CN116036102A - Use of Manacastine to reduce intestinal damage caused by XELOX combination treatment regimen - Google Patents
Use of Manacastine to reduce intestinal damage caused by XELOX combination treatment regimen Download PDFInfo
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- CN116036102A CN116036102A CN202310074395.9A CN202310074395A CN116036102A CN 116036102 A CN116036102 A CN 116036102A CN 202310074395 A CN202310074395 A CN 202310074395A CN 116036102 A CN116036102 A CN 116036102A
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- xelox
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Abstract
In the treatment of tumors with XELOX combination therapy regimens, there are often associated with extremely severe side effects, including colorectal and small intestine damage, manacastine is able to inhibit severe toxicological damage to the intestine by the XELOX combination therapy regimen by acting on the intestinal epithelial cells. The modified drug Mannastine can increase residence time in intestinal tract, increase the absorption capacity of intestinal cells, and make it better function when used together with XELOX combination therapy. The Manacastine can be applied to preparing medicines, pharmaceutical compositions or health care products for reducing the toxicological damage of the XELOX combined treatment scheme, can reduce the physical and mental damage of patients caused by chemotherapy, increases the treatment probability of tumors, does not influence the treatment effect of the XELOX combined treatment scheme on the tumors, and brings new hopes for the treatment of cancer patients.
Description
Technical Field
The invention relates to the field of medical science and technology, in particular to application of Mannich in reducing intestinal tract injury caused by an XELOX combined treatment scheme.
Background
Cancer is a serious problem in the world at present, with the continuous change of natural environment, the life style and diet mode of people are changed over the world, the incidence of cancer is increased year by year, and the cancer tends to be of young people. Cancer is an extremely serious disease, so far, the generation and development rules of tumors can not be completely mastered by human beings, the research on tumor treatment methods is also greatly limited, and the existing tumor treatment methods are often accompanied by extremely serious side effects. Chemotherapy (chemotherapy for short) is a very common clinical means for treating tumors, and the principle is that a chemical agent is used for killing tumor cells, but the treatment mode of chemotherapy is systemic, and the chemical agent kills a large number of cells in normal tissues of a human body while killing the tumor cells, so that extremely serious side effects are brought, wherein the side effects comprise most common hair loss, oral ulcer, nausea, vomiting, constipation, diarrhea and the like, and many tumor patients cannot finish the whole-course chemotherapy process because of being unable to bear the side effects caused by the chemotherapy drugs, so that tumors repeatedly occur or even transfer and spread. The invention of a mode capable of reducing the toxic and side effects of chemotherapy is particularly important at present.
The main components of the Mannastine (Manostatin) are mannose, sodium saxoate and sucralose, wherein the mannose is the main component, and Sha Jisuan sodium and sucralose can form a wrapping group with mannose in the intestinal tract, the group can be attached to the inner wall of the intestinal tract, the discharge of the active ingredients from the body is delayed, and meanwhile, the group can promote the intestinal epithelial cells to play an absorption function, so that the absorption capacity of the active ingredients of the medicine is improved. The components of the Manacastine can not produce toxic and side effects on human bodies.
Disclosure of Invention
The present invention aims to provide a novel use of Manacastine for reducing intestinal damage caused by a combination therapy regimen of XELOX. The main components of Mannostin (Manostatin) are mannose, sodium saboate and sucralose, wherein mannose is used as a main medicine, the rest is auxiliary medicine, and mannose is a monosaccharide substance.
The invention provides an application of Manacastine in medicines, pharmaceutical compositions or health care products for relieving toxicological damage caused by XELOX (Oxaliplatin) and Capecitabine (Capecitabine) combined treatment scheme, wherein the toxicological damage is organ damage.
The XELOX combination therapy regimen causes toxicologically damaging organs including the colorectal, small intestine.
The pharmaceutical composition comprises (i) a composition comprising a mannatine component and (ii) a combination therapy regimen comprising XELOX.
The present invention provides the use of Manacastine in the manufacture of a medicament for reducing colorectal toxicological damage caused by a combination therapy regimen of XELOX.
The invention provides the use of Manacastine in the manufacture of a medicament for reducing small intestine toxicological damage caused by an XELOX combination therapy regimen.
The medicament is prepared into the following forms: oral liquid, injection, tablet, and capsule.
The beneficial effects of the invention include:
in the treatment of tumors with XELOX combination therapy regimens, there are often associated with extremely severe side effects, including colorectal and small intestine damage, manacastine is able to inhibit severe toxicological damage to the intestine by the XELOX combination therapy regimen by acting on the intestinal epithelial cells. The modified drug Mannastine can increase residence time in intestinal tract, increase the absorption capacity of intestinal cells, and make it better function when used together with XELOX combination therapy. The Manacastine can be applied to preparing medicines, pharmaceutical compositions or health care products for reducing the toxicological damage of the XELOX combined treatment scheme, can reduce the physical and mental damage of patients caused by chemotherapy, increases the treatment probability of tumors, does not influence the treatment effect of the XELOX combined treatment scheme on the tumors, and brings new hopes for the treatment of cancer patients.
Drawings
FIG. 1 shows severe physiological structural toxicological damage to the small intestine following treatment with the XELOX combination regimen, which is seen as loss of the crypt of the small intestine and shortening of the villus length and reduction of the number of villi. Mannastine (Manostatin) is capable of inhibiting toxicological damage to the physiological structures of the small intestine caused by administration of an XELOX combination treatment regimen.
FIG. 2 is a graph showing the severe colorectal damage caused by the XELOX combination treatment regimen in mice, and showing that colorectal significantly shortens after treatment, mannostin (Manostatin) is capable of inhibiting colorectal toxicological damage caused by the XELOX combination treatment regimen.
Fig. 3 shows that XELOX combined treatment regimen treatment of mice in a chemically induced primary liver cancer mouse model can effectively inhibit liver tumor growth and reduce tumor number. The concurrent administration of Mannostin (Mannostin) with the XELOX regimen does not affect the efficacy of the combination therapy in treating liver tumors.
Fig. 4 shows that the XELOX combination treatment regimen can effectively kill liver tumor cells in mice. The concurrent administration of Mannostin (Mannostin) with the XELOX regimen did not affect its killing effect.
Detailed Description
In one embodiment, the invention provides a Mannostin (Manostatin) which comprises mannose, sodium sabafoate and sucralose as main components, wherein the mannose is used as a main medicine, and the rest is used as an auxiliary medicine.
Optionally, the mannatine (manostan) alleviates the toxic side effects of mouse small intestine and colorectal caused by XELOX combination treatment regimen during chemotherapy.
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 of the XELOX combination therapy regimen during chemotherapy without affecting the efficacy of the chemotherapeutic.
In one embodiment, the invention provides a pharmaceutical composition comprising (i) a composition comprising a mannatide component, (ii) a combination therapy regimen comprising XELOX.
In one embodiment, the invention provides a method of reducing the adverse effects of the intestinal tract caused by an XELOX combination therapy regimen, the method comprising administering to a subject an effective amount of a medicament of the invention, which may be administered simultaneously or sequentially comprising (i) a component comprising mannatide, (ii) a combination therapy regimen comprising XELOX, the intestinal tract comprising colorectal and small intestine.
In one embodiment, the invention provides a method of reducing the toxic side effects of an XELOX combination therapy regimen without affecting the efficacy of the therapy, the method comprising administering to a subject an effective amount of a medicament of the invention, which may be administered simultaneously or sequentially comprising (i) a component comprising manacastine and (ii) a combination therapy regimen comprising XELOX.
In one embodiment, the invention provides the use of Mannich in the manufacture of a medicament for alleviating colorectal toxicological damage caused by an XELOX combination therapy regimen, the medicament alleviating colorectal toxicological damage caused by an XELOX combination therapy regimen.
In one embodiment, the invention provides the use of Mannich in the manufacture of a medicament for alleviating small intestine toxicological damage caused by an XELOX combination therapy regimen, the medicament being capable of alleviating small intestine toxicological damage caused by an XELOX combination therapy regimen.
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 experimental procedures of the present invention are described below with reference to the accompanying drawings and specific examples, and will be understood by those skilled in the art. The following examples are only illustrative of the present invention and should not be construed as limiting the scope of the invention. The specific techniques or conditions are not identified in the examples and are performed according to techniques or conditions described in the literature in this field or according to the product specifications. The reagents or apparatus used are all conventional products commercially available and are not identified herein as production information.
Example 1
Effect of mannatide on mice intestinal toxicological lesions from XELOX combination treatment regimens.
The experimental method is as follows:
1. drug combination treatment mice
(1) Grouping: the mice used were SPF-grade C57BL/6 mice, aged 8 weeks, and were divided into four groups, namely a control group (Ctrl), a Mannostin group (Manostatin), an XELOX group and a Mannostin/XELOX combination treatment group (XELOX+Manostatin), and were fed with high-pressure sterile water, and the mice were kept under a strict lighting environment for 12 hours and overnight for 12 hours.
(2) The control group (Ctrl) mice were perfused with 800 μl of Phosphate Buffered Saline (PBS) per day, while the manostatin group (manostatin) mice were perfused with 800 μl of manostatin (manostatin, in solution form) per day, in the same manner as the manostatin group (manostatin) in the combination manostatin/XELOX treatment group (xelox+manostatin). The frequency was once daily and the treatment time was 5 days.
(3) After one day of Mannastine treatment, XELOX (Oxaliptin+Capecitabine, dissolved in physiological saline) treatment was performed on the XELOX group and the Mannastine/Oxaliplatin combination treatment group (XELOX+Manostatin) by intraperitoneal injection at a dose of Oxaliplatin (Oxaliptin) of 16mg/Kg and Capecitabine (Capecitabine) of 100mg/Kg, and the treatment was performed once.
2. Mouse colorectal isolation and measurement
Four groups of mice were sacrificed by carbon dioxide asphyxiation after 4 days of treatment with the XELOX combination treatment regimen, colorectal was dissected out of the four groups of mice, surface-adhered tissues were removed, bent portions thereof were straightened, and then length measurement was performed.
3. Mouse small intestine histochemical staining
The small intestine of the mice was removed from the abdominal cavity in time for histochemical staining analysis:
(1) The adipose tissue and the lymphatic tissue adhered on the surface of the small intestine are removed, the inside of the small intestine is washed, and 10cm sections of intestine are taken to be vertically sheared and rolled into a Swiss roll shape.
(2) Fixing the shaped intestinal segment in a fixing solution containing paraformaldehyde for 12-24 hours, dehydrating tissues after fixing, and embedding paraffin.
(3) The embedded intestinal sections were sectioned with a paraffin microtome to a thickness of 4. Mu.m.
(4) The sections of intestine were dewaxed and rehydrated.
(5) Hematoxylin-eosin staining is carried out, and after staining, the glass is dried and then subjected to lens sealing microscopy.
Results of the small intestine toxicological injury test resulting from the combination therapy regimen of Manacastine reduction XELOX are shown in FIG. 1
Figure 1 xelox combination treatment regimen induced small intestine toxicological damage can be significantly suppressed by mannatide treatment. Compared with the control group (Ctrl), the small intestine physiological structure injury of the mice in the XELOX group is obvious, wherein the small intestine physiological structure injury of the mice in the XELOX group is obviously well inhibited compared with the small intestine physiological structure injury of the mice in the XELOX group, and the small intestine physiological structure of the mice in the Mannastine/XELOX combined treatment group (XELOX+Manostatin) is not obviously changed. In conclusion, the treatment with the drug Mannastine according to the invention significantly reduces the toxic damage to the small intestine caused by the XELOX combination therapy, without affecting the normal physiological structure of the small intestine itself.
Analysis by Graphpad prism 9 statistical software, the obtained data are expressed as mean ± standard error; the control and experimental group variance analysis used a two-factor variance analysis and a fisher test, "ns" (p > 0.05) demonstrated no significant variance in the selected group, "+ (p < 0.05) demonstrated significant variance in the selected group," + (p < 0.01) demonstrated high significant variance in the selected group, "+ (p < 0.001) demonstrated extremely significant variance in the selected group. Analysis by software demonstrated that Manacastine did not affect normal physiological structure of the mouse small intestine (p > 0.05), but could reduce small intestine toxicological damage caused by XELOX combination treatment regimen (p < 0.001).
Results of colorectal toxicological damage assays resulting from the combination treatment regimen of Manacastine reduction XELOX are shown in FIG. 2
Figure 2 shows that colorectal toxicological damage caused by xelox combination treatment regimen can be significantly suppressed by mannatide treatment. There was no significant change in the colorectal length of the mice in the Manlastin group (Manlastin) compared to the control group (Ctrl), while the colorectal length of the mice in the XELOX group was significantly shortened, while the reduction in colorectal length of the mice in the Manlastin/XELOX combination treatment group (XELOX+Manlastin) was significantly inhibited compared to the XELOX group. In summary, the drug Mannich treatment of the present invention significantly reduces colorectal toxicological damage caused by the XELOX combination regimen, but Mannich itself does not affect the normal physiological state of the mouse colorectal.
Analysis by Graphpad prism 9 statistical software, the obtained data are expressed as mean ± standard error; the control and experimental group variance analysis used a two-factor variance analysis and a fisher test, "ns" (p > 0.05) demonstrated no significant variance in the selected group, "+ (p < 0.05) demonstrated significant variance in the selected group," + (p < 0.01) demonstrated high significant variance in the selected group, "+ (p < 0.001) demonstrated extremely significant variance in the selected group. Analysis by software demonstrated that Mannheistatin itself did not affect mouse colorectal (p > 0.05), but reduced colorectal length (p < 0.001) resulting from XELOX combination treatment regimen.
Example 2
Effect of mannatide on XELOX combination treatment regimen for the treatment of primary liver cancer.
The experimental method is as follows:
1. treatment of mice:
(1) Male mice born for 14 days were given an intraperitoneal injection of diethylnitrosamine (DEN in PBS) at a dose of 25mg DEN per kg of mice, followed by a weekly intraperitoneal injection of carbon tetrachloride (CCl4 in a liposoluble solvent) at a dose of 0.5mL CCl4 per kg of mice for 3-4 months until primary liver cancer was induced.
(2) The induced mice were grouped as in example 1 and the breeding environment was the same as in example 1.
(3) Mice were perfused with 800 μl of Phosphate Buffered Saline (PBS) per day in the gastric control group (Ctrl), while 800 μl of mannatide (manostatin, in solution form) per day was used in the gastric manostatin group (manostatin) mice and the combination mannatide/XELOX treatment group (xelox+manostatin). The frequency was once per day and the treatment time was 31 days.
(4) Mice in the XELOX group and the mannastin/XELOX combination treatment group (xelox+manostan) were subjected to the XELOX combination treatment one day after pretreatment, with a treatment frequency of 7 days.
2. Mouse liver tumor number count
After the drug treatment is completed, the mice are sacrificed by a carbon dioxide asphyxiation method, and the complete liver tissues of the four groups of mice are dissected and taken out for counting and counting the number of liver tumors.
3. Histochemical staining analysis of mouse liver tumor
(1) And separating the counted mouse liver tumors from the livers, and placing the mouse liver tumors into paraformaldehyde fixing solution for fixing.
(2) Tumor tissue is dehydrated and embedded, and paraffin sections are cut.
(3) The tissue sections were deparaffinized and rehydrated and stained according to TUNEL staining kit instructions.
(4) Slicing, airing, and performing microscopic examination on the sealing piece.
The efficacy of the XELOX combination treatment regimen in treating primary liver tumors was not affected by Mannich as shown in FIG. 3
Figure 3 Mannheim does not affect the effect of the XELOX combination treatment regimen on liver tumors. The number of tumors in the mice in the Mannastine group did not significantly change compared to the control group, while the number of liver tumors in the mice in the XELOX group was significantly reduced, while the number of liver tumors in the Mannastine/XELOX combination treatment group (XELOX+Manostatin) did not significantly change compared to the XELOX group. In conclusion, the treatment of the medicine Mannastine disclosed by the invention does not influence the treatment effect of the XELOX combined treatment scheme on the primary liver cancer of mice.
Analysis by Graphpad prism 9 statistical software, the obtained data are expressed as mean ± standard error; the control and experimental group variance analysis used a two-factor variance analysis and a fisher test, "ns" (p > 0.05) demonstrated no significant variance in the selected group, "+ (p < 0.05) demonstrated significant variance in the selected group," + (p < 0.01) demonstrated high significant variance in the selected group, "+ (p < 0.001) demonstrated extremely significant variance in the selected group. Analysis by software demonstrated that Manacastine treatment did not affect the therapeutic effect of the XELOX combination treatment regimen (p > 0.05).
The ability of the XELOX combination treatment regimen to kill liver tumor cells was not affected by Mannich as shown in FIG. 4
Figure 4. Manaastatin has no effect on oxaliplatin killing tumor cells. Compared with the control group, the ratio of the apoptosis cells of the mouse tumor in the Mannich group (TUNEL positive rate) is not changed obviously, while the ratio of the apoptosis cells of the liver tumor in the mouse in the XELOX group is increased obviously, and compared with the XELOX group, the ratio of the apoptosis cells of the liver tumor in the combined Mannich/XELOX group is not different obviously. In conclusion, the Mannastine treatment of the medicine disclosed by the invention does not influence the growth of primary liver cancer, but does not influence the killing effect of the XELOX combined treatment scheme on the primary liver cancer tumor cells of mice.
Analysis by Graphpad prism 9 statistical software, the obtained data are expressed as mean ± standard error; the control and experimental group variance analysis used a two-factor variance analysis and a fisher test, "ns" (p > 0.05) demonstrated no significant variance in the selected group, "+ (p < 0.05) demonstrated significant variance in the selected group," + (p < 0.01) demonstrated high significant variance in the selected group, "+ (p < 0.001) demonstrated extremely significant variance in the selected group. Analysis by software demonstrated that Mannich treatment did not affect the killing ability of the XELOX combination treatment regimen against primary liver cancer tumor cells (p > 0.05).
Claims (6)
1. Use of mannatide in a medicament, pharmaceutical composition or health care product for alleviating toxicological damage caused by XELOX (Oxaliplatin) and Capecitabine (Capecitabine) combination treatment regimen, wherein the toxicological damage is organ damage, and the main components of mannatide (manostatin) are mannose, sodium saxoate and sucralose, wherein mannose is the main drug, and the balance is auxiliary drug.
2. The use according to claim 1, wherein the organ in which the XELOX combination therapy regimen causes toxicologically-damaged is the colorectal, small intestine.
3. Use according to claim 1, characterized in that the medicament is made in the form of a medicament of the following form: oral liquid, injection, tablet, and capsule.
4. The use according to claim 1, wherein the pharmaceutical composition comprises (i) a mannastatin-containing ingredient and (ii) a XELOX-containing combination therapy regimen.
5. Use of mannatide in the manufacture of a medicament for reducing colorectal toxicological damage caused by XELOX combination therapy regimens during chemotherapy.
6. Use of mannatide in the manufacture of a medicament for reducing small intestine toxicological damage caused by XELOX combination therapy regimens during chemotherapy.
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