Cisplatin-Induced Nausea and Vomiting

Cisplatin-Induced Nausea and Vomiting: History

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Subjects: Integrative & Complementary Medicine

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Cisplatin is a chemotherapeutic agent that is widely used to treat various types of cancers. However, its side effects, most commonly nausea and vomiting, limit its widespread use. Although various drugs, such as ondansetron and aprepitant, are used to alleviate these side effects, their efficacy is still debated.

cisplatin
feeding disorder
herbal medicines

1. Introduction

Cisplatin is a widely used metal-based chemotherapeutic drug, and nearly 50% of platinum-based anticancer agents sold worldwide are cisplatin [1,2]. It is generally used for the treatment of solid cancers, such as testicular, ovarian, and gastric cancers [3]. This second-generation chemotherapeutic drug exerts anticancer effects by inhibiting cell division by blocking DNA, mRNA, and protein production [4,5,6]. With this mechanism, cisplatin effectively decreases tumor size. However, it can also induce several side effects, such as nephrotoxicity, hepatotoxicity, and gastrointestinal toxicity [3,7,8,9]. Nephrotoxicity is induced by accumulated cisplatin in tubular epithelial cells of the kidney, which leads to tubular cell injury or death [10,11]. Hepatotoxicity occurs when cisplatin is metabolized in the liver [12]. Cisplatin can also induce gastrointestinal toxicities, diarrhea, loss of taste, pancreatitis, and mucositis [13]. However, among these various gastrointestinal problems, nausea and vomiting are the most commonly induced by chemotherapeutic drugs such as cisplatin, with approximately 40% of treated patients complaining of these symptoms [14]. Nausea and vomiting in chemotherapy-treated patients can cause dehydration and undernourishment, which decrease the quality of life of patients if not appropriately controlled [15,16]. Moreover, it can cause discontinuation or reduced efficacy of the treatment [17,18,19]. Overall, these findings indicate the importance of controlling cisplatin-induced nausea and vomiting (CINV). CINV can be categorized as acute or delayed. Acute CINV occurs within the first 24 h after chemotherapy and is generally treated using serotonin (5-HT) receptor antagonists. Ondansetron suppresses the activation of 5-HT receptors located peripherally in the intestine and centrally in the area postrema [20]. Delayed CINV mostly occurs 24–120 h after chemotherapy and is related to the neurokinin 1 (NK1) receptor and pro-inflammatory cytokines [21,22]. NK1 receptor antagonists, such as aprepitant, are used to treat delayed CINV because they block the binding of substance P to the NK1 receptor [20]. In the area postrema, dopamine plays an important role, as dopamine 2-like receptors interact with the emetic receptors present in the area postrema and activate the nucleus of the solitary tract [23]. In line with this, the National Comprehensive Cancer Network has listed dopamine receptor antagonists, such as metoclopramide, as alternatives to treat emesis [20]. However, all the above-mentioned drugs can induce side effects that could limit their widespread use. Ondansetron can affect the electrical activity of the heart and cause abnormal cardiac rhythm [24]. In a study involving 1175 patients treated with 5-HT₃ antagonists, such as ondansetron, dolasetron, and granisetron, 27.5% of the patients experienced adverse events, such as constipation (9.2%), headache (7.4%), and alanine aminotransferase (ALT) increase (3.1%) [25]. Furthermore, in a study involving 521 patients (260 patients received aprepitant, and 261 patients received standard therapy), 14.6% of the patients experienced drug-related adverse events, such as asthenia/fatigue (17.2%), hiccups (13.8%), and constipation (8.0%) [26]. Finally, metoclopramide treatment has also been associated with side effects, such as headache, dizziness, and extrapyramidal reactions [27]. Thus, efforts to identify novel drugs with limited side effects are urgently required.

2. Kaolin Consumption

Kaolin is a type of clay that does not contain nutrients [48]; however, its consumption is usually used as a proxy for vomiting in rodents because this species cannot vomit [49]. Although rats have brain stem nuclei similar to those of humans, no motor component exists for vomiting [50]. Therefore, instead of vomiting, kaolin consumption is considered a sign of vomiting [51]. In total, 11 studies observed kaolin consumption in rats to assess the antiemetic effects of various herbal medicine extracts. The doses of cisplatin used were either 3 mg/kg [36,37,38,39] or 6 mg/kg [35,40,41,42,44]. Seven herbal medicines were used, all of which were administered orally [34,35,36,37,38,39,40,41,42,43,44]. These studies used male Wistar or Sprague–Dawley rats.

Aung et al. [39] assessed the effects of Scutellariae Radix (SR) on cisplatin-induced kaolin consumption in rats. Three different doses of cisplatin (3, 5, and 10 mg/kg) were intraperitoneally injected, and the lowest dose showed the strongest effect, as indicated by the continuous increase in kaolin consumption until 120 h compared with the baseline. SR was administered intraperitoneally at three different doses (1, 3, and 10 mg/kg). Results showed that pre-treatment with 1 and 3 mg/kg SR significantly reduced kaolin consumption compared with the baseline only at 24 h, whereas 10 mg/kg was effective at 24, 48, and 96 h [39]. The ratio of food intake and body weight was also measured, and only the 3 mg/kg SR-treated group showed a significant increase in kaolin consumption at 72 h. Similar to Aung et al. [39], Mehendale et al. [38] also investigated the effects of SR and observed that 3 mg/kg but not 10 mg/kg SR significantly decreased kaolin consumption after injecting 3 mg/kg cisplatin. In addition, they analyzed the effects of berries of Panacis Quinquefolii Radix (BPQ; American ginseng berry), which exerts antioxidant effects similar to those of SR. They found that intraperitoneal treatment with 50 mg/kg but not 10 mg/kg BPQ can attenuate kaolin consumption after injecting 3 mg/kg cisplatin. In their second study, Mehendale et al. [37] used higher doses of BPQ (50, 100, and 150 mg/kg) and concluded that 100 mg/kg is the most effective dose to relieve kaolin consumption. Furthermore, they assessed the effect of 5 mg/kg ginsenoside Re, the major component of the BPQ extract, and suggested that it contributed to the effect of BPQ.

Wang et al. [36] assessed the effects of the oriental fungus Ganoderma lucidum on kaolin consumption and found that treatment with 3 and 10 mg/kg G. lucidum can significantly decrease kaolin consumption at 24–120 h. G. lucidum, which contains 1.89% terpenoids and 15.8% polysaccharides, modulates immunity by increasing the percentages of CD5⁺, CD4⁺, and CD8⁺ T lymphocytes in peripheral blood lymphocytes [52].

The studies by Raghavendran et al. [40] and Sathyanath et al. [41] focused on Ginseng Radix (GR). Raghavendran et al. [40] applied GR pre-treatment at different doses before injecting cisplatin (7 mg/kg), but only 25 and 50 mg/kg attenuated kaolin consumption. However, when GR was administered after injecting cisplatin (6 mg/kg), three doses (12.5, 25, and 50 mg/kg) were effective in attenuating kaolin consumption. Sathyanath et al. [41] found that treatment with 6 mg/kg cisplatin can increase kaolin consumption. Although pre-treatment and post-treatment with steamed GR, also known as red ginseng, at different doses (i.e., 25, 50, and 100 mg/kg, p.o.) did not show any significant effect on kaolin consumption at 120 h, post-treatment with 50 and 100 mg/kg steamed GR significantly decreased kaolin consumption at 48 h compared with cisplatin alone. The components of GR can be divided into two categories: saponins and non-saponins. GR has relatively high concentrations of ginsenosides (GS), such as ginsenoside Rb₁ and Rg₃, whereas non-saponin ginsenosides (GNS) contain undetectable amounts of GS. The results indicate that post-treatment with GS and GNS orally can significantly decrease kaolin consumption at 24 h compared with cisplatin alone.

Tian et al. [43] and Cheng et al. [35] assessed the effects of gingerol after treatment with 3 and 6 mg/kg cisplatin, respectively. Tian et al. [43] found that oral treatment with 10, 20, and 40 mg/kg [6]-gingerol for three consecutive days can significantly attenuate kaolin consumption in rats up to 72 h after cisplatin treatment. Cheng et al. [35] reported that administering 50 and 100 mg/kg [6]-gingerol can significantly ameliorate cisplatin-induced kaolin consumption at 24 h [35].

Gingerol is one of the main components of Zingiberis rhizoma. Zingiberis rhizoma is a herbal medicine that has been widely used alone or in combination with other herbs. Among these, XBXT is widely used to treat various digestive problems.

In the study by Meng et al., kaolin consumption increased after treatment with 6 mg/kg cisplatin, but pre-treatment with XBXT 1.3 g/kg significantly decreased kaolin consumption compared with cisplatin alone at 24 and 72 h [34]. Similarly, Li et al. [44] showed that treatment with 6 mg/kg cisplatin dramatically increased kaolin consumption and that 1.6 g/kg XBXT significantly decreased kaolin consumption at 24–72 h. In another study, Meng et al. reported that oral treatment with 1.75 g/kg Forsythiae Fructus can significantly decrease kaolin consumption at 0–48 h in 6 mg/kg cisplatin-injected rodents [42].

3. Retching and Vomiting

Three studies used mink [43,45,46] and one used pigeon [47] to assess the effects of herbal medicines on CINV. Unlike rodents, minks and pigeons retch and vomit [53]. In minks, increased 5-HT from enterochromaffin cells of the intestine play an important role in humans [54].

Qian et al. [46] assessed the effects of gingerol on CINV in minks. Three doses (50, 100, and 200 mg/kg) of [6]-gingerol were intraperitoneally administered before injecting 7.5 mg/kg cisplatin. In the cisplatin-injected group, the numbers of retching and vomiting episodes for 6 h were 70.83 ± 16.49 and 9.67 ± 2.58, respectively. However, [6]-gingerol pre-treatment significantly attenuated these effects. In the 200 mg/kg-treated group, the effect was stronger as the numbers of retching and vomiting episodes decreased to 5.50 ± 13.47 and 0.84 ± 2.04, respectively. In the other study conducted by Qian et al. [45], the effect of XBXT on cisplatin-injected minks was assessed. Two doses of XBXT were injected intraperitoneally, and the results showed that they dose-dependently attenuated CINV for 72 h.

Tian et al. [43] used minks to assess the effects of [6]-gingerol. The doses used were also similar to those used by Qian et al. [46]; however, they administered gingerol orally and not intraperitoneally. The results showed that 100 and 200 mg/kg gingerol significantly decreased vomiting after 72 h, whereas the effect of 50 mg/kg gingerol diminished after 42 h. The anti-retching effect of gingerol did not last until 72 h in all three groups, and the significant differences disappeared before 72 h.

In contrast to the above-mentioned studies, Ullah et al. [47] used pigeons to observe changes in retching and vomiting after treatment with cisplatin and B. monnieri. They used methanol and n-butanol for extraction. The n-butanolic fractions of Bacopa monnieri are rich in bacoside. Their results showed that the methanolic (10–40 mg/kg) and bacoside-rich n-butanolic fractions of B. monnieri (5–20 mg/kg) attenuated cisplatin-induced emesis by 66.3% and 71.6%, respectively, whereas the widely used standard antiemetic drug metoclopramide (30 mg/kg) produced only a 48.9% reduction.

4. Food Intake

Decreased food intake following cisplatin injection has been reported in several studies [55]. Although the relationship of nausea and vomiting with decreased food intake is not clearly understood, cisplatin reportedly decreases food intake by inhibiting intestinal motility [56]. It induces morphological changes in the small intestine by lowering the area occupied by the microvilli and villi. Moreover, inflammation in the mucosal and submucosal layers has been shown [57]. In the present review, nine studies focused on the changes in food intake after treatment with cisplatin at 3 mg/kg [36,37,38,39] or 6 mg/kg [34,35,40,41,42,44] and seven herbal medicines. Three herbal medicines were administered intraperitoneally [37,38,39], and the others were administered orally [34,35,36,37,38,39,40,41,42,44].

In the studies by Aung et al. [39] and Wang et al. [36], 3 mg/kg cisplatin decreased food intake in rats. Aung et al. analyzed food intake by measuring the food intake: body weight ratio, whereas Wang et al. measured the 24 h food intake. In the study by Aung et al., 3 mg/kg SR significantly increased food intake at 72 h compared with cisplatin. Meanwhile, Wang et al. found that administration of an G. lucidum extract can dose-dependently (1, 3, and 10 mg/kg) increase food intake in rats.

Mehendale et al. [37] recorded the food intake percentage compared with the baseline. In the cisplatin group, food intake decreased to 57% of baseline at 24 h, whereas 50 and 100 mg/kg BPQ increased food intake to 76% and 85% of baseline at 24 h. However, 150 mg/kg BPQ failed to show any statistically significant differences compared with the control. Raghavendran et al. [40] and Sathyanath et al. [41] assessed the effects of GR on food consumption. Raghavendran et al. found that multiple pre-treatments with two low doses of GR (25 and 50 mg/kg, i.p.) increased food intake until 120 h, whereas pre-treatment with 100 mg/kg GR was ineffective. In multiple post-treatments with GR, only the lowest dose increased food intake until 72 h. In the study by Sathyanath et al., the steamed root of GR failed to affect food intake, and all three doses (25, 50, and 100 mg/kg) did not affect food intake in rats. However, pre-treatment with 10 and 100 mg/kg GS and GNS, respectively, increased food intake in rats. In a study by Meng et al. [42], Forsythiae Fructus significantly increased food intake compared with cisplatin only at 48 h but not at 24 and 72 h after cisplatin injection.

In contrast to other herbal extracts, XBXT treatment failed to increase food intake in cisplatin-injected rodents [34,44].

5. Body Weight

Cisplatin-induced gastrointestinal toxicity can decrease food intake and body weight. Eight studies reported changes in body weight after treatment. The doses of cisplatin used were 3 mg/kg [39], 6 mg/kg [34,35,40,41,42,44], and 7 mg/kg [47]. Six herbal medicines were used in the present study. One herbal medicine was administered intraperitoneally [39], and the others were administered orally [34,35,39,40,41,42,44,47].

In the study by Aung et al. [39] all three doses of SR failed to increase body weight, which was attenuated after cisplatin injection.

GR was assessed by Raghavendran et al. [40] and Sathyanath et al. [41]. In the study by Raghavendran et al. [40], pre- and post-treatment with GR significantly increased the body weights of cisplatin-treated rats. However, the effect was stronger in pre-treated rats than in post-treated rats. Specifically, pre-treatment with 25 and 50 mg/kg GR induced significant changes at 96 h after cisplatin injection, whereas post-treatment with 12.5 and 25 mg/kg GR induced changes at 48 h. In a study conducted by Sathyanath et al. [41], no significant differences were observed between rats treated with the extract of steamed GR and rats treated with its subcomponents GS and GNS. In the study by Ullah et al. [47] methanolic fractions of B. monnieri significantly increased body weight compared with cisplatin alone; the mean weight loss was 15.3% ± 1.4% in the cisplatin group, whereas the loss decreased to 8.3% ± 1.6%, 5.2% ± 1.0%, and 5.6% ± 1.6% in the groups treated with 5, 10, and 20 mg/kg B. monnieri, respectively. Similar to their effects on food intake, XBXT [34] and [6]-gingerol [35] failed to prevent or diminish body weight loss induced by cisplatin injection.

6. Herbal Medicines Used in the Studies

This entry also discussed the effects of eight types of herbal medicine extracts or their components, including seven single herbal extracts [35,36,37,38,39,40,41,42,43,45,46,47], one multiple herbal extract (i.e., XBXT) [34,44,45], and one component of Zingiberis rhizoma (i.e., [6]-gingerol), on CINV. Furthermore, eight studies [34,36,37,38,39,40,41,42,47] used high-performance liquid chromatography to identify and quantify the components in their herbal extracts.

7. Mechanisms of Action

Nine studies elucidated the underlying mechanisms of action of herbal extracts. Four studies [35,43,46,47] investigated neurotransmitters, particularly 5-HT and dopamine. Two studies [43,46] investigated substance P. Three studies [35,43,44] analyzed the effects of tryptophan hydroxylases (TPHs), which are enzymes engaged in 5-HT formation. 5-HT has been reported to play an important role in nausea and vomiting as a chemotherapeutic agent was shown to stimulate the EC cells of the gastrointestinal tract mucosa and induce a calcium-dependent 5-HT release [58]. The released 5-HT is known to affect the vagal afferent nerve and stimulate the vomiting center in the dorsal vagal center located in the brain [59]. The nucleus of the solitary tract (NTS) of the dorsal vagal center sends signals to the dorsal motor of the nucleus of the vagus nerve, which in turn mediates the emetic motor function of the gastrointestinal tract in the process of vomiting [60].

Two studies [34,42] investigated the impact of pro-inflammatory cytokines, such as interleukin (IL)-1 and IL-8, and substances that induce the formation and activation of cytokines, such as NLRP3, ASC, and Caspase-1. Pro-inflammatory cytokines are reported to affect the vagal afferent nerves endings and convey information to the NTS, as the vagus nerve is reported to be sensitive to peripheral pro-inflammatory cytokines, such as TNF-α, IL1-β, and IL-6 released by macrophages [61,62].

One study [40] reported their effects on white blood cells, such as leukocytes, hemoglobin, and NK cells. One study [45] reported their effects on NK receptor. Five studies [34,40,41,42,44] investigated histological deformities, and three studies [34,35,42] focused on the role of oxidative stresses, such as monoamine oxidase A (MAO-A) and serum reactive oxygen species (ROS).

This entry is adapted from the peer-reviewed paper 10.3390/plants11233395

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