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Haniadka et al.Integrative Cancer Therapies

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Integrative Cancer Therapies

Medicinal Plants as Antiemetics in

11(1) 18­–28
© The Author(s) 2012
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DOI: 10.1177/1534735411413266
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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 Depending on the time after administration of the che-

Despite significant progress in the field of cancer treat-
ment, effective management of chemotherapy- and radiation-
induced 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 ther-
apy. Severe nausea and vomiting at times leads to the devel-
opment of complications such as fluid–electrolyte 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 regi-
men. This will invariably affect the treatment outcome and
survival of the patient.1,2 It also increases patient’s 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.
motherapy/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; anticipa-
tory nausea, which occurs before a new cycle of chemo-
therapy in response to conditioned stimuli, such as the
smells, sights, and sound of the treatment room and break-
through nausea and vomiting that occurs despite preventive
therapy.1-3,5
The major factors that determine the incidence and sever-
ity of CINV include the dose and type of chemotherapy
1
Father Muller Medical College, Mangalore, Karnataka, India
2
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
Corresponding Author:
Manjeshwar Shrinath Baliga, Research and Development, Father Muller
Medical College, Father Muller Road, Kankanady, Mangalore 575002,
Karnataka, India
Email: msbaliga@gmail.com
Haniadka et al. 19
Table 1. Gradation of the Nausea,Vomiting, and Anorexia4
Grade Nausea
0 None None
1 Able to eat reasonable intake 1 episode in 24 hours
2 Intake reduced significantly 2 episode in 24 hours
3 Very poor intake Up to 10 episodes in 24 hours
4 >10 episodes in 24 hours. Requires parenteral support
administered, the treatment schedule, the use of combinations
of chemotherapeutic agents, and patients’ inherent charac-
teristics. 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 incom-
pletely 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 dehy-
drated, debilitated, those who have an electrolyte imbal-
ance, 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 vomit-
ing 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 ner-
vous system but by different mechanisms.4,9 Nausea is
Vomiting Anorexia
None
Mild
Moderate
Severe
Life threatening
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 chemore-
ceptor 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 vascu-
lature to cause vomiting and nausea.4,10
The cause of CINV has both components, that is, periph-
eral and central, which makes it difficult to treat. Serotonin
is produced by the enterochromaffin cells in the enteric ner-
vous system, which accounts for 80% of the total body sero-
tonin. 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 sub-
stance P, which is abundantly present in the CTZ and stimu-
lates 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 interven-
tional agents in the management of treatment-related nau-
sea and vomiting. Conventionally, an antiemetic agent
should be effective against the nausea and vomiting pro-
duced 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
20 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 effec-
tive 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 drug–drug (antiemetic–anticancer) 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 administra-
tion, and the treatment schedule.1,4
Regimens to prevent radiation- and chemotherapy-
induced 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 emeto-
genic potential chemotherapy, may require higher doses of
antiemetics, whereas those receiving highly emetogenic
chemotherapy on an outpatient basis may do best with sub-
lingual 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 can-
nabis 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 “man-
root.”13,14 There are 11 species of ginseng, but the most
important and the well-studied species are the Panax gin-
seng (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 body’s resistance to stress, to
increase vitality, increase general well-being, immune func-
tion, libido, and athletic performance. Preclinical studies
suggest it to possess adaptogenic, anti-inflammatory, anti-
neurological, hypoglycemic, antineoplastic, immunomodu-
latory, 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
Haniadka et al. 21

Table 3. Side Effects of Antiemetics Commonly Used in the Prevention of CINV and RINV

Class of Antiemetic Drugs Adverse Effects

5-HT3 receptor antagonists Ondansetron, tropisetron, Diarrhea, headache, light-headedness, asthenia, abdominal
granisetron, dolasetron, discomfort, rash and allergic reaction
palonosetron, ramosetron
Phenothiazines Prochlorperazine, promethazine, Drowsiness, hypotension, impaired psychomotor activity,
thiethylperazine agitation, insomnia, inversion of sleep, postural hypotension,
paroxysmal tachycardia, blurred vision, dry mouth,
constipation, paralytic illus, perspiration, hyperglycemia
Antidopaminergic drugs Neuroleptics: Chlorpromazine,  
Prochloropropazine
haloperidol, droperidol
  Prokinetic drugs: Cisapride, Extrapyramidal effects, dystonias usually occuring acutely after
mosapride, tegaserod, intravenous administration, Parkinsonian-like symptoms
fluphenazine, domperidone tardive dyskinesia with chronic treatment, galactorrhea,
diphenidol methemoglbinuri
  Substituted benzamides:  
Metoclopramide,
trimethobenzamide
H1 antihistaminics Dimenhydrinate, clizines, Sedation, dizziness, tinnitus, blurred vision, euphoria,
cinnarizine, diphenhydramine, uncoordination, constipation, dry mouth, dry cough.
promethazine, hydroxyzine, Infrequent adverse effects include urinary retention,
meclizine, doxylamine palpitations, and hypotension
Corticosteroids Dexamethasone, Pituitary adrenal suppression, suppression of HPA axis,
betamethasone, Cushing’s habitus, fragile skin, purple striae, easy bruising,
methylprednisolone telangectsias, hirsutism, hyperglycemia, muscular weakness
Muscarinic receptor Scopolamine, dicyclomine Dry mouth, xerostomia, reddened skin, increased body
antagonists diphenidol temperature, mydriasis, photophobia, loss of accommodation,
blurred vision, tachycardia, startled easily, urinary retention,
increased intraocular pressure, confusion, disorientation,
respiratory depression, memory problems
Benzodiazepines Diazepam, lorazepam, Vertigo, disorientation, amnesia, impairment of psychomotor
alprazolam skills, weakness, blurring of vision, dry mouth, urinary
incontinence, irritability, nightmares
Cannabinoids Dronabinol, nabilone, marinol 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
NK1 antogonists Aperpitant Asthenia, fatigue, anorexia, constipation, diarrhea, hiccups
  Casopitant Neutropenia, dehydration
  Fosaprepitant Hypotension, purities, headache, flushing, erythrema
  Maropitant Drooling, drowsiness, diarrhea, appetite loss
  Vestipitant Headache, fatigue, dry mouth
Abbreviations: CINV, chemotherapy-induced nausea and vomiting; RINV, radiotherapy-induced nausea and vomiting; HPA axis, hypothalamic–pituitary–adrenal

cisplatin-induced nausea and vomiting in experimental ani-
mals. The following section addresses these aspects.
Korean Red Ginseng in the
Prevention of CINV
In Korea, depending on the type of processing, ginseng is clas-
sified 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
22 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 administra-
tion of the extract (0.3, 1.0, and 3.0 g/kg) reduced the cispl-
atin-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 effec-
tive 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 cisplatin-
induced 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 con-
sumption 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 sapo-
nin fraction, panaxatriol saponin fraction, and ginsenoside-
Rb1 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 frac-
tions, 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 cisplatin-
induced nausea and vomiting. The extract possess free radi-
cal 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 baicalen-
sis 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, diar-
rhea, allergic and inflammatory diseases, allergic rhinitis, to
reduce cholesterol level, decrease blood pressures, athero-
sclerosis, hypertension, cholecystitis, hepatitis, cataract, dia-
betes complications, acute bronchitis, asthma, cold, cancer,
bacterial and viral infections of the respiratory and the gas-
trointestinal 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 water–soluble extract of the
roots of S baicalensis against cisplatin-induced alterations
in rats. When compared with the control animals, adminis-
tration of cisplatin (3 mg/kg) decreased the food intake at
all study time points (1, 2, 3 and 4 days post–cisplatin treat-
ment) with the nadir being observed at 24 hours posttreat-
ment. 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 con-
sumption 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
Haniadka et al. 23
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 con-
firmed that the antioxidant action of the herb may be, at
least in part, responsible for attenuating the cisplatin-
induced 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 mush-
room 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 hyperten-
sion, modulate immune response, and increase hematopoi-
etic activity.33-36 Pharmacological studies have shown that
the Reishi mushrooms possess immunomodulatory, anti-
atherosclerotic, anti-inflammatory, analgesic, chemopre-
ventive, 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 vomit-
ing 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, respec-
tively. The reduction in the area under the curves of kaolin
intake after 1, 3, and 10 mg/kg G lucidum extract adminis-
trations 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 sug-
gest 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 har-
vested 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 lip-
ids, 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 epicate-
chin 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 dis-
eases.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 investi-
gated the antiemetic effects of 3 grape seed extracts pre-
pared in the investigators’ laboratory, obtained from a
US-based dietary supplement company and from China.
Phytochemical studies showed a great variation in the con-
stituents of the 5 major constituents (gallic acid, catechin,
epicatechin, procyanidin B2, and epicatechin gallate). The
extract obtained from China had the highest level of poly-
phenols (194.21 mg/g), followed by the US-based dietary
supplement company sample level (35.84 mg/g). The low-
est 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
24 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 indi-
cating that effect was proportional to the content of poly-
phenol 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 medic-
inal plants in the world. In various traditional medicines,
mint is used as a stomachic, tonic, carminative, antispas-
modic, 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 diges-
tive ailments, for irritable bowel syndrome, headache, non-
ulcer dyspepsia such as indigestion, gas problem, and acidity.43
It is also a main ingredient for Ayurvedic medicines (eg,
Dabur’s “Pudin Hara” used for gastric disturbances.43
Scientific studies have shown that the mint oil possesses
analgesic, anti-inflammatory, antiseptic, anti-infectious, anti-
microbial, antispasmodic, astringent, carminative, digestive,
expectorant, febrifuge, fungicidal, nervine, vasoconstrictor,
decongestant, stimulant, cognitive enhancer, stomachic
properties and is also effective against irritable bowel syn-
drome.41-43 At the biochemical level, mint oil is reported to
modulate calcium channel–dependent processes in intesti-
nal, neuronal, and cardiac preparations.41-43 The oil is also
reported to possess neuromodulatory and performance-
enhancing 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 con-
trolled in rodents by the same pathways that control nausea
and vomiting in humans.45 It was observed that the intra-
peritoneal 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 contractil-
ity.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 tradi-
tional systems of medicine, ginger is reported to be a car-
minative, diaphoretic, antispasmodic, peripheral circulatory
stimulant, astringent, appetite stimulant, anti-inflammatory
agent in addition to being useful in treating cold, head-
aches, arthritis, rheumatological conditions, and muscular
discomfort.48-50
Studies have shown that ginger possesses antimicrobial,
antischistosomal, anti-inflammatory, antipyretic, antioxida-
tive, hypoglycemic hepatoprotective, diuretic, and hypo-
cholesterolemic effects.49,50 Ginger is also beneficial to the
gastrointestinal tract, to increase bile secretion, and to pre-
vent 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 observa-
tions 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 recep-
tor 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 effec-
tive 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 cispla-
tin 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
Haniadka et al. 25
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 anti-
emetic 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 obser-
vation 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 adminis-
tration of the hydroalcoholic extract of ginger 1 hour before
exposure to 2 Gy of γ irradiation was effective in blocking
the saccharin avoidance response for 5 posttreatment obser-
vational days. The study showed that intraperitoneal admin-
istration of the extract (50, 100, 150, and 200 mg/kg body
weight) to male rats caused a dose- and time-dependent pro-
tective 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 dif-
ferential 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 leuke-
mic 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 nau-
sea was observed in patients receiving ginger.56 Furthermore,
pilot studies by Meyer et al57 and Pecoraro et al58 have also
supported ginger’s use as an antiemetic in patients undergo-
ing chemotherapy.
Additionally, experiments have confirmed that ginger is
effective in reducing nausea and vomiting induced by low-
dose cyclophosphamide in combination with other antican-
cer drugs causing mild emesis.59 However, the antiemetic
efficacy of ginger was found to be equal to that of metoclo-
pramide but inferior to that of ondansetron.59 Combining
high-protein meals with ginger also reduced the chemotherapy-
induced 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 anti-
emetic regimen of gynecologic oncology patients receiving
cisplatin offered no advantage in reducing nausea or vomit-
ing 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 gin-
ger (0.5, 1.0, or 1.5 g) along with 5-HT3 receptor antago-
nists reduced the chemotherapy-induced nausea in patients
undergoing treatment for breast, alimentary, and lung can-
cers.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 effec-
tive in reducing the severity of acute and delayed CINV
when provided as a adjunct to ondensetron and dexametha-
sone in bone sarcoma patients receiving the highly emeto-
genic 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 obser-
vational 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
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 necessi-
tates performing detailed toxicological studies to under-
stand the antioxidant and pro-oxidant concentrations of
these plants. Some of the administration has been by intra-
peritoneal 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 com-
pounds 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 nau-
sea. 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 D’Sa (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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