Application of sesquiterpenoids in relieving nausea and vomiting

Abstract

The invention relates to the technical field of chemical medicines, in particular to application of sesquiterpenoids in relieving nausea and vomiting. The sesquiterpenoids disclosed by the invention are cedar wood alcohol with the following structure, an analogue of the cedar wood alcohol, a racemate of the cedar wood alcohol, a stereoisomer of the cedar wood alcohol, a tautomer of the cedar wood alcohol, a solvate of the cedar wood alcohol, a polymorphic substance of the cedar wood alcohol, a metabolite of the cedar wood alcohol, a metabolite of the cedar wood alcohol, a prodrug of the cedar wood alcohol or pharmaceutically acceptable salt of the cedar wood alcohol. The sesquiterpenoids can reduce kaolin intake of allotriophagia rats, and obviously alleviate nausea and vomiting symptoms generated when chemotherapeutic drugs such as cis-platinum are used for tumor treatment. And emesis caused by gastrointestinal injury, inflammatory diseases, anorexia and the like can be relieved. The compound can be used for preparing medicines for relieving / treating nausea and vomiting or preparing foods for assisting in protecting gastric mucosa. # imgabs0 #

Description

Technical Field

[0001] The invention belongs to the field of chemical medicine and relates to the application of sesquiterpenoid compounds in relieving nausea and vomiting, and specifically relates to the application of cedarwood alcohol and its analogs in the preparation of drugs for relieving nausea and vomiting. Background Art

[0002] Cancer has become a major killer facing mankind, with a mortality rate second only to cardiovascular disease, and it is showing an upward trend year by year. The latest statistics from the International Agency for Research on Cancer show that by 2040, cancer cases may increase to 28.4 million, an increase of 47% from 2020. At present, chemotherapy is still the most important means of treating malignant tumors, but long-term use of clinical drugs such as cisplatin, doxorubicin, imatinib, gefitinib, etc. will lead to different degrees of drug resistance and off-target effects, as well as side effects such as nausea and vomiting, fatigue, hair loss, low immunity, and anemia. Chemotherapy-induced nausea and vomiting (CINV) refers to nausea and vomiting caused by or related to chemotherapy drugs, which is the most common adverse reaction. CINV causes patients to have a decreased quality of life, metabolic disorders, malnutrition, and weight loss, which reduces treatment compliance. In severe cases, they have to reduce or even terminate anti-tumor treatment. The occurrence of CINV has undermined the confidence of cancer patients in defeating the disease, reduced patient compliance, and shortened the survival time of patients to a certain extent. Therefore, improving or alleviating the occurrence of nausea and vomiting in cancer patients plays a vital role in the treatment of cancer patients. Existing antiemetic drugs are expensive, and commonly used antiemetic drugs such as the 5-HTR blocker ondansetron often only act on one receptor, so combined medication is often required. However, existing triple and quadruple treatments are very likely to cause adverse reactions in patients to varying degrees, such as drowsiness, cognitive impairment, osteoporosis, etc. Therefore, it is urgent to seek new chemotherapy drugs with low toxicity, good efficacy, and low cost and easy availability.

[0003] Cedrol (CE) is a compound obtained from ginger and can be produced in large quantities from plants of the Cupressaceae family. Pharmacological studies have shown that cedrol has multiple biological activities such as anti-inflammatory, analgesic, anti-tumor, anti-anxiety, anti-aging, hair growth promotion, and osteoporosis relief.

[0004] There is no relevant report in the prior art on the effect of cedarwood alcohol and its analogs on relieving nausea and vomiting. Summary of the invention

[0005] In view of the defects existing in the prior art, the present invention provides the use of sesquiterpenoid compounds in the preparation of drugs for relieving / treating nausea and vomiting.

[0006] The sesquiterpenoid compound is cedarwood alcohol or its pharmaceutically acceptable salts, analogs, racemates, stereoisomers, tautomers, isotope-labeled substances, solvates, polymorphs, and metabolites having the following structure:

[0007]

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

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

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

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

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

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

[0014] Or R5 and R6, R5 and R7 form an epoxy group;

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

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

[0017] Preferably, the sesquiterpenoid compound is cedarwood alcohol or a pharmaceutically acceptable salt, analog, racemate, stereoisomer, tautomer, isotope-labeled substance, solvate, polymorph, metabolite thereof having the following structure:

[0018]

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

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

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

[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, =CH2;

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

[0025] Or R5 and R6, R5 and R7 form an epoxy group;

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

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

[0028] Preferably, the sesquiterpenoid compound is cedarwood alcohol or a pharmaceutically acceptable salt, analog, racemate, stereoisomer, tautomer, isotope-labeled substance, solvate, polymorph, metabolite thereof having the following structure:

[0029]

[0030] The sesquiterpenoid compound of the present invention can be used as a sole ingredient in preparing a drug for relieving / treating nausea and vomiting.

[0031] The sesquiterpenoid compounds of the present invention can be combined with other ingredients 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 preparation for oral administration, injection or external administration.

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

[0036] The chemotherapy drug is one or more of cisplatin, etoposide, teniposide, daunorubicin, doxorubicin, idarucirubicin, cyclophosphamide, mitoxantrone, aclarubicin, homoharringtonine, methotrexate, vincristine, and vindesine.

[0037] The nausea and vomiting described in the present invention may also refer to vomiting caused by gastrointestinal damage, inflammatory diseases, and anorexia.

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

[0039] The sesquiterpenoid compound or the pharmaceutical composition thereof of the present invention can also be used to prepare food for assisting in protecting gastric mucosa.

[0040] The food includes health food.

[0041] The sesquiterpenoid compound or the pharmaceutical composition thereof of the present invention can also alleviate the damage of drugs to kidneys and reduce the toxicity of drugs to kidneys.

[0042] The beneficial effects of the present invention are:

[0043] The present invention provides the use of sesquiterpenoid compounds cedarwood alcohol and analogs thereof or pharmaceutical compositions thereof in the preparation of drugs for relieving / treating nausea and vomiting. The cedarwood alcohol and analogs thereof can reduce the intake of kaolin by rats with pica, and significantly alleviate the nausea and vomiting symptoms caused by chemotherapy drugs such as cisplatin used for tumor treatment. They can also relieve vomiting caused by gastrointestinal damage, inflammatory diseases, anorexia, etc. BRIEF DESCRIPTION OF THE DRAWINGS

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

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

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

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

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

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

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

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

[0052] Figure 5 It is shown that CE in Example 5 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 intake of SD rats 0-120 hours after administration in Example 6 is shown.

[0055] Among them, On represents the ondansetron group, CEL represents the CE low-dose group, and CEH represents the CE high-dose group.

[0056] Figure 7 The normal feed intake of rats in each group in Example 7 from 0 to 120 hours after administration is shown.

[0057] Among them, On represents the ondansetron group, CEL represents the CE low-dose group, and CEH represents the CE high-dose group.

[0058] Figure 8 It is shown that CE in Example 8 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] Fig. 9 It is shown that CE in Example 9 improves cisplatin-induced gastrointestinal damage.

[0061] Fig.10 It was shown that CE in Example 10 improved cisplatin-induced kidney injury.

[0062] Fig.11 The protective effects of CE and its analogs in Example 11 in an in vitro cisplatin-induced cell injury model are shown. Compared with the model group, * P<0.05,** P<0.01. DETAILED DESCRIPTION

[0063] The present invention is further described below by way of examples, but the present invention is not limited thereto.

[0064] The key substance information involved in the examples is as follows:

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

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

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

[0068] Metoclopramide was 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 mitigates cisplatin-induced cell damage

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

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

[0073] The results showed that after 24 h of exposure to cisplatin (0.1625-40 μM), cell viability decreased in a dose-dependent manner ( Figure 1 B, p<0.05). When the concentration of cisplatin was 15 μM, the cell survival rate dropped to more than 50%. Therefore, 15 μM cisplatin was selected for subsequent experiments.

[0074] In addition, to screen the optimal dose, CE concentrations of 0.15625-40 μM were selected for toxicity and administration experiments. Figure 1 The results of A and 1C showed that CE had no cytotoxicity at a dose of 0.15625-40 μM, and had a significant protective effect on cell damage caused by cisplatin when administered at 2.5-20 μM for 24 hours (p<0.05).

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

[0076] Fluorescein-labeled dye DCFH-DA probe was used to detect the accumulation of ROS in IEC-6 cells, which further demonstrated the antioxidant effect of CE. Figure 2 As shown, after cisplatin (15 μM) modeling, intracellular ROS with green fluorescence were overproduced (p < 0.05), while pretreatment with 10 and 20 μM CE could significantly inhibit the overproduction of ROS. The above results show that CE can significantly reduce cisplatin-induced oxidative stress damage in IEC-6 cells, and the effect is more obvious when its concentration is 10-20 μM.

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

[0078] Mitochondrial membrane potential (MMP) was detected using JC1 dye (Sigma-Aldrich, Missouri, United States). 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. Subsequently, the cells were collected and washed with 1x PBS. The cells were incubated with 2 μM JC1 dye at 37°C in the dark for 30 min. Then, the cells were washed with 1x PBS and photographed using a fluorescence microscope (Olympus Corporation1601655S, Japan). When MMP is high, JC1 aggregates in the matrix to form polymers, which can produce red fluorescence. In contrast, when the mitochondrial membrane potential is low, JC1 cannot aggregate in the mitochondrial matrix and exists as a monomer, 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 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 content of inflammatory-related proteins (IL-6, Ikb-α, p-NF-κb, p-NF-κb) 24 hours after cisplatin modeling. The samples were subjected to protein denaturation, electrophoresis separation, electrotransfer and other operations, and the protein membrane was incubated with the corresponding primary antibody at 4°C overnight, with β-actin as a control for total protein. In the presence of horseradish peroxidase-conjugated secondary antibody, ECL reagent was used for reaction, and the signal was observed in real time in Tanon 4600, and the protein bands were analyzed by Image J. The results are shown in Figure 4 .

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

[0082] Example 5 CE relieves cisplatin-induced anorexia

[0083] Western blotting was used to detect the expression of growth factor GDF-15 in cells 24 hours after cisplatin modeling, verifying that CE alleviates anorexia caused by cisplatin from an in vivo and in vitro perspective. Figure 5 The results showed that CE could reduce the level of GDF-15 in cells compared with the model group, indicating that CE could improve cisplatin-induced anorexia.

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

[0085] In order to verify the anti-CINV ability of the compound of the present invention, a rat pica model was constructed, and the antiemetic ability of different groups was compared by kaolin intake.

[0086] SPF SD rats, male, weighing 200-220 g, were purchased from Liaoning Changsheng Animal Co., Ltd. (Liaoning, China) and kept at a temperature of 23±2°C, a relative humidity of 50±10%, good ventilation, and a 12h / 12h light-dark cycle. After three days of adaptive feeding, kaolin particles were placed in the rat cage and fed to the rats at the same time as normal feed to adapt the animals to the presence of kaolin. The kaolin surface was observed for bite marks, and the kaolin consumption was weighed every 12 h. When the rats stopped chewing kaolin, the formal experiment began.

[0087] The experiment was divided into control group, model group, On group, CE low-dose (CEL) group, and CE high-dose (CEH) group. 1h before modeling (8:00am), On group, CE low-dose group, and CE high-dose group were given ondansetron (1.3mg / kg), low-dose CE (40mg / kg), and high-dose CE (80mg / kg), respectively. The control group and model group were gavaged with equal volume of distilled water, twice a day, with an interval of 12h. 1h after the first administration (9:00am), the model group, On group, CE low-dose group, and CE high-dose group were modeled by a single ip injection of 6mg / kg cisplatin. The rats in each group were treated with cisplatin 120h after modeling.

[0088] The test drug was prepared 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 obtain a 0.5% CMC-Na solution.

[0090] Preparation of CE samples and On positive control samples: Weigh appropriate amounts of CE and On, grind them into powders, and prepare the test drugs 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. Figure 6 As shown in the figure, the rats in the model group ate significantly more kaolin than those in the control group (P<0.001), indicating that the rat pica model was successfully established. Figure 6 The results showed that the kaolin intake in rats increased significantly 24-120 hours after cisplatin administration, indicating the occurrence of acute (24 hours) and delayed (72-120 hours) phases of CINV. At 24 hours after administration, the kaolin intake decreased with the increase of CE administration dose compared with the model group. At 48-120 hours after administration, the antiemetic effect of the drug group was significantly better than that of the positive drug. Figure 7 The results showed that after cisplatin modeling, the feed intake of rats in the model group and the drug-treated group was significantly reduced from 0 to 120 hours. The normal feed intake of each drug-treated group was higher than that of the model group, and the difference was significant. As the medication time prolonged, the feed intake of rats in each drug-treated group increased, indicating that CE alleviated the gastrointestinal damage caused by cisplatin to a certain extent and had the effect of reducing 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), CE low dose (CEL) group (ig 56 mg / kg + ip cisplatin 2 mg / kg), CE high dose (CEH) group (ig 112 mg / kg + ip cisplatin 2 mg / kg). The mice were fed adaptively for 7 days before drug administration. The control group and the model group were gavaged with distilled water. The drug administration group was the same as above, once a day, for a total of 4 days. From the first day of gavage, except for the control group, which was intraperitoneally injected with saline, all other groups were intraperitoneally injected with cisplatin 2 mg / kg, once a day, for a total of 4 days. Before oral administration on the 4th day, the animals were fasted but not watered for 18 hours. One hour after oral administration, cisplatin was injected intraperitoneally. 20 minutes later, 0.8 mL of nutritious semisolid paste was administered by oral administration, and the animals were killed 20 minutes later under pentobarbital anesthesia. The abdominal cavity was opened, the gastric cardia and pylorus were ligated, the stomach was removed, and the total weight was weighed after wiping it dry with filter paper. The stomach was then cut open along the greater curvature of the stomach, the stomach contents were washed out, wiped dry, and the net weight was weighed. The difference between the total weight of the stomach and the net weight of the stomach was taken as the weight of the stomach contents. The stomach and small intestine were taken, and the gastric residual rate and small intestinal propulsion rate were calculated. The results are shown in Figure 8 .

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

[0095] At the same time, the small intestine was quickly taken out, the mesentery was gently peeled off and laid directly on the tray. The distance from the pylorus to the ileocecum was the total length of the small intestine, and the distance from the pylorus to the front of the nutrient semi-solid paste was the advancement distance of the nutrient semi-solid paste in the small intestine. The small intestine advancement rate was calculated as:

[0096] Small intestine propulsion rate (%) = distance propagated by semisolid paste 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 residual rate of the model group animals increased significantly (P<0.0001), indicating that the model was successfully established.

[0098] Compared with the model group, the gastric residual rate in the CE group was significantly reduced (P<0.01), and there was no significant difference in CEH between the two groups (P>0.05), indicating that the improvement effect of CE on gastric emptying disorder caused by cisplatin can be basically restored.

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

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

[0101] Mice were randomly divided into 4 groups (N=10): control group (ip saline), scopolamine group (iv 1mg / kg), CEL group (ig 56mg / kg), CEH group (ig 112mg / kg). CE group was gavaged 30min before rotation stimulation, and scopolamine was injected intraperitoneally in the positive drug group. The DSL-1 small animal centrifuge was used to establish a mouse motion sickness model. The uniform speed mode performed horizontal uniform circular motion around a vertical axis perpendicular to the ground, with a peak speed of 360° / s and a rotation time of 40min. After the rotation stimulation, the animal was placed on the ground and the relevant conditions of the animal were immediately observed. All reactions occurred within 5min after the rotation. According to the evaluation criteria (see Table 1), the results were recorded and the motion sickness reaction index was calculated (see Table 2).

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

[0103] Dizziness Index Score Stool particles None: 0 points; 1 point / pill urination No: 0 points; Yes: 1.2 points Piloerection None: 0 points; Mild: 0.6 points; Severe: 1.2 points Tremor No: 0 points; Yes: 1.2 points

[0104] Table 2. Experimental results of motion sickness symptom scores of mice in each group

[0105] Group Total score of dizziness index 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 reaction index in the CE-administered 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 recovery of pathological damage of the gastric antrum and ileum by the composition was observed by histopathological staining. The gastric antrum and ileum of rats were taken and pre-cooled with 4% paraformaldehyde for 24 hours. After dehydration and paraffin embedding, the tissues were cut into 4 μm slices for HE staining to observe the histological changes of the gastric antrum and ileum.

[0109] The results are as follows Fig. 9As shown in the results, compared with the control group, the tissues after cisplatin administration showed obvious pathological changes, including damage to the surface layer of the gastric antrum and damage to the mucosal structure of the ileum, severe intestinal tissue damage, uneven intestinal wall villi, and obvious inflammatory infiltration. Compared with the cisplatin group, CE reduced the pathological damage of the gastric antrum and ileum, including reducing inflammatory infiltration and mucosal damage. The above results suggest that CE can alleviate cisplatin-induced gastrointestinal damage by reducing pathological damage.

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

[0111] The pathological damage recovery of the composition to the gastric antrum and ileum was observed by histopathological staining. The rat kidney was taken and pre-cooled with 4% paraformaldehyde for 24 hours. After dehydration and paraffin embedding, the tissue was cut into 4 μm slices for HE staining to observe its histological changes.

[0112] The results are as follows Fig.10 As shown, the kidney morphology of rats in the control group was normal, and the renal tubules were arranged in an orderly manner; the renal tubules of rats in the cisplatin group were degenerated, epithelial cells were shed, and the tubular lumen was dilated, accompanied by inflammatory cell infiltration; compared with the model group, CE could alleviate the lesions of rat renal tissue to varying degrees.

[0113] Embodiment 11 CE and its analogs alleviate gastrointestinal damage.

[0114] Small intestinal epithelial cell line 6 (IEC-6) was cultured at 2×10 5 The cells were seeded in a 96-well plate at a density of 10 cells. After overnight incubation, CE (Formula 1, 10 μM), cedrene (Formula 2, 10 μM) 8,13-cedrene glycol (Formula 3, 10 μM), epoxy cedrene (Formula 4, 10 μM), acetate cedrene (Formula 5, 10 μM), acetyl cedrene (Formula 6, 10 μM), methyl cedrene ether (Formula 7, 10 μM) and α-epoxy cedrene (Formula 8, 10 μM) were administered, and the model group was given cisplatin (15 μM) alone, with 100 μL added to each well. After 1 hour, 15 μM cisplatin was administered to induce chemotherapy cell damage. After incubation in the dark for 24 hours, 10% CCK-8 reagent diluted with DMEM was added to each well. After incubation for 4 hours, the absorbance of each well was measured at 450 nm.

[0115] The experimental results showed that in vitro culture of IEC-6 showed that cisplatin treatment significantly reduced the activity of IEC-6 cells. Compared with the model group, CE and its analogs groups had a significant protective effect on the activity of IEC-6 cells after cisplatin treatment, among which CE had the best protective effect.

[0116] In summary, CE and its analogs have the efficacy of alleviating CINV.

Claims

1. Use of sesquiterpenoid compounds in the preparation of medicines or foods for relieving / treating nausea and vomiting, characterized in that: The sesquiterpenoid compound is cedarwood alcohol or a pharmaceutically acceptable salt, analog, racemate, stereoisomer, tautomer, isotope-labeled substance, solvate, polymorph, or metabolite thereof having the following structure; in, R1 is any one or more of H, -OH, -OOH, -CH2OH, C1-C6 alkyl; R2 is any one or more of H, -OCOCH3, -OH, C1-C6 alkyl, =CH2, -CH2OH, epoxy; R3 is any one or more of H, -OCOCH3, -OH, C1-C6 alkyl, =CH2, -CH2OH, epoxy; R4 is any one or more of H, -OH, C1-C6 alkyl, C1-C6 alkoxy; R5 is any one or more of H, -COCH3, -CHO, C1-C6 alkyl, -OH, =CH2; R6 is any one or more of H, -OH, -CH2OH, C1-C6 alkyl, C1-C6 alkoxy; Or R5 and R6, R5 and R7 form an epoxy group; R7 is any one or more of H, -OH, -CH2OH, C1-C6 alkyl, C1-C6 alkoxy; R8 is any one or more of C1-C6 alkyl, CH2OH.

2. The use of sesquiterpenoid compounds in the preparation of food for assisting in protecting gastric mucosa, characterized in that: The sesquiterpenoid compound is cedarwood alcohol or a pharmaceutically acceptable salt, analog, racemate, stereoisomer, tautomer, isotope-labeled substance, solvate, polymorph, or metabolite thereof having the following structure; in, R1 is any one or more of H, -OH, -OOH, -CH2OH, C1-C6 alkyl; R2 is any one or more of H, -OCOCH3, -OH, C1-C6 alkyl, =CH2, -CH2OH, epoxy; R3 is any one or more of H, -OCOCH3, -OH, C1-C6 alkyl, =CH2, -CH2OH, epoxy; R4 is any one or more of H, -OH, C1-C6 alkyl, C1-C6 alkoxy; R5 is any one or more of H, -COCH3, -CHO, C1-C6 alkyl, -OH, =CH2; R6 is any one or more of H, -OH, -CH2OH, C1-C6 alkyl, C1-C6 alkoxy; Or R5 and R6, R5 and R7 form an epoxy group; R7 is any one or more of H, -OH, -CH2OH, C1-C6 alkyl, C1-C6 alkoxy; R8 is any one or more of C1-C6 alkyl, CH2OH.

3. The use according to claim 1 or 2, characterized in that: The sesquiterpenoid compound is cedarwood alcohol or its pharmaceutically acceptable salts, analogs, racemates, stereoisomers, tautomers, isotope-labeled substances, solvates, polymorphs, and metabolites having the following structure: Wherein, R1 is any one or more of H, -OH, -OOH, -CH2OH, C1-C4 alkyl; R2 is any one or more of H, -OCOCH3, -OH, C1-C4 alkyl, =CH2, -CH2OH, epoxy; R3 is any one or more of H, -OCOCH3, -OH, C1-C4 alkyl, =CH2, -CH2OH, epoxy; R4=any one or more of H, -OH, C1-C4 alkyl, C1-C4 alkoxy; R5=H, -COCH3, -CHO, C1-C4 alkyl, -OH, =CH2, any one or more thereof; R6=H, -OH, -CH2OH, C1-C4 alkyl, C1-C4 alkoxy, any one or more thereof; Or R5 and R6, R5 and R7 form an epoxy group; R7 is any one or more of H, -OH, -CH2OH, C1-C4 alkyl, C1-C4 alkoxy; R8 is any one or more of C1-C4 alkyl, CH2OH.

4. The use according to claim 1 or 2, characterized in that: The sesquiterpenoid compound is cedarwood alcohol or its pharmaceutically acceptable salts, analogs, racemates, stereoisomers, tautomers, isotope-labeled substances, solvates, polymorphs, and metabolites having the following structure:

5. The use according to any one of claims 1 to 4, characterized in that: The sesquiterpenoid compound and a pharmaceutically acceptable carrier form a pharmaceutical composition.

6. The use according to claim 5, characterized in that The pharmaceutical composition is a clinically acceptable pharmaceutical preparation, which is an oral preparation, an injection preparation or an external preparation, and is selected from one or more of tablets, capsules, powders, mixtures, pills, granules, decoctions, emulsions, suspensions, glycerin agents, tinctures, liniments, coatings, patches, microneedles, gels, liposomes, ethosomes or nanoparticles.

7. The use according to any one of claims 1 to 6, characterized in that: The nausea and vomiting include nausea and vomiting caused by chemotherapy drugs, nausea and vomiting caused by radiotherapy, anorexia or anorexia nervosa, gastrointestinal damage, weight loss and inflammatory diseases related to gastrointestinal damage, vomiting caused by anorexia, postoperative vomiting, vomiting during pregnancy, and vomiting caused by motion sickness.

8. The use according to claim 7, characterized in that The chemotherapy drug is one or more of cisplatin, etoposide, teniposide, daunorubicin, doxorubicin, idarucirubicin, cyclophosphamide, mitoxantrone, aclarubicin, homoharringtonine, methotrexate, vincristine, and vindesine.

9. The use according to claim 1 or 2, characterized in that: The food is a health food.

10. The use according to any one of claims 1 to 9, characterized in that: The sesquiterpenoid compound is used alone or in combination with other ingredients.

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