Eur opean Rev iew for Med ical and Pharmacol ogical Sci ences 2015; 19: 1291-1296 Can nausea and vomiting be treated with extract?

A. GIACOSA 1, P. MORAZZONI 2, E. BOMBARDELLI 2, A. RIVA 2, G. BIANCHI PORRO 3, M. RONDANELLI 4

1Department of Gastroenterology, Policlinico di Monza, Monza, Italy 2R&D Department, Indena Spa, Milano, Italy 3Department of Gastroenterology, Luigi Sacco University, University of Milan, Milan, Italy 4Department of Public Health, Experimental and Forensic Medicine, Section of Human Nutrition, University of Pavia, Pavia, Italy

Abstract. – Ginger ( Zingiber officinale ) is a but the results are controversial because of the spice traditionally used to treat indigestion, nau - well-known chemical instability of ginger most sea and vomiting. Ginger extracts accelerate active ingredients, , which are readily- gastric emptying and stimulate gastric antral oxidizable substances. contractions. These effects are mainly due to the presence of gingerols and shogaols and their Ginger consists of the dried, whole cut rhi - activity on cholinergic M receptors and seroton - zome of Zingiber officinale Roscoe , with the cork ergic 5-HT and 5-HT receptors. Various research - removed either completely or from the wide flat es on this subject have led to controversial re - surfaces only. Whole or cut, it contains not less sults, due to the chemical instability of ginger than 15 ml/kg of essential oil, calculated with extracts and particularly of gingerols, which are reference to the anhydrous drug 1. readily-oxidizable substances. A systematic re - 2-5 view of double-blind, placebo-controlled, ran - The essential oil of ginger (0.25-3.3% V/m) domized studies highlighted the potential effica - contains monoterpenes – mainly geranial (citral a) cy of ginger on the prevention and treatment of and neral (citral b) – and sesquiterpenes (30.7%) – nausea and vomiting of various origins, even mainly Beta-sesquiphellandrene, Beta-bisabolene, though additional controlled studies are needed. ar-curcumene and alpha-zingiberene 4-6 . Moreover, This review focuses on pregnancy-induced nau - pungent principles (4.7-5% w/w) 7 consisting of sea and vomiting and on chemotherapy induced gingerols , shogaols and related phenolic ketone nausea, and hypothesizes a therapeutic role for 8-11 ginger extracts in case of side effects, as an al - derivatives can be foun d . Other consituents in - 12 13,14 ternative to traditional prokinetic drugs such as clude diarylheptenones , diterpenes , 6-ginge - domperidone, levosulpiride or metoclopramide. sulphonic-acid 15 and monoacyldigalactosyl glyc - erols 15 . Key Words: Ginger, Gingerols , Prokinetic drugs, Nausea, Vom - Mechanism of Action of Ginger Extracts iting, Gastric motility, Zingiber officinale . The herbal drug ginger (Zingiber officinale Roscoe ) may be effective for treating nausea, vomiting and gastric hypomotility. Cholinergic M3 receptors and serotonergic 5-HT 3 and 5-HT 4 Introduction receptors are involved in these conditions. The major chemical constituents of ginger are 6-gin - Ginger ( Zingiber officinale) is a plant that has gerol, 8-, 10-gingerol, and 6-shogaol. been cultivated and used for centuries for health Pertz et al 16 studied the interaction of 6-gingerol, purposes: its medical use is well described in 8-gingerol, 10-gingerol (racemates) and 6- Chinese treaties from 400 BC. Ginger is known shogaol with guinea pig M 3 receptors, guinea pig everywhere as a spice and traditionally used as a 5-HT 3 receptors and rat 5-HT 4 receptors . In medicinal plant to treat indigestion, flatulence, whole segments of guinea pig ileum (bioassay for fever, nausea and vomiting. The plant rhizome is contractile M 3 receptors), 6-gingerol, 8-gingerol, included in different pharmacopeias. Recent clin - 10-gingerol and 6-shogaol slightly but significant - ical studies confirmed many of these activities, ly depressed the maximal carbachol response at an

Corresponding Author: Mariangela Rondanelli, MD; e-mail: [email protected] 1291 A. Giacosa, P. Morazzoni, E. Bombardelli, A. Riva, G. Bianchi Porro, M. Rondanelli antagonist concentration of 10 µM. In the guinea ducible form of cyclooxygenase COX-2, but not pig myenteric plexus preparation (bioassay for the constitutive form COX-1. Since inhibition of contractile 5-HT 3 receptors), the 5-HT maximal COX-1 is associated with gastrointestinal side ef - response was depressed by 10-gingerol from 93 ± fects, selective inhibition of COX-2 should help 3% to 65 ± 6% at an antagonist concentration of minimize these side effects. 3 µM and to 48 ± 3% at an antagonist concentra - tion of 5 µM , following desensitization of 5-HT 4 Gastric Motility receptors and blockade of 5-HT 1 and 5-HT 2 re - Great attention has always been paid to the an - ceptors. 6-Shogaol (3 µM) induced depression to ti-nausea effect of ginger extracts, while very few 61 ± 3%. In rat esophageal tunica muscularis studies have been conducted about the effects of mucosae (bioassay for relaxant 5-HT 4 receptors), ginger on gastric emptying and gastrointestinal 6-gingerol, 8-gingerol, 10-gingerol and 6- motility before and after meals. Micklefield et shogaol (2-6.3 µM) showed no agonist effects. al 20 investigated the effects of a ginger extract The maximal 5-HT response remained unaffect - (100 mg, corresponding to 2 g of rhizome twice a ed in the presence of these compounds. It can day) on gastroduodenal motility in a double- therefore be concluded that the efficacy of ginger blind , randomized, placebo-controlled trial on a in reducing nausea and vomiting may be based group of 12 volunteers, by using the manometric on a weak inhibitory effect of gingerols and technique. In this study, a statistically significant shogaols on M 3 and 5-HT 3 receptors. 5-HT 4 re - increase in interdigestive motility was observed ceptors, which play a role in gastroduodenal in the intervention group in comparison with the motility, do not appear to be involved in the ac - placebo group. tivity of these compounds. Other studies demonstrated a prokinetic effect Another study 17 suggests that 6-, 8-, 10-gin - of ginger extracts, in agreement with the indica - gerol and 6-shogaol exert their anti-emetic effect tions of popular medicine. Wu et al 21 showed that at least partly by acting on the 5-HT 3 receptor ginger accelerates gastric emptying and stimulates ion-channel complex, probably by binding to a antral contractions in healthy volunteers. Twenty- modulatory site distinct from the serotonin bind - four healthy volunteers were studied in a random - ing site. This may lead to indirect effects in the ized double-blind trial 21 . After ingestion of 1200 signal cascade behind the 5-HT 3 receptor channel mg of ginger extract or placebo, followed after 1 h complex, through receptors such as by 500 ml of low-nutrient soup, the antral area, the and muscarinic receptors. However, this hypothe - fundus area and diameter, and the frequency of sis needs further investigation since ginger is ef - antral contractions were measured using an ultra - fective against motion sickness which is treated sound technique at frequent intervals over 90 min. by some vanilloids and by anticholinergics such The antral area decreased more rapidly ( p < 0.001) as scopolamine. and the gastric half-emptying time was shorter af - Ginger preparations have a long history of hu - ter ginger than after placebo ingestion; whereas man use for their anti-inflammatory properties. the frequency of antral contractions was greater in However, only recently some of the compounds the ginger group vs the placebo group 21 . Fundus responsible for this activity and their mecha - dimensions did not differ between the two groups, nisms of action have been identified. 6-Shogaol and there was no significant difference in any gas - exhibited the most potent antioxidant and anti-in - trointestinal symptoms 21 . flammatory properties: these effects can be at - A similar experiment has been performed in tributed to the presence of alpha,beta-unsaturated patients with functional dyspepsia. The study 22 ketone moiety 18 . The carbon chain length also has been conducted including 11 patients with plays a significant role in making 10-gingerol the functional dyspepsia, Gastric emptying was most potent among all the gingerols. faster after ginger than after placebo. There was a Van Breemen and Tao 19 provided information trend towards more antral contractions, but fun - regarding the identification of gingerol-related dus dimensions and gastrointestinal symptoms compounds that have anti-inflammatory activity did not differ between the two groups, nor did through the specific inhibition of COX-2. Ac - serum concentrations of GLP-1, motilin and cording to these data, although the enzyme in - ghrelin. It is important to underline that different hibitory activities observed are weak, at least types of functional dyspepsia were not specifical - some gingerol-related compounds, including gin - ly considered in this study and that the number of gerols and shogaols, selectively inhibit the in - studied patients was very small (11 patients).

1292 Can nausea and vomiting be treated with ginger extract?

Based on these experiences it can be conclud - A 2010 Cochrane review 25 assessed the effec - ed that the effects of ginger extracts on gastric tiveness and safety of interventions for nausea motility appear interesting and promising, but and vomiting in pregnancy before 20 weeks of have still to be confirmed by controlled clinical gestation . The interventions included acupres - studies conducted on a larger number of patients sure, acustimulation, acupuncture, ginger, vita - in order to ensure an objective statistical assess - min B6, and antiemetic medications. The review ment and final conclusions. evaluated nine RCTs involving ginger. Ginger was compared with placebo in four studies , with

Nausea and Vomiting pyridoxine (vitamin B 6) in four studies and with A systematic review of double-blind, placebo- dimenhydrinate in one study. The Cochrane re - controlled, randomized studies on the prevention view found that pyridoxine and one antihista - of nausea and vomiting of various origins high - mine compound (hydroxyzine) reduced nausea lighted the potential efficacy of ginger, albeit more than placebo; however, the authors cau - with the limits of the chemical stability of the tioned that the evidence was not very strong. preparations 23 . Four trials with ginger versus placebo demon - In 2000, Ernst and Pittler 23 performed a sys - strated a greater reduction of nausea with ginger tematic review of randomized controlled trials treatment, and three studies showed reduced for or against the efficacy of ginger in the treat - vomiting after ginger use. However, only two ment of nausea and vomiting . Six studies met all out of four studies reported statistically signifi - the inclusion criteria and were reviewed. Three cant differences. Cochrane reviewers could not studies on postoperative nausea and vomiting perform a global meta-analysis because of the were identified and two of these suggested that heterogeneous outcomes used in the studies, al - ginger was superior to placebo and equally effec - though they were able to perform a meta-analy - tive as metoclopramide 23 . However, the pooled sis of four RCTs that compared ginger (975 to absolute risk reduction for the incidence of post - 1500 mg per day) with pyridoxine (30 to 75 mg operative nausea indicated a non-significant dif - per day). Two trials found no difference in nau - ference between 1 g of ginger and placebo taken sea and vomiting by day 3. In addition the other before operation (absolute risk reduction: 0.052). two trials , surveying the percentage of women One study was found for each of the following reporting no relief, did not find any statistically conditions: seasickness, morning sickness and significant difference between ginger and pyri - chemotherapy-induced nausea 23 . These studies doxine. The study comparing ginger with di - collectively favored ginger over placebo. menhydrinate revealed that the two products had similar effectiveness. Pregnancy-Induced Nausea and Vomiting A systematic literature search on herb reme - Ginger has been used throughout the world for dies during pregnancy, covering the period from centuries as a therapeutic agent for pregnancy-in - January 1990 to September 2010, was performed duced nausea and vomiting (PINV). using various electronic databases 26 . Out of 511 In 2013, four randomised controlled trials identified papers, 14 RCTs were eligible. Ginger (RCTs) 24 on the use of ginger for PINV were was the most investigated remedy and was con - sourced from CINAHL, the Cochrane library, sistently reported to ameliorate nausea and vom - MEDLINE and TRIP . All the trials showed that iting during pregnancy better than placebo; its ef - orally administered ginger was significantly ficacy was noted to be equal to that of vitamin more effective than placebo in reducing the fre - B6 and dimenhydrinate 26 . A recently published quency of vomiting and the intensity of nausea. metanalysis on the effects of ginger for nausea Adverse events were generally mild and infre - and vomiting in early pregnancy (NVEP) identi - quent. fied 135 potentially relevant records 27 . Only 6 Therefore, the best available evidence suggests studies met the final criteria. Out of 508 subjects, that ginger is a safe and effective treatment for 256 were randomly assigned to receive ginger, PINV. However, there is still uncertainty regard - while 252 received placebo. The use of ginger ing the maximum safe dosage of ginger, the ap - (~1 g daily) for at least 4 days was associated propriate duration of treatment, the consequences with a 5-fold likelihood of improvement in of over-dosage and potential drug-herb interac - NVEP and the authors concluded that ginger is tions, all of which are important areas for future an effective non-pharmacological treatment for research. NVEP 27 .

1293 A. Giacosa, P. Morazzoni, E. Bombardelli, A. Riva, G. Bianchi Porro, M. Rondanelli

In addition to this, the American College of of nausea was observed in the ginger group Obstetricians and Gynecologists (ACOG) states during 6 to 24 hours post-chemotherapy. De - that : “treatment of nausea and vomiting of preg - spite this effect, no other significant additional nancy with ginger has shown beneficial effects benefits were observed with ginger (1.5 g/d) in and can be considered as a non-pharmacologic terms of prevalence or severity of nausea, vom - option.” However, ACOG acknowledges that the iting or retching ,in any of the assessed periods. recommendation is based on limited or inconsis - Furthermore, studies conducted in cultured tent scientific evidence. Moreover, the U.K. Na - cells as well as in experimental animals revealed tional Health Service, through the National Insti - that ginger contains several nonvolatile pungent tute for Health and Clinical Excellence, has in - phenolics (gingerols, shogaols, and cluded ginger in its list of acceptable therapies ,) which possess anticarcinogenic prop - for the treatment of nausea and vomiting during erties 30 . early pregnancy.

Chemotherapy-Induced Nausea Conclusions Nausea and vomiting are among the most prevalent and disturbing side effects of Ginger ( Zingiber officinale ) may represent a chemotherapy and various attempts have been reasonable and safe alternative to treat PINV made to evaluate the role of ginger in the treat - and it may be useful to treat CINV. The proki - ment and prevention of these symptoms. Recent - netic effects shown on gastric motility may sug - ly, a well conducted NCI-supported multi-center, gest a potential role of ginger extracts in the randomized, double blind and placebo controlled treatment of various digestive diseases and par - study 28 in cancer patients submitted to ticularly in functional dyspepsia , as well as in chemotherapy has been published . In this trial, patients with neurologic or endocrinologic side 744 cancer patients were randomly assigned to effects to traditional prokinetic drugs such as four arms (placebo, 0.5 g ginger, 1 g ginger, 1.5 g domperidone, levosulpiride or metoclopramide. ginger). Patients, co-treated with 5-HT3 receptor In particular, treatment with ginger extracts antagonists on day 1 of all cycles, received treat - could avoid the risk of sudden cardiac death ob - ments with placebo or ginger preparations for 6 served in the elderly treated with domperidone days , starting 3 days before the first day of at doses of more than 30 mg per day 31-34 . Addi - chemotherapy. The results of the study clearly tional controlled studies are needed to confirm showed that all doses of ginger significantly re - these interesting hypotheses. In addition, ginger duced acute nausea severity compared to placebo does present other intriguing properties that on day 1 of chemotherapy. The largest reduction may be worth investigation 35 . in nausea intensity occurred with 0.5 g and 1.0 g of ginger . 29 ––––––––––––––––– –– Another study evaluated the effects of gin - Acknowledgements ger against both acute and delayed forms of chemotherapy-induced nausea and vomiting Editorial assistance for the preparation of this manuscript was provided by Luca Giacomelli, PhD, and Ambra Corti; (CINV ) in a population with advanced breast this assistance was funded by Indena Spa . cancer as the main malignancy. In this pilot, randomized, open-label clinical trial, 100 women with advanced breast cancer , who were initially assigned to standard chemotherapy protocol with docetaxel, epirubicin and cy - References clophosphamide (the TEC regimen) , were ran - 1) COUNCIL OF EUROPE : Ginger-Zingiberis rhizome. In: domized to receive ginger (1.5 g/d in 3 divided European Pharmacopoeia, 6th ed, 2009. doses every 8 hours) plus standard antiemetic 2) GOVINDARAJAN VS . Ginger-chemistry, technology, regimen (granisetron plus dexamethasone) or and quality evaluation: part 1. Crit Rev Food Sci standard antiemetic regimen alone (control Nutr 1982; 17: 1-96. group). The duration of treatment with ginger 3) GOVINDARAJAN VS . Ginger-chemistry, technology, was limited to 4 days from the initiation of and quality evaluation: part 2. Crit Rev Food Sci chemotherapy. A significantly lower prevalence Nutr 1982; 17: 189-258.

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