Formula product for preventing and / or treating peripheral neuropathy caused by chemotherapy of tumor patient

Abstract

The invention provides a formula product for preventing and / or treating peripheral neuropathy caused by chemotherapy of tumor patients, and belongs to the field of medical nutrition. Based on the fact that CIPN caused by chemotherapy of a tumor patient is closely related to the nutritional state of the tumor patient during treatment, systematic research on metabonomics is carried out on the tumor patient with the CIPN caused by chemotherapy, the precise nutritional requirement for preventing and treating the CIPN caused by chemotherapy of the tumor patient is found, a clear biomarker and a new nutritional intervention target are found, and the clinical application prospect is wide. Therefore, food, medical nourishment, tumor special medical food or medicine based on precise nutritional requirements of CIPN of tumor patients caused by prevention and treatment of chemotherapy are prepared. The product provided by the invention reduces the incidence rate of CIPN after chemotherapy of tumor patients and alleviates clinical symptoms of CIPN, and is beneficial to the tumor patients who are expected to benefit chemotherapy in the aspects of preventing and treating CIPN and improving the nutritional state of the tumor patients.

Description

Technical Field

[0001] The present invention relates to the field of medical technology, and in particular to an application of spermidine in the preparation of special medical food or medicine for preventing and / or treating peripheral neuropathy caused by chemotherapy. Background Art

[0002] Chemotherapy-induced neuropathy in cancer patients is a serious clinical problem and is caused by a large number of cytotoxic drugs, including taxanes, platinums, vinca alkaloids, epothilones, eribulin, and bortezomib. These drugs cause different pathological damage to neurons. This chronic neuropathy is mainly a sensory neuropathy rather than a motor or autonomic neuropathy. The most common descriptions of this sensory neuropathy are numbness, tingling, and pain. Numbness and tingling appear early and are usually more prominent problems than pain. The stocking-glove distribution of symptoms usually starts from the distal fingers and toes and can progress proximally as the disease worsens. Some patients will improve their symptoms over time, but some patients may persist for many years and become a serious debilitating problem. Chemotherapy-induced peripheral neuropathy can significantly affect patients' quality of life (QOL). In addition, it may be detrimental to their cancer outcomes because it may limit the amount of chemotherapy that clinicians can give. Data show that the incidence of CIPN is 80%.

[0003] At present, clinical strategies and measures for the prevention and treatment of CIPN mainly include drug and non-drug methods. Drugs used for prevention include all-trans retinoic acid, amitriptyline, calcium magnesium, cannabinoids, carbamazepine, L-carnosine, gabapentin / pregabalin, venlafaxine, vitamin B, vitamin E, etc., and non-drug methods include acupuncture, cryotherapy, compression therapy, exercise therapy, etc. However, the US ASCO guidelines further evaluated and demonstrated these strategies and measures in 2020, pointing out that these prevention and treatment strategies and measures have no obvious benefits in clinical research, and the level of evidence for their recommended use is low, so their use is not recommended. The conclusion is that at the current review stage, there is no research to support the use of methods to prevent and treat CIPN. Summary of the invention

[0004] In view of the above problems existing in the prior art, the present invention provides a formula product for preventing and treating peripheral neuropathy induced by chemotherapy in tumor patients. Based on the fact that CIPN caused by chemotherapy in tumor patients is closely related to their nutritional status during treatment, the present invention conducts a systematic metabolomics study on tumor patients with CIPN caused by chemotherapy, finds the precise nutritional needs for preventing and treating CIPN caused by chemotherapy in tumor patients, discovers clear biomarkers and new targets for nutritional intervention, and prepares foods, medical nutrition products, special medical foods or drugs based on the precise nutritional needs for preventing and treating CIPN caused by chemotherapy in tumor patients.

[0005] The technical solution of the present invention is as follows:

[0006] (1) New targets for nutritional intervention in preventing and treating CIPN caused by chemotherapy in cancer patients

[0007] CIPN caused by chemotherapy in cancer patients is closely related to their nutritional status during treatment, but the precise nutritional needs of CIPN, biomarkers and nutritional intervention targets have not yet been clarified. The present invention selected 219 patients with colorectal cancer admitted to the Affiliated Hospital of Jiangnan University in Wuxi from July 2022 to May 2023. Among them, 65.75% (144 cases) developed CIPN, as the CIPN group; 34.25% (75 cases) did not develop CIPN, as the non-CIPN group. Treatment plan: FOLFOX: oxaliplatin + calcium folinate + 5-fluorouracil treatment, combined (or not combined) with targeted preparations (such as bevacizumab, sintilimab, etc.), and observe the occurrence of CIPN in patients after chemotherapy.

[0008] Experimental methods:

[0009] Sample collection: 2 mL of fasting venous blood was drawn in the morning (after the last chemotherapy ended and before the current chemotherapy started), stored in a -80°C refrigerator, and a blood cell analyzer was used to measure albumin levels, peripheral blood lymphocytes, hemoglobin, etc. Height and weight were measured, and the patient's body mass index (BMI) was calculated.

[0010] Nutritional assessment criteria: when NRS2002 ≥ 3 points, it is judged as having nutritional risk, and when NRS2002 < 3 points, it is judged as having no nutritional risk;

[0011] Neurotoxicity grading and neurological score: Routine physical examination, blood routine, biochemical examinations and other tests were performed after chemotherapy, and neurotoxicity grading and neurological score were calculated. Evaluation of CIPN: Grade I is the disappearance of deep tendon reflexes or paresthesia, which has no effect on physical function, and is asymptomatic or can only be found by examination; Grade II is the presence of pins and needles or other paresthesias, with mild symptoms affecting physical function but no effect on daily life; Grade III is abnormal sensory changes, which slightly affect daily life, and walking requires auxiliary tools such as canes and wheelchairs; Grade IV is disability, which is life-threatening.

[0012] Sample analysis: Metabolomics analysis was performed on serum samples of colorectal cancer patients. The samples were divided into the whole group (219 cases) CIPN (144) vs. CONT (75); the malnutrition group (NRS-2002≥3) 189 cases CIPN (131) vs. CONT (58); and the well-nourished group (NRS-2002<3) 30 cases CIPN (13) vs. CONT (17).

[0013] Discovery of new targets for nutritional intervention of CIPN: Using multivariate or univariate statistical significance criteria (VIP>1.5, FC>2 or <0.5, P<0.05), we screened out the variables that were expressed differently between CIPN and CONT, malnutrition, and well-nourished groups. 33 DEMs were identified as significantly differential metabolites in CIPN and CONT, and 33 DEMs were identified in the malnutrition group and 42 DEMs were identified in the well-nourished group. In contrast, 10 (30.3%) metabolites were significantly downregulated in the CIPN group in the analysis of the whole group, while 26 (78.8%) metabolites were significantly downregulated in the CIPN group in the malnutrition group and 23 (54.8%) metabolites were significantly downregulated in the CIPN group in the well-nourished group. These results indicate that CIPN has produced significant differential accumulation of metabolites in CONT patients. At the same time, in contrast, the number of downregulated metabolites was the highest in malnutrition, especially in the case of malnutrition, suggesting that the influence of malnutrition on the occurrence of CIPN is clear. The significantly differentially expressed compounds of amino acids and their derivatives were identified on a large scale. L-proline and spermidine were found in the CIPN group of CONT. Figure 1 In the figure, L-Proline and Spermidine, *P<0.05, **P<0.01, ***P<0.001; indicating that the metabolic pathway of L-Proline and Spermidine can be used as a new target for nutritional intervention to prevent and treat CIPN caused by chemotherapy in tumor patients.

[0014] (2) Design, preparation and application effects of products based on new targets of CIPN nutritional intervention

[0015] Based on the results that L-proline and spermidine metabolic pathways can serve as new targets for nutritional intervention to prevent and treat CIPN caused by chemotherapy in cancer patients, we designed foods, medical nutritional products, or special medical foods for cancer based on the precise nutritional needs of cancer patients for preventing and treating CIPN caused by chemotherapy, and prepared and verified their effects.

[0016] A nutritional intervention method for preventing and treating peripheral neuropathy induced by chemotherapy in tumor patients, comprising the following steps:

[0017] (1) We identified the precise nutritional requirements for the prevention and treatment of CIPN caused by chemotherapy in cancer patients and found that L-proline, spermidine, or food components rich in these functional ingredients are new targets for nutritional intervention in CIPN;

[0018] (2) Prepare foods, medical nutritional products or special medical foods for cancer based on the precise nutritional needs of cancer patients for the prevention and treatment of CIPN caused by chemotherapy.

[0019] Human trials have confirmed that the product of the present invention can reduce the incidence of CIPN in tumor patients after chemotherapy and alleviate the clinical symptoms of CIPN.

[0020] A formulation product for preventing and / or treating peripheral neuropathy induced by chemotherapy in tumor patients, the formulation product containing spermidine.

[0021] In one embodiment of the present invention, the effective content of spermidine is 0.001-30 g / Kg.

[0022] In one embodiment of the present invention, the product further contains proline, and the effective content of proline is 0.05-50 g / Kg.

[0023] In one embodiment of the present invention, the chemotherapy-induced peripheral neuropathy is chemotherapy-induced peripheral neuropathy-associated cold sensitivity, throat discomfort, discomfort swallowing cold liquids, muscle spasms or pain syndrome.

[0024] In one embodiment of the invention, the chemotherapy-induced peripheral neuropathy is caused by a chemotherapeutic agent that is a platinum-based drug.

[0025] In one embodiment of the present invention, the platinum-based drug is oxaliplatin.

[0026] In one embodiment of the present invention, the formulated product is a special medical purpose formulated food, a functional food or a pharmaceutical composition.

[0027] A special medical food for preventing and / or treating peripheral neuropathy caused by chemotherapy in tumor patients, the raw materials comprising:

[0028] Hydrolyzed whey protein powder 55g / Kg, maltodextrin 100g / Kg, spermidine 20g / Kg, proline 30g / Kg, white sugar 100g / Kg, medium chain triglycerides 27g / Kg, dipotassium hydrogen phosphate 4g / Kg, sodium chloride 6g / Kg, magnesium chloride 3g / Kg, vitamin premix 0.7g / Kg, trace element premix 0.3g / Kg, microcrystalline cellulose 0.1g / Kg, practical flavor 20g / Kg, and the balance is reverse osmosis water.

[0029] Application of spermidine in the preparation of a drug for preventing and / or treating peripheral neuropathy induced by chemotherapy in tumor patients.

[0030] In one embodiment of the present invention, the drug further comprises a pharmaceutically acceptable carrier.

[0031] In one embodiment of the present invention, the pharmaceutically acceptable carrier includes a drug carrier or a drug excipient.

[0032] In one embodiment of the present invention, the pharmaceutical excipients include one or more of a filler, a flavoring agent, a binder, a disintegrant, a lubricant, and an antacid.

[0033] In one embodiment of the present invention, the drug is in the form of oral solution, granules, capsules or injection preparations.

[0034] The beneficial technical effects of the present invention are:

[0035] The present invention conducts a systematic metabolomics study on tumor patients with CIPN caused by chemotherapy, finds that CIPN caused by chemotherapy in tumor patients is closely related to their nutritional status during treatment, finds the precise nutritional requirements for preventing and treating CIPN caused by chemotherapy in tumor patients, and finds that L-proline, spermidine or food components rich in such functional ingredients are new targets for nutritional intervention of CIPN. Based on this, foods, medical nutritional products, special medical foods for tumors, and drugs based on the precise nutritional requirements for preventing and treating CIPN caused by chemotherapy in tumor patients are prepared.

[0036] The product of the present invention can improve the malnutrition state of tumor patients, improve the clinical nutritional indicators (hemoglobin, neutrophil count, albumin, BMI) of the tumor patients, improve the nutritional risk screening NRS2002 score, and improve the PG-SGA assessment results.

[0037] The product of the present invention prevents and treats CIPN in tumor patients, including cold sensitivity, throat discomfort, discomfort with swallowing cold liquids, muscle spasms and pain syndrome. BRIEF DESCRIPTION OF THE DRAWINGS

[0038] Figure 1 This is an example of the significant difference in the metabolite quantification of CIPN versus CONT in the whole group;

[0039] Figure 2 is the chemical structural formula of proline;

[0040] Figure 3 is the chemical structural formula of spermidine;

[0041] Figure 4 Comparison of CIPN incidence rates under the intervention of the product in Example 1 of the present invention;

[0042] Figure 5 Comparison of CIPN incidence rates under the intervention of the product in Example 2 of the present invention;

[0043] Figure 6 The figure is a comparison of the CIPN incidence rates under the intervention of the product in Example 3 of the present invention. DETAILED DESCRIPTION

[0044] The present invention is described in detail below in conjunction with the accompanying drawings and embodiments.

[0045] In the embodiment of the present invention, the special medical food is prepared by dissolving various raw materials in reverse osmosis water.

[0046] Example 1

[0047] A special medical food for preventing and / or treating peripheral neuropathy caused by chemotherapy in tumor patients, the raw material composition is shown in Table 1 below:

[0048] Table 1

[0049]

[0050]

[0051] 48 tumor patients who were treated with taxane, platinum and vinca alkaloid chemotherapy were collected and randomly divided into an intervention group of 24 cases and a control group of 24 cases. The intervention group was treated with the product of Example 1, three times a day, 110 ml each time, for 2 weeks, and the control group was given routine care. The clinical nutritional status of the patients before and after the intervention, the occurrence of CIPN and the improvement of related clinical symptoms are shown in Tables 2 and 3 below.

[0052] Table 2 Effect of improving clinical nutritional status of cancer patients

[0053]

[0054] *P<0.05, **P<0.01

[0055] As shown in Table 2, the clinical nutritional status indicators of the intervention group and the control group were compared, among which NRS-2002 (P value = 0.02), albumin (P value = 0.003), and hemoglobin (P value = 0.04) showed statistically significant differences.

[0056] Table 3 Effect of preventing and treating CIPN in tumor patients

[0057]

[0058] As can be seen from Table 3, the use of the product of Example 1 to intervene in patients' CIPN symptoms such as duration, frequency of attacks and severity of toxicity has a significant improvement effect.

[0059] Example 2

[0060] A special medical food for preventing and / or treating peripheral neuropathy caused by chemotherapy in tumor patients, the raw material composition is shown in Table 4 below:

[0061] Table 4

[0062] Raw material name Content g / Kg Hydrolyzed Whey Protein Powder 55 Maltodextrin 100 Spermidine 20 Proline 30 white sugar 100 Medium Chain Triglycerides 27 Dipotassium hydrogen phosphate 4 Sodium chloride 6 Magnesium chloride 3 Vitamin premix 0.7 Trace element premix 0.3 Microcrystalline Cellulose 0.1 Practical Fragrance 20

[0063] 48 tumor patients who were treated with taxane, platinum and vinca alkaloid chemotherapy were collected and randomly divided into an intervention group of 24 cases and a control group of 24 cases. The intervention group was treated with the product of Example 2, three times a day, 110 ml each time, for 2 weeks, and the control group was given routine care. The clinical nutritional status of the patients before and after the intervention, the occurrence of CIPN and the improvement of their related clinical symptoms are shown in Tables 5 and 6 below.

[0064] Table 5 Effect of improving clinical nutritional status of cancer patients

[0065]

[0066] *P<0.05, **P<0.01

[0067] As shown in Table 5, the clinical nutritional status indicators between the intervention group and the control group were compared, among which NRS-2002 (P value = 0.01), albumin (P value = 0.004), peripheral lymphocyte count (P value = 0.05), and hemoglobin (P value = 0.02) showed statistically significant differences.

[0068] Table 6 Effect of preventing and treating CIPN in tumor patients

[0069]

[0070] It can be seen from Table 6 that the use of the product of Example 2 to intervene in patients' CIPN symptoms such as duration, frequency of attacks and severity of toxicity has a significant improvement effect.

[0071] Embodiment 3:

[0072] A special medical food for preventing and / or treating peripheral neuropathy caused by chemotherapy in tumor patients, the raw material composition is shown in Table 7 below:

[0073] Table 7

[0074] Raw material name Content g / Kg Hydrolyzed Whey Protein Powder 60 Maltodextrin 85 Spermidine 5 Proline 50 white sugar 100 Medium Chain Triglycerides 27 Dipotassium hydrogen phosphate 4 Sodium chloride 6 Magnesium chloride 3 Vitamin premix 0.7 Trace element premix 0.3 Microcrystalline Cellulose 0.1 Practical Fragrance 20

[0075] 48 tumor patients who were treated with taxane, platinum and vinca alkaloid chemotherapy were collected and randomly divided into an intervention group of 24 cases and a control group of 24 cases. The intervention group was treated with the product of Example 3, three times a day, 110 ml each time, for 2 weeks, and the control group was given routine care. The clinical nutritional status of the patients before and after the intervention, the occurrence of CIPN and the improvement of related clinical symptoms are compared as shown in Tables 8 and 9 below.

[0076] Table 8 Effect of improving clinical nutritional status of cancer patients

[0077]

[0078]

[0079] *P<0.05, **P<0.01

[0080] As shown in Table 8, the clinical nutritional status indicators between the intervention group and the control group were compared, among which NRS-2002 (P value = 0.002), albumin (P value = 0.004), peripheral lymphocyte count (P value = 0.05), and hemoglobin (P value = 0.002) showed statistically significant differences.

[0081] Table 9 Effect of preventing and treating CIPN in tumor patients

[0082]

[0083] As can be seen from Table 9, the use of the product of Example 3 to intervene in patients' CIPN symptoms such as duration, frequency of attacks and severity of toxicity has a significant improvement effect.

[0084] Comparative Example 1:

[0085] Referring to other components in Example 1, the content of the components remains unchanged, and the only difference is that the spermidine component is deleted, which is designed as a comparative example.

[0086] 48 tumor patients who were clinically treated with taxane, platinum, and vinca alkaloid chemotherapy were collected and randomly divided into 24 cases in the Example 1 product intervention group and 24 cases in the Comparative Example 1 product intervention group. The Example 1 intervention group and the Comparative Example 1 product intervention group were fed with the Example 1 product and the Comparative Example 1 product, respectively; three times a day, 110 ml each time, for 2 weeks, and other routine care was the same. The occurrence of CIPN in the patients after the respective interventions and the improvement of their related clinical symptoms are shown in Table 10 below.

[0087] Table 10 Effect of preventing and treating CIPN in tumor patients

[0088]

[0089]

[0090] By comparing the occurrence of CIPN and the improvement of related clinical symptoms of patients after intervention using Example 1 and the control group, it can be seen that when spermidine is not added, the product has no obvious effect on improving symptoms; the product of the embodiment of the present invention has a significant effect on improving clinical symptoms.

[0091] The embodiments provided above are not intended to limit the scope of the present invention, and the steps described are not intended to limit the execution order thereof. Those skilled in the art may make obvious improvements to the present invention in combination with existing common knowledge, which also fall within the scope of protection defined by the claims of the present invention.

Claims

1. A formulation product for preventing and / or treating chemotherapy-induced peripheral neuropathy in tumor patients, characterized in that: The formulation contains spermidine.

2. The formulated product according to claim 1, characterized in that The effective content of spermidine is 0.001-30 g / Kg.

3. The formulated product according to claim 1, characterized in that The product also contains proline, and the effective content of proline is 0.05-50g / Kg.

4. The formulation product according to claim 1, characterized in that: Chemotherapy-induced peripheral neuropathy is defined as cold sensitivity, throat discomfort, discomfort with swallowing cold liquids, muscle spasms, or pain syndrome associated with chemotherapy-induced peripheral neuropathy.

5. The formulation product according to claim 1, characterized in that: Chemotherapy-induced peripheral neuropathy is caused by chemotherapeutic agents such as platinum-based drugs.

6. The formulation product according to claim 5, characterized in that The platinum-based drug is oxaliplatin.

7. The formulation product according to claim 5, characterized in that The formulated product is a special medical purpose formulated food, a functional food or a pharmaceutical composition.

8. Use of spermidine in the preparation of a drug for preventing and / or treating chemotherapy-induced peripheral neuropathy in tumor patients.

9. The use according to claim 8, characterized in that: The medicament further includes a pharmaceutically acceptable carrier.

10. The use according to claim 9, characterized in that: The pharmaceutically acceptable carrier includes a drug carrier or a drug excipient.

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