CN116077512A - Application of Manacastine in relieving multi-organ damage caused by chemotherapeutic drug cisplatin - Google Patents

Application of Manacastine in relieving multi-organ damage caused by chemotherapeutic drug cisplatin Download PDF

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CN116077512A
CN116077512A CN202310101885.3A CN202310101885A CN116077512A CN 116077512 A CN116077512 A CN 116077512A CN 202310101885 A CN202310101885 A CN 202310101885A CN 116077512 A CN116077512 A CN 116077512A
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cisplatin
manacastine
cells
mice
manostatin
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吴流政
刘紫琪
刘凡健
刘龙宇
王维嘉
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Xiamen University
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Abstract

Cisplatin is a common chemotherapeutic drug in clinic, which can effectively kill various tumor cells, but its clinical application is greatly limited by its severe side effects. The Mannastine (Manostatin) of the present invention comprises three components: the main component mannose and auxiliary medicines sodium saxoate and sucralose can stay in the digestive tract for a long time and fully contact with intestinal epithelial cells, so that the absorption of cells to the medicine components is increased, and the action time of the medicine is prolonged. After entering normal tissue cells, the Manacastine can inhibit the killing effect of a chemotherapeutic medicament cisplatin on the cells, and experiments show that the Manacastine can effectively inhibit damage of colorectal, small intestine and kidney caused by cisplatin, and meanwhile, the Manacastine does not influence the killing effect of cisplatin on tumor cells, so that a new scheme is provided for the treatment of cancer patients.

Description

Application of Manacastine in relieving multi-organ damage caused by chemotherapeutic drug cisplatin
Technical Field
The invention relates to the field of medical science and technology, in particular to an application of Manacastine in relieving multi-organ damage caused by chemotherapeutic cisplatin.
Background
Chemotherapy (chemotherapy for short) is the most common cancer treatment means clinically adopted at present, has universality and high efficiency on cancer treatment, cisplatin is a platinum compound and is often used for treating various types of cancers clinically, and the cisplatin can effectively kill tumor cells, but has a systemic action range, and can kill a large number of normal tissue cells when killing the tumor cells, so that severe side effects caused by the cisplatin are also caused. The known side effects of cisplatin at present mainly comprise alopecia, nausea, diarrhea, neuromuscular system injury and the like, wherein most of the side effects are from wrong killing of normal cells of intestinal tracts and kidneys by cisplatin, and no scheme for clearly and effectively solving the side effects generated in the treatment process of cisplatin is available clinically at present.
Manaastatin is a mixed drug of mannose, sodium saxoate and sucralose, wherein mannose has been used for hundreds of years, and is often used for treating urinary tract infection, but the absorption efficiency of the mannose by human body is poor, and by mixing sodium saxoate and sucralose, a mixture is formed, and the mixture can be adhered to digestive tract epithelial cells, so that the residence time of the mixture in the intestinal tract is longer, and meanwhile, the absorption effect of the sodium saxoate on mannose by the intestinal tract epithelial cells can be increased. The components of the Manacastine do not influence the functions of normal cells of a human body, and the application of the Manacastine in tumor treatment is a lack of research.
Disclosure of Invention
The invention aims to provide the application of Manacastine in relieving multi-organ damage caused by cisplatin serving as a chemotherapeutic medicine. The main components of Mannostin (Manostatin) are mannose, sodium saxoate and sucralose, wherein the mannose is a main drug with a pharmacodynamic effect, the sodium saxoate and the sucrose only have an auxiliary effect, and the mannose is a monosaccharide substance.
The invention provides application of Manacastine in medicines, kits, pharmaceutical compositions or health care products for relieving toxic and side effects caused by Cisplatin (Cisplatin), wherein the toxic and side effects are multiple organ injuries.
The organ injury is toxic and side effects of organs such as intestines, kidneys and the like caused by cisplatin.
The kit comprises (i) a reagent comprising Mannastine and (ii) a reagent comprising cisplatin.
The invention provides the use of Manacastine in the manufacture of a medicament for reducing damage to an organ of the digestive tract caused by cisplatin during chemotherapy.
The invention provides application of Manacastine in preparing a medicament for reducing toxic kidney injury caused by cisplatin during chemotherapy.
The medicine is prepared from the following medicament forms: oral liquid, injection, tablet, and capsule.
The beneficial effects of the invention include:
cisplatin is a common clinical chemotherapeutic drug, and can effectively kill various tumor cells, but is greatly limited in clinical application due to severe side effects. The Mannich statin can stay in the digestive tract for a long time and fully contacts with intestinal epithelial cells, so that the absorption of cells to medicine components is increased, and the acting time of the medicine is prolonged. After entering normal tissue cells, the Manacastine can inhibit the killing effect of a chemotherapeutic medicament cisplatin on the cells, and experiments show that the Manacastine can effectively inhibit damage of colorectal, small intestine and kidney caused by cisplatin, and meanwhile, the Manacastine does not influence the killing effect of cisplatin on tumor cells, so that a new scheme is provided for the treatment of cancer patients.
Drawings
FIG. 1 shows that treatment with Cisplatin (Cisplatin) as a chemotherapeutic agent results in colorectal shortening, and that Mannasstatin (Manostatin) according to the present invention can reduce damage to the colorectal of mice caused by Cisplatin (Cisplatin).
FIG. 2 shows the damage of Cisplatin (Cisplatin) to small intestine villi and crypt in mice, including shortening the length of small intestine villi (a) (b) and reducing intact crypt (a) (c), wherein said Mannasstatin (Manostatin) according to the present invention can reduce the damage of Cisplatin (Cisplatin) to small intestine crypt and villi in mice.
FIG. 3 shows a number of lesions of renal morphology and function caused by the chemotherapeutic agent Cisplatin (Cisplatin), including an increase in renal PAS positive staining area (a) (b), a significant increase in Blood Urea Nitrogen (BUN) (C), a significant increase in blood creatinine (d) and a significant increase in blood cystatin C (e), an indication of impaired renal function. The Mannasstatin (Manostatin) can reduce damage of Cisplatin (Cisplatin) to the kidney of a mouse.
FIG. 4 shows that treatment with the chemotherapeutic agent Cisplatin (Cisplatin) or with Mannostin (Manostatin) significantly inhibited tumor growth and decreased tumor number (a) (b) in mice bearing primary liver cancer. The Mannastine (Manostatin) disclosed by the invention does not influence the treatment effect of Cisplatin (Cisplatin) on primary liver cancer tumors of mice.
Detailed Description
In one embodiment, the invention provides a Mannostin (Manostatin) which comprises mannose, sodium saboate and sucralose as main components, wherein the mannose is a main drug for acting the drug effect, and the sodium saboate and the sucrose only have auxiliary effects.
Optionally, the mannatide (Manostatin) alleviates toxic side effects of Cisplatin (Cisplatin) induced organs such as the intestines, kidneys, and the like of mice.
Optionally, the component of Mannastine (Manostatin) does not affect the normal physiological state of each tissue and organ of the body.
Optionally, the mannatine (Manostatin) alleviates the toxic side effects caused by Cisplatin (Cisplatin) without affecting the efficacy of the chemotherapeutic agent.
In one embodiment, the invention provides a kit comprising (i) a reagent comprising Mannastine and (ii) a reagent comprising cisplatin.
In one embodiment, the invention provides a method of reducing intestinal, renal toxic side effects caused by Cisplatin (cispratin), comprising administering to a subject an effective amount of a kit of the invention, which may be administered simultaneously or sequentially comprising (i) an agent comprising Mannastine and (ii) an agent comprising Cisplatin.
In one embodiment, the invention provides a method of reducing toxic side effects caused by Cisplatin (cispratin) without affecting the efficacy of the treatment, comprising administering to a subject an effective amount of a kit of the invention, which may be administered simultaneously or sequentially comprising (i) an agent comprising Manacastin and (ii) an agent comprising Cisplatin.
In one embodiment, the invention provides the use of Manacastine in the manufacture of a medicament for reducing damage to the digestive tract caused by cisplatin at chemotherapy, which medicament reduces the toxic damage to the digestive tract caused by cisplatin at chemotherapy.
In one embodiment, the invention provides the use of Manacastine in the manufacture of a medicament for reducing toxic kidney damage caused by cisplatin at chemotherapy, which medicament can reduce toxic kidney damage caused by cisplatin at chemotherapy.
In one embodiment, the medicaments according to the invention can also be formulated into other pharmaceutically acceptable dosage forms for enteral or parenteral administration, such as oral solutions, injections, tablets, capsules, etc., according to methods known in the art.
The process of carrying out the invention is described in detail below with reference to the accompanying drawings and detailed description for the understanding of those skilled in the art. The following examples are merely illustrative of the invention in question and should not be construed as limiting the scope of the invention in question. If the embodiment does not specify a particular technique or condition, it must be performed according to the methods or conditions described in the literature in the field or according to a product manual. The reagents or tools used are common products on the market unless the manufacturer is identified.
Example 1
Effect of mannatine on chemotherapy-directed cisplatin-induced intestinal and renal damage in mice.
The experimental method is as follows:
1. treatment of mice:
(1) Several C57BL/6 mice (about 20 g) of SPF grade were randomly divided into four groups including control group (Ctrl), mannasstatin group (Manostatin), cisplatin group (Cisplatin), cisplatin/Mannasstatin combined treatment group (Cisplatin+Manostatin), and feeding conditions were 12h light period and 12h dark period.
(2) Mice in the control group (Ctrl) were treated daily with 800 μl of Phosphate Buffer (PBS) for intragastric administration, once daily for 5 days, with the first day being pretreatment, of the mice in the mannatide group (manostatin) and the Cisplatin/mannatide combination treatment group (cispratin+manostatin).
(3) Cisplatin (cispratin) and Cisplatin/Mannostin (cispratin+Manostatin) treatment groups (Cisplatin dissolved in sterile saline) were treated by intraperitoneal injection at a dose of 17mg/kg, and Manostatin pretreatment was injected once.
2. The colorectal length of the mice was measured:
after mice were treated with cisplatin formulation, sacrificed by carbon dioxide asphyxiation, and after dissection, the mice were removed for colorectal observation, length was measured and counted.
3. Histochemical analysis of staining:
the small intestine of the mice was removed to analyze the histochemical staining of H & E:
(1) The inside of the small intestine was rinsed with pre-chilled PBS, the small intestine was cut to a length of about 8 cm, cut longitudinally with scissors, and then the small intestine was rolled into a "Swiss roll" shape with a paperclip.
(2) Small intestine fixed tissues were fixed with 4% paraformaldehyde for 18-24 hours.
(3) The fixed tissue of the small intestine is then dehydrated and paraffin is introduced.
(4) Paraffin sections were performed on the embedded tissues.
(5) The cut tissue was dewaxed and rehydrated, and then stained with hematoxylin eosin.
(6) After natural drying, the films were sealed and then examined microscopically.
The kidneys of mice were removed to analyze the histochemical staining of PAS:
(1) The kidneys of the mice were rinsed with PBS at room temperature.
(2) Kidney tissue was fixed with 4% paraformaldehyde for 24-48 hours.
(3) The fixed tissue is then dehydrated and paraffin is introduced.
(4) Paraffin sections were performed on the embedded tissues.
(5) Dewaxing and rehydrating the cut tissues, and performing PAS staining. PAS staining is also known as snow-fu periodate staining or glycogen staining. Typically used to display glycogen and other polysaccharide materials. Principle of: the periodic acid oxidizes the intracellular polysaccharide glycol groups to glyoxal, which is then combined with the colorless fuchsin of Schiff's fluid to make it red and localized in the cytoplasm. When the kidneys were damaged, uromodulin (Uromodulin) increased drastically and was stained by PAS. PAS staining can therefore reflect the extent of morphological structural damage to the kidneys.
(6) And (5) performing microscopic examination after sealing the sheet.
5. Determination of Blood Urea Nitrogen (BUN), creatinine (Creatinine) and Cystatin C (Cystatin C):
after treatment of mice with cisplatin formulation, blood was taken by extraction of the eyeballs and the blood was stratified at 37 ℃.
The top serum was collected by centrifugation using a high speed centrifuge at 3000rpm for 25 minutes. Serum is sent to hospitals to determine indicators related to kidney function, such as Blood Urea Nitrogen (BUN), creatinine (creatinine) and cystatin C (cystatin C). A significant increase in urea nitrogen (BUN), creatinine, and cystatin C levels in the blood suggests impaired renal function.
Manacastine reduced cisplatin results of colorectal injury test in mice are shown in FIG. 1.
Figure 1 Manacastine can alleviate cisplatin-induced colorectal shortening in mice. There was no significant change in colorectal length in the Manlastin group (Manostatin) compared to the control group (Ctrl), the colorectal length in the Cisplatin group was significantly shortened compared to the control group (Ctrl), and the colorectal length in the Cisplatin/Manlastin co-treated group (Cisplatin+Manostatin) was significantly normalized compared to the Cisplatin (Cisplatin) group. The Manacastine treatment disclosed by the invention does not influence the colorectal length of experimental mice, but can reduce the damage to the colorectal of the mice caused by chemotherapy-guided administration of cisplatin.
Statistical analysis was performed on the obtained data using Graphpad prism 9 statistical software, and experimental data were expressed as mean ± standard error. The difference between the control group and the experimental group is analyzed by adopting a two-factor analysis of variance and Fisher test, ns represents p >0.05, and the difference has no statistical significance. * P <0.05, the difference is significant; * Represents p <0.01, the difference is highly significant; indicating p <0.001, the difference was very significant; statistical analysis showed that Manacastine treatment did not affect the colorectal length of mice (p > 0.05), but could alleviate colorectal damage in mice caused by chemotherapy-directed cisplatin administration (p < 0.001).
Manacastine reduced cisplatin results of mice intestinal function and structural injury assays are shown in FIG. 2.
Figure 2 Manacastine can alleviate cisplatin-induced small intestine villus shortening and crypt loss. The Manniche length and number of the Mannastine group were unchanged compared to the control group (Ctrl), the small intestine villus number and small intestine crypt number of the Cisplatin group (Cisplatin) were reduced compared to the control group (Ctrl), and the treatment group receiving Cisplatin/Mannastine (Cisplatin+Manostatin) was significantly restored to normal compared to the Cisplatin group mice (Cisplatin).
Statistical analysis was performed on the obtained data using Graphpad prism 9 statistical software, and experimental data were expressed as mean ± standard error. The difference between the control group and the experimental group is analyzed by adopting a two-factor analysis of variance and Fisher test, ns represents p >0.05, and the difference has no statistical significance. * P <0.05, the difference is significant; * Represents p <0.01, the difference is highly significant; indicating p <0.001, the difference was very significant; statistical analysis showed that mannatide treatment did not affect the mouse intestinal villus and crypt (p > 0.05), but could alleviate the damage to the mouse intestinal villus and crypt caused by chemotherapy-directed cisplatin administration (p < 0.001).
Results of the release of cisplatin-induced nephrotoxicity in mice by Manacastine are shown in FIG. 3.
Fig. 3a, b. Manacastine can reduce cisplatin-induced kidney injury in mice. The kidney tissue of the mannatide group (Ctrl) was unchanged compared to the control group (Ctrl), whereas the Cisplatin group (cispratin) showed a significant increase in the positive area of kidney-stained PAS compared to the control group (Ctrl) mice, and the evaluation of tubular injury also showed significant kidney injury, and the combination treatment of Cisplatin/mannatide group (cispratin+manostatin) significantly restored the normal state compared to the kidney tissue of the Cisplatin (cispratin) group, and the evaluation of kidney injury also significantly indicated an improvement in deterioration. The Mannich statin treatment disclosed by the invention does not influence the normal physiological structure and function of the kidney of the mouse, but can relieve the damage of the kidney tissue of the mouse caused by chemotherapy-guided administration of cisplatin.
Statistical analysis was performed on the obtained data using Graphpad prism 9 statistical software, and experimental data were expressed as mean ± standard error. The difference between the control group and the experimental group is analyzed by adopting a two-factor analysis of variance and Fisher test, ns represents p >0.05, and the difference has no statistical significance. * P <0.05, the difference is significant; * Represents p <0.01, the difference is highly significant; indicating p <0.001, the difference was very significant; statistical analysis showed that mannatine treatment did not affect the kidney of mice (p > 0.05), but could alleviate tissue damage in the kidney of mice caused by the chemotherapeutic drug cisplatin (p < 0.001).
Fig. 3c, d, e. Mannatide can reduce cisplatin-induced impairment of renal function. The levels of Blood Urea Nitrogen (BUN), creatinine (Creatinine) and Cystatin C (Cystatin C) were not significantly changed in the mannastine group (Manostatin) compared to the control group (Ctrl) and the levels of Blood Urea Nitrogen (BUN), creatinine (Creatinine) and Cystatin C (Cystatin C) were significantly increased in the Cisplatin/mannastine co-treated group (cispratin + Manostatin) compared to the Cisplatin group (cispratin) and the levels of Blood Urea Nitrogen (BUN), creatinine (Creatinine) and Cystatin C (Cystatin C) were significantly reduced in the Cisplatin group (cispratin) mice. The Mannich treatment disclosed by the invention does not affect the kidney of the mouse, but can reduce the damage of the kidney function of the mouse caused by cisplatin as a chemotherapeutic drug.
Statistical analysis was performed on the obtained data using Graphpad prism 9 statistical software, and experimental data were expressed as mean ± standard error. The difference between the control group and the experimental group is analyzed by adopting a two-factor analysis of variance and Fisher test, ns represents p >0.05, and the difference has no statistical significance. * P <0.05, the difference is significant; * Represents p <0.01, the difference is highly significant; indicating p <0.001, the difference was very significant; statistical analysis showed that mannatide treatment did not affect kidney function in mice (p > 0.05), but reduced kidney function impairment in mice caused by the chemotherapeutic drug cisplatin (p < 0.001).
Example 2
Influence of Manacastine on the effect of chemotherapy-guided cisplatin on inhibiting the occurrence and development of primary liver cancer.
The experimental method is as follows:
1. treatment of mice:
(1) Establishing a primary liver cancer model of a mouse: male mice were intraperitoneally administered diethylnitrosamine (DEN in PBS) at a dose of 25mg/kg 14 days postnatally, and carbon tetrachloride (CCl 4 in corn oil) at a dose of 0.5mL/kg weekly for about 3-4 months after one week.
(2) Mice induced by successful liver cancer are randomly divided into a control group, a Mannostin group, a cisplatin group and a cisplatin/Mannostin combined treatment group, and feeding conditions are a 12h illumination period and a 12h dark period.
(3) Mice in the control group (Ctrl) were gavaged daily with 800 μl of Phosphate Buffer (PBS), manostatin group (manostatin) and Cisplatin/manostatin combination treatment group (cisplatin+manostatin) mice were gavaged with 800 μl of manostatin (manostatin, in solution form) using gavage, once daily for a pretreatment time of one day, and post-treatment for 4 weeks.
(4) Cisplatin (cispratin, dissolved in sterile saline) and Cisplatin/Mannostin co-treatment group (cispratin+Manostatin) mice were subjected to Cisplatin (cispratin, dissolved in sterile saline) treatment by intraperitoneal injection at a dose of 17mg/kg once a week for 4 weeks.
2. Primary liver cancer tumor number:
after treatment of mice with cisplatin formulation, mice were sacrificed by carbon dioxide asphyxiation, and after dissection, the mice were removed from the liver and tumor numbers were recorded.
Manacastine does not affect the inhibition of primary liver cancer by cisplatin, a chemotherapeutic drug, as shown in FIG. 4.
Fig. 4. The volume and number of liver tumors in the Cisplatin group (cispratin) compared to the control group (Ctrl) were significantly reduced/decreased, whereas the volume and number of liver tumors in the Cisplatin/mannastine co-treated group (cispratin + manostatin) compared to the Cisplatin group (cispratin) mice were unchanged. The invention shows that the Manacastine does not influence the inhibition effect of the chemotherapeutic drug cisplatin on the primary liver cancer.
Statistical analysis was performed on the obtained data using Graphpad prism 9 statistical software, and experimental data were expressed as mean ± standard error. The difference between the control group and the experimental group is analyzed by adopting a two-factor analysis of variance and Fisher test, ns represents p >0.05, and the difference has no statistical significance. * P <0.05, the difference is significant; * Represents p <0.01, the difference is highly significant; indicating p <0.001, the difference was very significant; statistical analysis shows that the Manacastine does not influence the inhibition effect (p > 0.05) of the chemotherapeutic drug cisplatin on the primary liver cancer.

Claims (6)

1. The application of the mannatide in medicines, kits, pharmaceutical compositions or health care products for relieving toxic and side effects caused by Cisplatin (Cisplatin), wherein the toxic and side effects are multi-organ injuries, the main components of the mannatide (Manostin) are mannose, sodium sahexanoate and sucralose, the mannose is the main medicine for acting in a drug effect, and the sodium sahexanoate and sucrose only act in an auxiliary effect.
2. The use according to claim 1, wherein the organ injury is a toxic side effect of cisplatin on the intestinal, renal and other organs.
3. Use according to claim 1, characterized in that the medicament is made in the form of: oral liquid, injection, tablet, and capsule.
4. The use according to claim 1, characterized in that the kit comprises (i) an agent comprising mannatide and (ii) an agent comprising cisplatin.
5. Use of mannatide in the manufacture of a medicament for reducing damage to an organ of the digestive tract caused by cisplatin during chemotherapy.
6. Use of mannatide in the manufacture of a medicament for reducing cisplatin-induced toxic renal injury upon chemotherapy.
CN202310101885.3A 2023-02-08 2023-02-08 Application of Manacastine in relieving multi-organ damage caused by chemotherapeutic drug cisplatin Withdrawn CN116077512A (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023217179A1 (en) * 2022-05-11 2023-11-16 厦门大学 Use of mannose in inhibiting pyroptosis or relieving toxic and side effects of chemotherapy drug

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023217179A1 (en) * 2022-05-11 2023-11-16 厦门大学 Use of mannose in inhibiting pyroptosis or relieving toxic and side effects of chemotherapy drug

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