats.21) The phytochemical ginsenoside Re also caused a
significant reduction in the intake of kaolin and the optimal
protective effect was observed at 5 mg/kg.18
The extract also decreased the amount of kaolin consumption at all time points (24, 48, 72, 96, and 120 hours)
with differing levels of efficacy. The lowest dose of 50 mg/
kg significantly attenuated the pica but did not improve the
food intake, whereas the next higher dose of 100 mg/kg was
effective in eliminating pica at 24 to 120 hours time point
and also improved the food intake. With further increase in
the dose to 150 mg/kg, pica was attenuated, especially when
compared with the cisplatin alone cohorts at both 24 and 48
hours but showed a prolonged reduction in food intake from
24 to 96 hours.18
The extract was observed to be effective in scavenging
superoxide anion and hydroxyl radicals in vitro, thereby
contributing to the protective effects at least in part.18,22 In
vitro studies with the recombinant 5-hydroxytryptamine-3A
(5-HT3A) receptor expressing xenopus oocyte have shown
that the ginseng saponins (total saponin, panaxadiol saponin fraction, panaxatriol saponin fraction, and ginsenosideRb1 and -Rg1) inhibit the peak current induced by the
agonist 5-HT on the 5-HT3A receptor in a dose-dependent,
reversible, and voltage-independent manner. Of all the fractions, optimal results were observed with the panaxatriol
saponin fraction, suggesting that some of the specific types

of ginsenoside might have an antagonistic action against


5-HT3A receptor related to nausea and vomiting.23
The observation that 100 mg/kg completely reversed
pica and significantly improved food intake suggests the
effectiveness of ginseng berry extracts in treating cisplatininduced nausea and vomiting. The extract possess free radical scavenging and antagonistic action against 5-HT3A
receptor suggest its possible use in the prevention of CINV.
Detailed studies with other emetogenic antineoplastic drugs
and also with other animal models of studies are required to
confirm its efficacy before initiating clinical studies.

Scutellaria baicalensis Georgi


in the Prevention of CINV
Commonly known as Baikal skullcap, Scutellaria baicalensis is a perennial herb of the family Lamiaceae with fleshy
root, branched stems, papery leaves, purple-red to blue
flowers, and black-brown ovoid nutlets.24-27 For more than
2000 years, it has been one of the most widely used herbs
in the traditional Chinese herbal system of medicine.24 Its
use was first documented in the Shen Nong Ben Cao Jing
circa 100 bc, and it is currently listed in the Chinese
Pharmacopoeia as one of most important herbs.25-27
The roots are of use in the treatment of dysentery, diarrhea, allergic and inflammatory diseases, allergic rhinitis, to
reduce cholesterol level, decrease blood pressures, atherosclerosis, hypertension, cholecystitis, hepatitis, cataract, diabetes complications, acute bronchitis, asthma, cold, cancer,
bacterial and viral infections of the respiratory and the gastrointestinal tract, hepatitis, jaundice, tumor, and leukemia
in the traditional Chinese medicine.26,28,29
With regard to inhibition of CINV, Aung et al30 studied
the antiemetic effects of hot watersoluble extract of the
roots of S baicalensis against cisplatin-induced alterations
in rats. When compared with the control animals, administration of cisplatin (3 mg/kg) decreased the food intake at
all study time points (1, 2, 3 and 4 days postcisplatin treatment) with the nadir being observed at 24 hours posttreatment. A progressive recovery in food consumption was
observed from day 3 onward suggesting recovery. Cisplatin
treatment also increased the intake of kaolin at all the time
points, suggesting that the prolonged increase in pica consumption corresponds to a prolonged and delayed emetic
response to cisplatin in humans.31
Pretreatment with water-soluble extract of S baicalensis
30 minutes before cisplatin administration caused a decrease
in the intake of pica at the 2 lower doses of 1 and 3 mg/kg.
At a higher dose of 10 mg/kg the kaolin consumption
increased, suggesting a possible pro-oxidant effect.
However, there was no significant improvement in the food
intake. The authors proposed that the observed beneficial
effects may be because of the antioxidant effects of S

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Haniadka et al.
baicalensis and its binding to 5-HT1A receptors.30,32 Similar
results were also observed in another study and the reported
in vitro free radical scavenging effects of the extract confirmed that the antioxidant action of the herb may be, at
least in part, responsible for attenuating the cisplatininduced nausea and vomiting.22

Ganoderma lucidum (Fr.) Karst in the


Prevention of CINV
Commonly known as Reishi mushroom, this white rot
lamellaless macrofungus belonging to the phylum
Basidiomycetes and family Polyporaceae is an important
mushroom in the herbal system of medicine in China,
Japan, and other East Asian countries.33,34 It is found to
grow on the dried trunks of dead plum, Guercus serrata or
pasonia trees in densely wooded mountains where humidity
is high and the lighting is dim.35 The Chinese name of this
mushroom is Lingzhi, which means spiritual potency.33,34
This mushroom was also regarded by the Chinese as the
Medicine of Kings and mushroom of immortality
for more than 2000 years.33-35 Phytochemical studies have
shown that the basidiocarp, mycelia, and spores of Reishi
contain triterpenoids, polysaccharides, nucleotides,
sterols, steroids, fatty acids, proteins/peptides, and trace
elements.33,36
In traditional Chinese system of medicine, Reishi mushroom has long been used as a medicine to treat various
human diseases.36 These mushrooms are supposed to
enhance intellectual capacity and memory, promoting agility,
increase life span, inhibit tumor growth, reduce hypertension, modulate immune response, and increase hematopoietic activity.33-36 Pharmacological studies have shown that
the Reishi mushrooms possess immunomodulatory, antiatherosclerotic, anti-inflammatory, analgesic, chemopreventive, antitumor, chemo- and radioprotective, sleep
promoting, antibacterial, antiviral (including anti-HIV),
hypolipidemic, anti-fibrotic, hepatoprotective, anti-diabetic,
anti-androgenic, anti-angiogenic, anti-herpetic, anti-oxidative,
and radical-scavenging, anti-aging, hypoglycemic, estrogenic,
and anti-ulcer properties.33-36
Experimental studies have shown that intraperitoneal
administration of 1, 3, and 10 mg/kg G lucidum extract was
effective in attenuating cisplatin-induced nausea and vomiting in the rat pica model. Additionally, the area under the
curve for kaolin intake from time 0 to 72 hours for cisplatin
only, 1, 3, and 10 mg of the extracts along with cisplatin
treatment was 327.6, 264.0, 169.2, and 88.8 g/h, respectively. The reduction in the area under the curves of kaolin
intake after 1, 3, and 10 mg/kg G lucidum extract administrations were 19.4%, 48.4%, and 72.9%, respectively.
Additionally, when compared with the cisplatin alone
cohorts, administering G lucidum extract was observed to
be effective in increasing the intake of food and lacked

adverse effects, such as restlessness or respiratory distress


following the injections. Together, these observations suggest that in addition to reducing the nausea and vomiting,
the extract also has a supportive effect in improving the
general health and appetite in animals.37

Grape Seed Polyphenols in


the Prevention of CINV
For thousands of years, the fruit and the plant Vitis vinifera,
commonly referred to as grapes have been grown and harvested for medicinal, nutritional, and economic value. The
seeds of grapes have been a waste product of the winery
and grape juice industry, but recent studies suggest that
they possess immense health benefits.38,39 Depending on
the variety of grapes, the seeds are reported to contain lipids, proteins, carbohydrates, and 5% to 8% polyphenols.
The polyphenols in grape seeds are mainly flavonoids,
including gallic acid, the monomeric flavan-3-ols catechin,
epicatechin, gallocatechin, epigallocatechin, and epicatechin 3-O-gallate, and procyanidin dimers, trimers, and
more highly polymerized procyanidins.38
Scientific studies have shown that grape seed extract is a
powerful antioxidant and its effect is 20 times greater than
vitamin E and 50 times greater than vitamin C,39 and it also
protects the body from premature aging and various diseases.38 Studies also indicate that because of its antioxidant
effect, it is useful in promoting youthful skin, good cell
health, elasticity, and flexibility. Animal studies have also
shown that grape seed extract possess cardioprotective,
anticancer, and anti-inflammation properties.39 Proantho
cyanidins are also reported to protect the body from sun
damage, to improve vision, to improve flexibility in joints,
arteries, and body tissues such as the heart, and to improve
blood circulation by strengthening capillaries, arteries,
and veins.38
With regard to prevention of CINV, Wang et al40 investigated the antiemetic effects of 3 grape seed extracts prepared in the investigators laboratory, obtained from a
US-based dietary supplement company and from China.
Phytochemical studies showed a great variation in the constituents of the 5 major constituents (gallic acid, catechin,
epicatechin, procyanidin B2, and epicatechin gallate). The
extract obtained from China had the highest level of polyphenols (194.21 mg/g), followed by the US-based dietary
supplement company sample level (35.84 mg/g). The lowest total polyphenol content (27.27 mg/g) was observed in
the sample prepared in the investigators laboratory.40
Pretreatment with the grape seed extract (3 mg/kg), by
intraperitoneal route reduced the cisplatin-induced pica
from 0 to 72 hours but did not alter food intake or body
weight. Conversely, with increase in the concentration to
10 mg/kg, all 3 extracts decreased the cisplatin-induced
pica and with 30 mg/kg, the antiemetic effect of all the

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Integrative Cancer Therapies 11(1)

extracts was further reduced. Among the 3 samples studied,


the investigators laboratory sample reduced emesis by 45%,
the US-based dietary supplement company extract by 54%,
and the extract obtained from China by 66%, clearly indicating that effect was proportional to the content of polyphenol in the extract. Additionally, the area under the curve
for kaolin intake from time 0 to 72 hours for cisplatin only,
laboratory sample, US company sample, and Chinese
company samples were 518.0, 284.0, 238.2, and 178.7 g/h,
respectively.40

Mint Oil in the Prevention of RINV


Mint is a broad term given for a group of aromatic perennial
herbs belonging to the genus Mentha and the family
Labiatae. It is one of the most important culinary and medicinal plants in the world. In various traditional medicines,
mint is used as a stomachic, tonic, carminative, antispasmodic, and anthelmintic.41 Mint oil extracted from the stem,
leaves, and flowers of the plant by steam distillation is used
all over the world for flavoring, cosmetic, and medicinal
purposes.41,42 The oil is traditionally used in relieving digestive ailments, for irritable bowel syndrome, headache, nonulcer dyspepsia such as indigestion, gas problem, and acidity.43
It is also a main ingredient for Ayurvedic medicines (eg,
Daburs Pudin Hara used for gastric disturbances.43
Scientific studies have shown that the mint oil possesses
analgesic, anti-inflammatory, antiseptic, anti-infectious, antimicrobial, antispasmodic, astringent, carminative, digestive,
expectorant, febrifuge, fungicidal, nervine, vasoconstrictor,
decongestant, stimulant, cognitive enhancer, stomachic
properties and is also effective against irritable bowel syndrome.41-43 At the biochemical level, mint oil is reported to
modulate calcium channeldependent processes in intestinal, neuronal, and cardiac preparations.41-43 The oil is also
reported to possess neuromodulatory and performanceenhancing properties.44
Studies have shown that mint oil (Mentha spicata Linn.)
was effective in mitigating radiation-induced conditioned
taste aversion (CTA), a phenomenon understood to be controlled in rodents by the same pathways that control nausea
and vomiting in humans.45 It was observed that the intraperitoneal administration of mint oil (5, 7.5, 10, 12.5, and
15% v/v) 1 hour before exposure to 2 Gy of whole body
irradiation showed significant decrease in CTA at all doses,
when compared with the 2 Gy radiation control at all time
points (1, 2, 3, 4, and 5 days post irradiation). However, the
best effect was observed as follows 10% > 12.5% > 15% >
7.5% > 5%.45
Mechanistically, it is quite possible that the free radical
scavenging and the antioxidant effects of mint may have
contributed to the reduction in CTA. Studies have also
shown that rotundifolone, an active constituent of mint oil,
mimics the effects produced by calcium channel blockers,

and thus can neutralize the injurious effects of biogenic


amines such as histamines and 5-HT and also modulate
vagal activity and reduce intestinal motility and contractility.46 Mint oil is also known to exert neurobehavioral effects,
increase alertness, sharpen mental process, and rejuvenate a
sluggish and tired mind.47 All these properties may have
contributed to the observed effect.

Ginger in the Prevention of CINV and RINV


The rhizome of Zingiber officinale (family Zingiberaceae),
commonly known as ginger, is an important herb in the
various traditional systems of medicine.48 It is an integral
part of several medicinal formulations in Ayurveda, the
traditional system of Indian medicine. In various traditional systems of medicine, ginger is reported to be a carminative, diaphoretic, antispasmodic, peripheral circulatory
stimulant, astringent, appetite stimulant, anti-inflammatory
agent in addition to being useful in treating cold, headaches, arthritis, rheumatological conditions, and muscular
discomfort.48-50
Studies have shown that ginger possesses antimicrobial,
antischistosomal, anti-inflammatory, antipyretic, antioxidative, hypoglycemic hepatoprotective, diuretic, and hypocholesterolemic effects.49,50 Ginger is also beneficial to the
gastrointestinal tract, to increase bile secretion, and to prevent gastric ulcers.49,50 Scientific studies have also shown
that ginger prevents nausea and/or emesis resulting from
pregnancy, motion sickness, postoperation chemotherapy,
and radiation, thereby validating the traditional observations and emphasizing its broad-spectrum antiemetic
effects.49,50 In the United States, ginger is recommended to
relieve and prevent nausea.48
Preclinical studies have shown that ginger possesses
antiemetic effects and prevents gastric emptying against the
highly emetogenic cisplatin. Sharma et al51 evaluated the
anitemetice effects of various ginger extracts (acetone, 50%
ethanolic and aqueous) against emesis induced by 3 mg/kg
cisplatin in the healthy mongrel dogs with the 5-HT3 receptor antagonist granisetron as a known control. The authors
observed that the acetone and 50% ethanolic extract at the
doses of 25, 50, 100, and 200 mg/kg per os (p.o.). exhibited
significant protection whereas aqueous extract at these
doses was ineffective against emesis. The acetone extract
was more effective than ethanolic extract but was less effective than granisetron.51
The acetone and 50% ethanolic extract of ginger in the
doses of 100, 200, and 500 mg/kg (p.o.) and fresh ginger
juice (2 and 4 mL/kg) were also investigated against cisplatin effect on gastric emptying in rats. It was observed that
all the 3 ginger preparations reversed the cisplatin-induced
delay in gastric emptying, and the ginger juice and acetone
extract were more effective than the 50% ethanolic extract.52
The reversal produced by the ginger juice was better than

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25

Haniadka et al.

Figure 1. Structure of gingerol, an important phytochemical


present in ginger rhizome

the 5-HT3 receptor antagonist ondansetron, whereas that of


the acetone extract of ginger was similar to ondansetron.52
Together, these studies suggest that ginger possesses antiemetic effects and also reduces the gastrointestinal side
effects of cisplatin.51,52
Gingerol (Figure 1), the active principle of raw ginger,
was also investigated for its antiemetic effects against the
cisplatin (7.5 mg/kg i.p.)-induced emesis in minks.53
Pretreatment with gingerol (50, 100, or 200 mg/kg, i.g.)
caused a concentration-dependent reduction in the number
of retching and vomiting incidents during the 6-hour observation period. The effects of 200 mg/kg of gingerol and the
positive control ondansetron were almost similar.53
Immunohistochemical studies showed that gingerol caused
a dose-dependent suppression in the levels of substance P
and NK1 receptors in area postrema and ileum.53
Studies by Sharma et al54 have shown that the administration of the hydroalcoholic extract of ginger 1 hour before
exposure to 2 Gy of irradiation was effective in blocking
the saccharin avoidance response for 5 posttreatment observational days. The study showed that intraperitoneal administration of the extract (50, 100, 150, and 200 mg/kg body
weight) to male rats caused a dose- and time-dependent protective effect and that the best effects were observed at
200 mg/kg body weight.54 It was also observed that in the
female rats (administered with 150, 200, 250, and 300 mg/
kg body weight) the optimal effect was observed at 250 mg/
kg by intraperitoneal route, confirming the existence of
gender difference in relation to behavioral responses or differential metabolism.55 The authors hypothesize that the
observed protective effects of ginger may be because of its
antioxidant properties.54,55
The antiemetic studies with ginger in humans have been
mixed and contradictory. In one of the earliest studies,
Pace56 investigated the antiemetic effect of ginger in leukemic patients receiving chemotherapy. The patients were
randomized to receive oral ginger or placebo in addition to
prochlorperazine. The results showed that when compared
with those receiving placebo, a significant reduction in nausea was observed in patients receiving ginger.56 Furthermore,

pilot studies by Meyer et al57 and Pecoraro et al58 have also


supported gingers use as an antiemetic in patients undergoing chemotherapy.
Additionally, experiments have confirmed that ginger is
effective in reducing nausea and vomiting induced by lowdose cyclophosphamide in combination with other anticancer drugs causing mild emesis.59 However, the antiemetic
efficacy of ginger was found to be equal to that of metoclopramide but inferior to that of ondansetron.59 Combining
high-protein meals with ginger also reduced the chemotherapyinduced delayed nausea and the use of standard antiemetic
medications in patients with cancer.60
In a double-blinded crossover study, Manusirivithaya et al61
have observed that the addition of ginger to standard antiemetic regimen of gynecologic oncology patients receiving
cisplatin offered no advantage in reducing nausea or vomiting in the acute phase of cisplatin-induced emesis, whereas in
the delayed phase it was effective and that the beneficial
effect was comparable to that of metoclopramide.
Studies have also shown that the administration of ginger (0.5, 1.0, or 1.5 g) along with 5-HT3 receptor antagonists reduced the chemotherapy-induced nausea in patients
undergoing treatment for breast, alimentary, and lung cancers.62 The optimal effect was observed for the cohorts who
had received 0.5 or 1.0 g of ginger.62 Very recently, Pillai et
al63 have also observed that ginger root powder was effective in reducing the severity of acute and delayed CINV
when provided as a adjunct to ondensetron and dexamethasone in bone sarcoma patients receiving the highly emetogenic chemotherapy containing cisplatin/doxorubicin.
Together, these reports clearly suggest the usefulness of
ginger as an adjuvant to the conventional antiemetic agents.
Contradictory to these observations is the recent study
by Zick et al64 suggesting that ginger offers no benefit in
reducing the prevalence or severity of acute or delayed
CINV when combined with 5-HT3 receptor antagonists
and/or aprepitant. Furthermore, the authors also observed
that the participants who took both ginger and aprepitant
had more severe acute nausea than participants who took
only aprepitant, suggesting a possible antagonism.64
Overall, these observations clearly suggest that more observational studies, with a larger sample size, are needed to
confirm the encouraging preliminary data on ginger safety.

Conclusions
Numerous preclinical studies in the past 2 decades have
demonstrated unequivocally that traditionally used plants
such as S baicalensis, Korean red ginseng, American ginseng
berry, G lucidum, ginger, and grape seed extract possess
antiemetic actions against CINV, and mint oil and ginger
against RINV. Most of the antiemetic studies against CINV
have been with cisplatin and future studies are required with
other chemotherapeutic agents and their combinations that

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26

Integrative Cancer Therapies 11(1)

induce emesis. This would clearly indicate the spectrum of


efficacy of these plants in preventing CINV. The outcomes
of such studies may be useful for the clinical applications of
these plants and their phytochemicals as antiemetic agents
and may open up a new therapeutic avenue.
Most of the plants studied have been used in traditional
systems of medicine for many centuries. These plants are
consumed by humans and are reported to be devoid of toxic
effects at the permissible doses. However, the observation
that some of the plants possess pro-oxidant effects necessitates performing detailed toxicological studies to understand the antioxidant and pro-oxidant concentrations of
these plants. Some of the administration has been by intraperitoneal route, which is not the preferred route for humans.
Studies should be planned to test the efficacy of these plants
when administered through oral route. Experimental studies
should also be performed with tumor-bearing animals to
rule out the possibility of interference of these plant compounds with the antineoplastic activity of the emetogenic
anticancer agents. Only when these studies are performed
and satisfactory results obtained, can the value of these
plants as antiemetic agents be appreciated.
From the contradictory clinical observations with ginger
and the animal studies with grape seed extracts it is very
evident that the concentration of phytochemical plays a
major role in the observed pharmacological effects. Therefore,
studies should also be performed with well-characterized
and standardized extracts. Studies should also be aimed at
identification of the bioactive compounds present in the
respective plants that are responsible for the antiemetic
effects. Currently, only gingerol and ginsenoside, the active
principles of raw ginger and ginseng, respectively, have
been reported to possess antiemetic effects. Similar studies
should also be performed with other phytochemicals. When
these studies are performed, it will clearly indicate the
potential of these plants as possible nontoxic antiemetic
agents against chemotherapy- and radiation-induced nausea. Till then, caution needs to be taken especially with the
plants that exhibit pro-oxidant effects (at higher doses) as
their use can further increase emesis and aggravate side
effects, thereby affecting the treatment response/regimen
and survival of the patient.
Acknowledgments
Mr Raghavendra Haniadka, Dr Princy Louis Palatty, and Dr
Manjeshwar Shrinath Baliga are grateful to Rev Fr Patrick Rodrigus
(Director), Rev Fr Denis DSa (Administrator), and Dr Jaya Prakash
Alva (Dean). Dr Rajesh Arora is grateful to Dr W Selvamurthy, Chief
controller Research and Development (Life Sciences and International
Collaboration) for support and encouragement.

Declaration of Conflicting Interests


The author(s) declared no potential conflicts of interests with respect
to the research, authorship, and/or publication of this article.

Funding
The author(s) received no financial support for the research,
authorship, and/or publication of this article.

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