Application of sesquiterpenoids in relieving nausea and vomiting

Abstract

This invention relates to the field of chemical pharmaceutical technology, specifically to the application of sesquiterpenoid compounds in relieving nausea and vomiting. The sesquiterpenoid compounds of this invention are cypressin and its analogues, racemates, stereoisomers, tautomers, isotope-labeled compounds, solvates, polymorphs, metabolites, prodrugs, or pharmaceutically acceptable salts thereof, having the following structures, wherein R1-R8 are as described in the claims and specification. These sesquiterpenoid compounds can reduce kaolin ingestion in pica rats and significantly alleviate nausea and vomiting symptoms induced by chemotherapeutic drugs such as cisplatin during tumor treatment. They can also relieve vomiting caused by gastrointestinal damage, inflammatory diseases, anorexia, etc. They can be used to prepare drugs for relieving / treating nausea and vomiting or to prepare foods that help protect the gastric mucosa.

Description

Technical Field

[0001] This invention belongs to the field of chemical medicine and relates to the application of sesquiterpenoids in relieving nausea and vomiting, specifically the application of cypressin and its analogues in the preparation of drugs for relieving nausea and vomiting. Background Technology

[0002] Cancer has become a major killer of humankind, second only to cardiovascular disease in mortality rate, and its incidence is increasing year by year. The latest statistics from the International Agency for Research on Cancer indicate that by 2040, cancer cases may increase to 28.4 million, a 47% increase from 2020. Currently, chemotherapy remains the most important treatment for malignant tumors, but long-term use of clinical drugs such as cisplatin, doxorubicin, imatinib, and gefitinib can lead to varying degrees of drug resistance and off-target effects, as well as side effects such as nausea and vomiting, fatigue, hair loss, weakened immunity, and anemia. Chemotherapy-induced nausea and vomiting (CINV) refers to nausea and vomiting caused by or related to chemotherapy drugs, and is the most common adverse reaction. CINV causes a decline in patients' quality of life, metabolic disorders, malnutrition, and weight loss, leading to decreased treatment adherence, and in severe cases, necessitating dose reduction or even termination of anti-tumor treatment. The occurrence of CINV undermines cancer patients' confidence in fighting the disease, reduces patient adherence, and to some extent shortens their survival time. Therefore, improving or alleviating nausea and vomiting in cancer patients plays a crucial role in their treatment. Existing antiemetic drugs are expensive, and commonly used medications such as the 5-HTR blocker ondansetron often act on only one receptor, thus requiring combination therapy. However, existing triple and quadruple therapies are highly likely to cause varying degrees of adverse reactions in patients, such as drowsiness, cognitive impairment, and osteoporosis. Therefore, the search for novel chemotherapy drugs with low toxicity, good efficacy, and low cost and easy availability is urgently needed.

[0003] Cedrol (CE) is a compound obtained from ginger and can be extracted in large quantities from plants in the Cupressaceae family. Pharmacological studies have shown that cedrol possesses a variety of biological activities, including anti-inflammatory, analgesic, antitumor, anti-anxiety, anti-aging, hair growth promotion, and osteoporosis relief effects.

[0004] There are no existing reports on the use of cypressin and its analogues in relieving nausea and vomiting. Summary of the Invention

[0005] To address the shortcomings of existing technologies, this invention provides the application of sesquiterpenoid compounds in the preparation of drugs for relieving / treating nausea and vomiting.

[0006] The sesquiterpenoids mentioned are cypressin or its pharmaceutically acceptable salts, analogs, racemates, stereoisomers, tautomers, isotope labels, solvates, polymorphs, and metabolites having the following structures;

[0007]

[0008] Wherein, R1 is any one or more of H, -OH, -OOH, -CH2OH, and C1-C6 alkyl groups;

[0009] R2 is any one or more of H, -OCOCH3, -OH, C1-C6 alkyl, =CH2, -CH2OH, and epoxy groups;

[0010] R3 is any one or more of H, -OCOCH3, -OH, C1-C6 alkyl, =CH2, -CH2OH, and epoxy groups;

[0011] R4 is any one or more of H, -OH, C1-C6 alkyl, and C1-C6 alkoxy;

[0012] R5 is any one or more of H, -COCH3, -CHO, C1-C6 alkyl, -OH, and =CH2;

[0013] R6 is any one or more of H, -OH, -CH2OH, C1-C6 alkyl, and C1-C6 alkoxy.

[0014] Or R5 forms an epoxy group with R6, or R5 forms an epoxy group with R7;

[0015] R7 is any one or more of H, -OH, -CH2OH, C1-C6 alkyl, and C1-C6 alkoxy.

[0016] R8 is any one or more of C1-C6 alkyl groups and CH2OH;

[0017] Preferably, the sesquiterpene compound is cypressol or its pharmaceutically acceptable salt, analogue, racemate, stereoisomer, tautomer, isotope label, solvate, polymorph, or metabolite having the following structure;

[0018]

[0019] Wherein, R1 is any one or more of H, -OH, -OOH, -CH2OH, and C1-C4 alkyl groups;

[0020] R2 is any one or more of H, -OCOCH3, -OH, C1-C4 alkyl, =CH2, -CH2OH, and epoxy groups;

[0021] R3 is any one or more of H, -OCOCH3, -OH, C1-C4 alkyl, =CH2, -CH2OH, and epoxy groups;

[0022] R4 is any one or more of H, -OH, C1-C4 alkyl, and C1-C4 alkoxy;

[0023] R5 is any one or more of H, -COCH3, -CHO, C1-C4 alkyl, -OH, and =CH2;

[0024] R6 is any one or more of H, -OH, -CH2OH, C1-C4 alkyl, and C1-C4 alkoxy.

[0025] Or R5 forms an epoxy group with R6, or R5 forms an epoxy group with R7;

[0026] R7 is any one or more of H, -OH, -CH2OH, C1-C4 alkyl, and C1-C4 alkoxy.

[0027] R8 is any one or more of C1-C4 alkyl groups and CH2OH;

[0028] Preferably, the sesquiterpene compound is cypressol or its pharmaceutically acceptable salt, analogue, racemate, stereoisomer, tautomer, isotope label, solvate, polymorph, or metabolite having the following structure;

[0029]

[0030] The sesquiterpenoid compounds of this invention can be used as the sole ingredient in the preparation of drugs to relieve / treat nausea and vomiting.

[0031] The sesquiterpenoid compounds of the present invention can be combined with other components to prepare drugs for relieving / treating nausea and vomiting.

[0032] The sesquiterpenoid compounds of the present invention can be combined with other antiemetics to prepare drugs for relieving / treating nausea and vomiting.

[0033] Furthermore, the sesquiterpenoid compounds of the present invention can be prepared into pharmaceutical compositions with pharmaceutically acceptable carriers or excipients.

[0034] The pharmaceutical composition can be further prepared into a pharmaceutical formulation for oral, injectable or topical administration.

[0035] The nausea and vomiting mentioned include nausea and vomiting caused by chemotherapy drugs, nausea and vomiting caused by radiotherapy, postoperative vomiting, pregnancy vomiting, motion sickness, etc.

[0036] The chemotherapy drugs mentioned are one or more of cisplatin, etoposide, teniposide, daunorubicin, doxorubicin, daunorubicin, cyclophosphamide, mitoxantrone, aclarubicin, homoharringtonine, methotrexate, vincristine, and vindesin.

[0037] The nausea and vomiting mentioned in this invention can also refer to vomiting caused by gastrointestinal damage, inflammatory diseases, or anorexia.

[0038] Furthermore, the sesquiterpenoid compounds or pharmaceutical compositions thereof of the present invention can be used to relieve nausea and vomiting caused by cisplatin.

[0039] The sesquiterpenoid compounds or pharmaceutical compositions thereof of the present invention can also be used to prepare foods that help protect the gastric mucosa.

[0040] The food products mentioned include health food products.

[0041] The sesquiterpenoid compounds or pharmaceutical compositions thereof of the present invention can also reduce drug-induced kidney damage and decrease drug-induced kidney toxicity.

[0042] The beneficial effects of this invention are as follows:

[0043] This invention provides the application of sesquiterpene compounds, such as cylindricalol and its analogues, or pharmaceutical compositions thereof, in the preparation of drugs for relieving / treating nausea and vomiting. The cylindricalol and its analogues can reduce the intake of kaolin in pica rats and significantly alleviate nausea and vomiting symptoms induced by chemotherapy drugs such as cisplatin during tumor treatment. Furthermore, they can also relieve vomiting caused by gastrointestinal damage, inflammatory diseases, and anorexia. Attached Figure Description

[0044] Figure 1 The effect of CE on cisplatin-induced IEC-6 cytotoxicity in Example 1 is shown.

[0045] A: The impact of CE on IEC-6 toxicity;

[0046] B: Inhibition rate of cisplatin on IEC-6 cells;

[0047] C: The pre-protective effect of CE on cisplatin-induced apoptosis in IEC-6 cells.

[0048] Figure 2 The effect of CE on cisplatin-induced oxidative stress in IEC-6 cells is shown in Example 2.

[0049] Figure 3 The effect of CE on cisplatin-induced mitochondrial membrane potential in IEC-6 cells is shown in Example 3.

[0050] Figure 4The effect of CE on cisplatin-induced inflammation in IEC-6 cells is shown in Example 4.

[0051] Compared with the blank group, #### P < 0.0001; compared with the model group, ** P<0.01, **** P<0.0001.

[0052] Figure 5 Example 5 illustrates how CE alleviates cisplatin-induced anorexia.

[0053] Compared with the blank group, #### P < 0.0001; compared with the model group, ** P<0.01, **** P<0.0001.

[0054] Figure 6 The kaolin uptake of SD rats after 0-120 h of administration is shown in Example 6.

[0055] In this context, On represents the ondansetron group, CEL represents the low-dose CE group, and CEH represents the high-dose CE group.

[0056] Figure 7 The normal feed intake of rats in each group during 0-120 h after drug administration is shown in Example 7.

[0057] In this context, On represents the ondansetron group, CEL represents the low-dose CE group, and CEH represents the high-dose CE group.

[0058] Figure 8 The example 8 illustrates how CE alleviates the inhibition of gastrointestinal emptying caused by cisplatin.

[0059] Compared with the blank group, # P<0.05, #### P < 0.0001; compared with the model group, * P<0.05, ** P<0.01, *** P<0.001.

[0060] Figure 9 Example 9 illustrates how CE improves cisplatin-induced gastrointestinal injury.

[0061] Figure 10 Example 10 illustrates how CE improves cisplatin-induced kidney injury.

[0062] Figure 11 The protective effect of CE and its analogues in an in vitro cisplatin-induced cell damage model is shown in Example 11. Compared with the model group, * P<0.05,** P<0.01. Detailed Implementation

[0063] The invention will be further described below with examples, but the invention is not limited thereto.

[0064] The key material information involved in the embodiments is as follows:

[0065] CE, cypressin, purchased from Zhejiang Hangzhou Green Biotechnology, batch number 0100186383;

[0066] Ondansetron, purchased from Chenxin Pharmaceutical Co., Ltd., batch number 221003C11;

[0067] Cisplatin (lyophilized form), purchased from Qilu Pharmaceutical (Hainan) Co., Ltd., batch number H37020523;

[0068] Metoclopramide, purchased from Pengyao Pharmaceutical, batch number 2025041;

[0069] Scopolamine hydrobromide hydrochloride injection was purchased from Henan Furen Huaiqingtang Pharmaceutical Co., Ltd., batch number H19994038.

[0070] Example 1 CE slows down cisplatin-induced cell damage

[0071] Cells were seeded in 96-well plates (2 × 10⁶ cells per well). 4 Cells were incubated at 90% confluence with cisplatin and CE at the following concentrations (0.1625, 0.3125, 0.625, 1.25, 2.5, 5, 10, 20, and 40 μM) for 24 h, followed by incubation with MTT (5 mg / mL) for an additional 4 h. The culture supernatant was discarded, and 150 μL of DMSO was added to each well and mixed to completely dissolve the crystals. The absorbance at 490 nm was measured using a microplate reader (SPECTROstarNano, Ortenberg, Germany) to verify the optimal modeling and administration doses.

[0072] To verify the protective effect of CE against cisplatin-induced in vitro intestinal injury, IEC-6 cells were treated for 24 hours using the optimal modeling dose and CE concentration. The supernatant was then discarded, and the cells were incubated with cisplatin (15 μM) and CE. Absorbance was measured as described above.

[0073] The results showed that cisplatin (0.1625-40 μM) exposure for 24 hours reduced cell viability in a dose-dependent manner. Figure 1 B, p<0.05). When the cisplatin concentration was 15 μM, the cell viability decreased to over 50%. Therefore, 15 μM cisplatin was chosen for subsequent experiments.

[0074] In addition, to screen for the optimal dose, 0.15625-40 μM concentrations of CE were selected for toxicity and dosing experiments. Figure 1 Results A and 1C showed that CE was non-cytotoxic at doses of 0.15625-40 μM and had a significant protective effect against cisplatin-induced cell damage at doses of 2.5-20 μM for 24 h (p<0.05).

[0075] Example 2 Effects of CE on cisplatin-induced oxidative stress in IEC-6 cells

[0076] The use of a fluorescently labeled dye DCFH-DA probe to detect ROS accumulation in IEC-6 cells further demonstrates the antioxidant effect of CE. Figure 2 As shown, after modeling with cisplatin (15 μM), excessive production of intracellular ROS with green fluorescence occurred (p<0.05), while pretreatment with 10 and 20 μM CE significantly inhibited the excessive production of ROS. These results indicate that CE can significantly reduce cisplatin-induced oxidative stress damage in IEC-6 cells, with a more pronounced effect at concentrations of 10–20 μM.

[0077] Example 3 Effect of CE on cisplatin-induced mitochondrial membrane potential in IEC-6 cells

[0078] Mitochondrial membrane potential (MMP) was detected using JC1 dye (Sigma-Aldrich, Missouri, United States). 2 x 10⁻⁶ 5 IEC-6 cells were seeded in 6-well plates and treated with different doses of CE (10 and 20 μM) and cisplatin (15 μM) for 24 h. Cells were then collected and washed with 1x PBS. Cells were incubated with 2 μM JC1 dye at 37°C in the dark for 30 min. Cells were then washed with 1x PBS and photographed using a fluorescence microscope (Olympus Corporation 1601655S, Japan). When MMP was high, JC1 aggregated in the matrix to form polymers, producing red fluorescence. Conversely, when the mitochondrial membrane potential was low, JC1 could not aggregate in the mitochondrial matrix and existed as monomers, producing green fluorescence. Figure 3 As shown, cisplatin significantly induced a decrease in mitochondrial membrane potential, while CE reversed this phenomenon, indicating that CE can protect against cisplatin-induced cell damage.

[0079] Example 4 CE improves cisplatin-induced cellular inflammation

[0080] Western blotting was used to detect the effect of CE on the levels of inflammation-related proteins (IL-6, Ikb-α, p-NF-κb, p-NF-κb) 24 h after cisplatin-induced modeling. Samples underwent protein denaturation, electrophoretic separation, and electroporation. Protein membranes were incubated overnight at 4°C with the corresponding primary antibodies, with β-actin serving as a total protein control. ECL reagent was used in the presence of horseradish peroxidase-conjugated secondary antibody, and signals were observed in real-time on a Tanon 4600. Protein bands were analyzed using ImageJ. Results are shown below. Figure 4 .

[0081] The results showed that cisplatin-induced cellular inflammation was induced by elevated levels of the inflammation-related proteins IL-6, p-NF-κb, and NF-κb. However, compared with the cisplatin group, CE treatment effectively reversed the expression of these proteins. These results confirm that CE can inhibit cisplatin-induced cellular inflammation.

[0082] Example 5 CE relieves anorexia induced by cisplatin

[0083] Western blotting was used to detect the expression of growth factor GDF-15 in cells 24 hours after cisplatin-induced anorexia, thus verifying the effect of CE on cisplatin-induced anorexia from both in vivo and in vitro perspectives. Results are shown below. Figure 5 The results showed that, compared with the model group, CE could reduce the level of GDF-15 in cells, indicating that CE can improve cisplatin-induced anorexia.

[0084] Example 6 CE reduced kaolin intake in rats with pica.

[0085] To verify the anti-CINV ability of the compounds described in this invention, a rat pica model was constructed, and the antiemetic ability of different groups was compared based on the amount of kaolin ingested.

[0086] SPF-grade male SD rats, weighing 200-220g, were purchased from Liaoning Changsheng Animal Co., Ltd. (Liaoning, China). The rearing temperature was 23±2℃, relative humidity 50±10%, with good ventilation and a 12h / 12h day / night cycle. After three days of acclimatization, kaolin granules were placed in the rat cages and fed along with normal feed to allow the animals to adapt to the presence of kaolin. The surface of the kaolin was observed for bite marks, and the amount of kaolin consumed was measured every 12 hours. The formal experiment began once the rats stopped consuming the kaolin.

[0087] The experiment was divided into a control group, a model group, an On group, a low-dose CE (CEL) group, and a high-dose CE (CEH) group. One hour before modeling (8:00 am), the On group, the low-dose CE group, and the high-dose CE group were administered ondansetron (1.3 mg / kg), low-dose CE (40 mg / kg), and high-dose CE (80 mg / kg), respectively. The control group and the model group were administered an equal volume of distilled water by gavage twice daily, with an interval of 12 hours. One hour after the first administration (9:00 am), a single intraperitoneal injection of 6 mg / kg cisplatin was used to induce modeling in the model group, the On group, the low-dose CE group, and the high-dose CE group. The rats in each group were treated with cisplatin for 120 hours after modeling.

[0088] The reagent preparation is as follows:

[0089] 0.5% CMC-Na solution: Add 0.5g of CMC-Na powder to 100mL of distilled water, heat, stir, and dilute to volume to obtain a 0.5% CMC-Na solution.

[0090] Preparation of CE samples and On positive control samples: Weigh appropriate amounts of CE and On respectively, grind them into powder, and prepare the reagents using 0.5% CMC-Na solution as the matrix.

[0091] Experimental results: 24 hours after intraperitoneal injection of cisplatin, the amount of kaolin consumed by rats in each group increased to varying degrees. For example... Figure 6 As shown in the figure, the amount of kaolin consumed by rats in the model group was significantly higher than that in the control group (P<0.001), indicating that the rat pica model was successfully established. Figure 6 The results showed that kaolin uptake in rats increased significantly 24-120 h after cisplatin administration, indicating the occurrence of the acute (24 h) and delayed (72-120 h) phases of CINV. At 24 h after administration, kaolin uptake decreased with increasing CE dosage compared to the model group. At 48-120 h after administration, the antiemetic effect in the treated group was significantly better than that in the positive control group. Figure 7 The results showed that after cisplatin-induced modeling, the feed intake of rats in both the model group and the treatment group was significantly reduced from 0 to 120 hours. The normal feed intake in each treatment group was significantly higher than that in the model group. With prolonged treatment time, the feed intake of rats in each treatment group increased, indicating that CE alleviated cisplatin-induced gastrointestinal damage to some extent and had a reducing effect on toxic side effects.

[0092] Example 7 CE antagonizes the inhibitory effect of cisplatin on gastrointestinal emptying.

[0093] Mice were randomly divided into 6 groups (N=10): normal group (ip saline), model group (ip cisplatin 2 mg / kg), metoclopramide (Meto) group (ig 5 mg / kg + ip cisplatin 2 mg / kg), ondansetron (ig 1.82 mg / kg + ip cisplatin 2 mg / kg), low-dose CE (CEL) group (ig 56 mg / kg + ip cisplatin 2 mg / kg), and high-dose CE (CEH) group (ig 112 mg / kg + ip cisplatin 2 mg / kg). After 7 days of acclimatization, mice were given medication. The control and model groups were given distilled water by gavage, while the medication groups received the same treatment, once daily for 4 days. From day 1 of gavage, except for the control group which received intraperitoneal injection of saline, all other groups received intraperitoneal injection of cisplatin 2 mg / kg once daily for 4 days. On day 4, before gavage administration, animals were fasted for 18 hours but allowed free access to water. One hour after gavage, cisplatin was injected intraperitoneally. Twenty minutes later, each animal was given 0.8 mL of a nutritional semi-solid paste via gavage. The animals were then euthanized under pentobarbital anesthesia 20 minutes later. The abdominal cavity was opened, the gastric cardia and pylorus were ligated, and the stomach was harvested. After drying with filter paper, the total weight was measured. The stomach body was then cut along the greater curvature, the contents were washed away, and the stomach was dried again; the net weight was measured. The difference between the total stomach weight and the net stomach weight was used as the weight of the stomach contents. The stomach and small intestine were then harvested, and the gastric residue rate and small intestinal propulsion rate were calculated. Results are shown below. Figure 8 .

[0094] Gastric residual rate (%) = weight of gastric contents (g) / weight of nutritional semi-solid charcoal paste (g) × 100%.

[0095] Simultaneously, the small intestine is quickly removed, the mesentery is gently peeled off, and it is laid directly on a tray. The distance from the pylorus to the ileocecal junction is taken as the total length of the small intestine, and the distance from the pylorus to the leading edge of the nutritional semi-solid paste is taken as the propulsion distance of the nutritional semi-solid paste in the small intestine. The propulsion rate of the small intestine is calculated.

[0096] Small intestinal propulsion rate (%) = Distance of semi-solid paste propulsion in the small intestine (cm) / Total length of small intestine (cm) × 100%.

[0097] The experimental results showed that, compared with the normal group, the gastric residue rate of the model group animals was significantly increased (P<0.0001), indicating that the model was successfully established.

[0098] Compared with the model group, the CE administration group significantly reduced the gastric residual rate (P<0.01), and there was no statistically significant difference between the CE and normal groups (P>0.05), indicating that the effect of CE on improving cisplatin-induced gastric emptying disorder can be basically restored.

[0099] Compared with the normal group, the small intestinal propulsion rate of the model group animals was significantly increased (P<0.05), indicating that the model was successfully established. Compared with the model group, CE had a significant promoting effect on small intestinal propulsion in the model animals (P<0.001), indicating that CE promotes small intestinal emptying.

[0100] Example 8 CE reduces the motion sickness response index in mice.

[0101] Mice were randomly divided into four groups (N=10): control group (ip saline), scopolamine group (iv 1 mg / kg), CEL group (ig 56 mg / kg), and CEH group (ig 112 mg / kg). The CE group received scopolamine via gavage 30 minutes before the rotational stimulation, while the positive control group received scopolamine via intraperitoneal injection. A mouse motion sickness model was established using a DSL-1 small animal centrifuge. The mice were rotated in a uniform horizontal circular motion around a vertical axis perpendicular to the ground, with a peak velocity of 360° / s and a rotation time of 40 minutes. After the rotational stimulation, the animals were placed on the ground, and their condition was immediately observed. All responses occurred within 5 minutes after the rotation ended. The results were recorded and the motion sickness response index was calculated according to the evaluation criteria (see Table 1) (see Table 2).

[0102] Table 1. Evaluation criteria for the degree of dizziness response in mice

[0103] Dizziness Index Score Stool granules None: 0 points; 1 point / pill urination None: 0 points; Yes: 1.2 points Hair standing up None: 0 points; Mild: 0.6 points; Severe: 1.2 points Tremor None: 0 points; Yes: 1.2 points

[0104] Table 2. Results of motion sickness symptom scoring in each group of mice

[0105] Group Dizziness Reaction Index Total Score control group 3.86±1.76 Scopolamine group 1.35±0.78 CEL group 1.67±0.32 CEH group 1.36±1.22

[0106] The experimental results showed that the total score of the motion sickness response index in the CE-treated group was significantly lower than that in the control group, and the difference was statistically significant, indicating that CE has a certain anti-motion sickness effect.

[0107] Example 9 CE improves cisplatin-induced gastrointestinal injury

[0108] The effects of the composition on the recovery of pathological damage in the gastric antrum and ileum were observed using histopathological staining. The gastric antrum and ileum of rats were pre-cooled and preserved in 4% paraformaldehyde for 24 hours. After dehydration and paraffin embedding, the tissues were cut into 4 μm sections for HE staining to observe histological changes in the gastric antrum and ileum.

[0109] The results are as follows Figure 9As shown, compared with the control group, cisplatin administration resulted in significant pathological changes in the tissues, including damage to the surface of the gastric antrum and the ileal mucosal structure. The intestinal tissue was severely damaged, with uneven intestinal villi and significant inflammatory infiltration. Compared with the cisplatin group, CE alleviated the pathological damage in the gastric antrum and ileum, including reducing inflammatory infiltration and mucosal damage. These results suggest that CE can alleviate cisplatin-induced gastrointestinal damage by reducing pathological damage.

[0110] Example 10 CE improves cisplatin-induced kidney injury

[0111] The effects of the composition on the recovery of pathological damage in the gastric antrum and ileum were observed using histopathological staining. Rat kidneys were collected and pre-cooled with 4% paraformaldehyde for 24 hours. After dehydration and paraffin embedding, the tissue was cut into 4 μm sections for HE staining to observe histological changes.

[0112] The results are as follows Figure 10 As shown, the kidneys of the control group rats had normal morphology and orderly arrangement of renal tubules; the kidneys of the cisplatin group rats showed renal tubular degeneration, epithelial cell shedding, lumen dilation, and inflammatory cell infiltration; compared with the model group, CE could alleviate the lesions of rat kidney tissue to varying degrees.

[0113] Example 11 CE and its analogues alleviate gastrointestinal damage.

[0114] Small intestinal epithelial cell line 6 (IEC-6) was used at a density of 2 × 10⁶ cells per well. 5 Cells were seeded at a density of 100 μL in 96-well plates. After overnight incubation, CE (Formula 1, 10 μM), cedrol (Formula 2, 10 μM), 8,13-cedrol (Formula 3, 10 μM), epoxidized cedrolane (Formula 4, 10 μM), cedrol acetate (Formula 5, 10 μM), acetylated cedrolene (Formula 6, 10 μM), methyl cedrolene (Formula 7, 10 μM), and α-epoxidized cedrolane (Formula 8, 10 μM) were administered, while the model group was treated with cisplatin (15 μM) alone, 100 μL per well. After 1 h, 15 μM cisplatin was administered to induce chemotherapeutic cell damage. After 24 h of incubation in the dark, 10% CCK-8 reagent diluted with DMEM was added to each well. After 4 h of incubation, the absorbance of each well was measured at 450 nm.

[0115] Experimental results showed that in vitro culture of IEC-6 cells showed that cisplatin treatment significantly reduced the viability of IEC-6 cells. Compared with the model group, CE and its analogues had a significant protective effect on the viability of IEC-6 cells after cisplatin treatment, with CE showing the best protective effect.

[0116] In conclusion, CE and its analogues are effective in alleviating CINV.

Claims

1. Use of a sesquiterpene compound for the manufacture of a medicament for the relief / treatment of nausea and vomiting, characterized in that, The nausea and vomiting is caused by chemotherapy drugs; the sesquiterpenes compound is cembranolide with the following structure or a pharmaceutically acceptable salt thereof; 。 2. Use according to claim 1, wherein The sesquiterpenes compound and a pharmaceutically acceptable carrier constitute a pharmaceutical composition.

3. Use according to claim 2, wherein the compound is ###0002### The pharmaceutical composition is a clinically acceptable pharmaceutical preparation, which is an oral preparation, an injection preparation or a topical preparation, selected from one or more of tablets, capsules, powders, mixtures, pills, granules, decoctions, emulsions, suspensions, glycerin preparations, tinctures, liniments, film-coating preparations and patches.

4. The use according to claim 1, wherein The chemotherapy drugs are one or more of cisplatin, etoposide, teniposide, daunorubicin, doxorubicin, idarubicin, cyclophosphamide, mitoxantrone, aclarubicin, homoharringtonine, methotrexate, vincristine and vindesine.

5. Use according to claim 1, characterized in that, The sesquiterpenes compound is used alone or in combination with other ingredients.

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