CN110169968A - Rapamycin prevents and treats the application in radiation-induced injury of small intestine drug in preparation - Google Patents
Rapamycin prevents and treats the application in radiation-induced injury of small intestine drug in preparation Download PDFInfo
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- CN110169968A CN110169968A CN201910525169.1A CN201910525169A CN110169968A CN 110169968 A CN110169968 A CN 110169968A CN 201910525169 A CN201910525169 A CN 201910525169A CN 110169968 A CN110169968 A CN 110169968A
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- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 238000012109 statistical procedure Methods 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 201000011549 stomach cancer Diseases 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000007939 sustained release tablet Substances 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 229940037128 systemic glucocorticoids Drugs 0.000 description 1
- 210000003684 theca cell Anatomy 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 230000001256 tonic effect Effects 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- 230000001228 trophic effect Effects 0.000 description 1
- JFALSRSLKYAFGM-UHFFFAOYSA-N uranium(0) Chemical compound [U] JFALSRSLKYAFGM-UHFFFAOYSA-N 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
- 238000001262 western blot Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
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- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
- A23L33/127—Antibiotics
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/436—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
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- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
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Abstract
The present invention provides a kind of safely and effectively macrolides compound rapamycins to prevent and treat the application in radiation-induced injury of small intestine.The results showed that rapamycin is short-term, low concentration effect has significant small intestine radiation injury protective action.No apparent toxic side effect is used in Rational Dosage, it is therefore, normal using with safety.
Description
Technical field
The invention belongs to medicinal application technical field, it is related to a kind of known macrolides compound and radiates in small intestine to damage
Hurt the application in protective agents.It in particular is rapamycin answering in the radiation-induced injury of small intestine drug of preparation prevention and treatment
With.
Background technique
The various adverse factors that body is exposed to extraneous physical chemistry and metabolism generates in vivo are such as exposed to radiation or certain
Chemical toxicant and clinic receive radiotherapy, patients undergoing chemotherapy.Small intestine is radiation sensitive tissue, and clinical abdominal cavity and pelvic cavity receive radiotherapy
Patient and accidental exposure victim, may occur in which small intestine radiation injury, show as small intestinal mucosa epithelium necrosis fall off, inflammation, crypts
Cell apoptosis & necrosis, crypts number are reduced, and the symptoms such as nausea,vomiting,diarrhea, bloody stool, electrolyte disturbance occurs in patient.Small intestine radiation
The generation of damage causes serious harm even threat to life to the life quality of patient.
It is clinically at present to use fasting water, intravenous nutrition or give glucocorticoid to control to there is small intestine radiation injury mostly
It treats, other has the compound of anti oxidative damage.There are many medicament categories, are mostly use in conjunction, individually treat when evaluation
Effect not bery determines, also has the generation of various side effects, such as glucocorticoids, there is more side effect.
Mammal rapamycin target protein (Mammalian target of rapamycin, mTOR), is a kind of ammonia
Acid/threonine kinase is adjusted by PTEN-PI3K-AKT access, can be by rapamycin inhibitory activity.MTOR downstream target proteins are main
Have p70S6K and S6RP, to experience trophic signals, adjust cell growth in proliferation, Apoptosis etc. there is adjustment effect.?
Under the adjusting of Akt signal, mTOR can inhibit Atg13 and Atg1 combination and form autophagosome, to inhibit the formation of autophagosome film, press down
Autophagy processed, correlative study show that inhibition mTOR can improve the autophagocytosis under stressed condition, provide cellular damage reparation and proliferation
Ability and substance.The generation of mTOR and inflammation related disease has correlation, and rapamycin is activated by inhibition mTOR,
The expression of cytokine profiles and Chemokines can be reduced, damage of the inflammation to histoorgan can be improved.It is glutinous to oral cavity
Studies have shown that inhibiting mTOR that can improve the oxidative stress in mucomembranous cell by ionization radiation induction, alleviation radiation lures theca cell
The mucosal cell damage led improves the occurrence and development of radioactivity oral mucosa damage.
Rapamycin is to be widely used in clinical drug, and safety and reliability is widely recognized.In last century
At the beginning of the seventies, rapamycin is by as antifungal drug, its main feature is that liver renal toxicity is low；Development rapamycin is as device within 1989
The therapeutic agent of official's graft-rejection is studied, from the effect of zoopery and clinical application in terms of, rapamycin be efficiently,
Low toxicity reliable immunosuppressor, can long-term safety use, become the postoperative standard care drug of Organ Transplantation Patients, can
Effectively improve transplant operation success rate and postoperative patient survival rate.Short Term Clinical experiment discovery rapamycin is to Alzheimer
Disease has therapeutic effect, is furthermore also carrying out extensively to the clinical research of malignant tumor patients being treated with radiotherapy enhanced sensitivity.But related rapamycin pair
Ionization radiation induction injury of small intestine has the research of protective action, has no document report.
Summary of the invention
The technical problem to be solved by the present invention is to find the drug that can prevent and treat small intestine radiation injury, radiation can be protected
The injury of small intestine drug of factor induction.
To achieve the above object, the invention discloses following technology contents:
The first purpose of the invention is to provide rapamycins to prevent and treat the application in radiation-induced injury of small intestine drug in preparation.
A second object of the present invention is to provide rapamycins to prevent and treat in radiation-induced injury of small intestine drug in preparation
Using；Drug therein is rapamycin or rapamycin and other nutriments, the drug for promoting crypts of small intestine cell Proliferation
Or antiradiation drug shares.
Injury of small intestine of the present invention includes intestinal villi damage, crypts of small intestine cellular damage, mucous membrane of small intestine shielding function
It can decline.
Radiation-induced injury of small intestine of the present invention, including receiving the tumor patient of radiotherapy, the work of radioactive exposure
Make the personnel of personnel, the exposure of accidental exposure isotope.
Drug of the present invention includes therapeutic agent, prophylactic agent or the health food of clinical various dosage forms.
Drug of the present invention is tablet, capsule, granule, pill, pre- emulsion, microemulsion, suspension, syrup
Agent, enteric coated preparations or injection.
Rapamycin of the present invention is purchased from Sigma Co., USA.
The tumor patient of the present invention for receiving radiotherapy such as receives the carcinoma of the rectum, gastric cancer, kidney, bile duct of radiotherapy
Cancer, cancer of pancreas, carcinoma of endometrium, cervical cancer patient；The staff of radioactive exposure of the present invention, such as hospital's X-ray, CT
Staff, the cutter of uranium ore；The personnel of accidental exposure isotope exposure of the present invention, such as former Soviet Union Qie Ernuo
Baily nuclear power plant accident and the favorite outer personnel radiated of Fukushima, Japan nuclear power plant accident.
The content that the present invention is studied includes the following aspects:
1. rapamycin has protective effect to small intestinal cell damage caused by radiating.
2. rapamycin does not have apparent cytotoxicity to small intestinal cell.
3. rapamycin has protective effect to caused injury of small intestine is radiated.
Rapamycin disclosed by the invention is the advantages of preparation prevents and treats the application in radiation-induced injury of small intestine drug:
1, rapamycin is clinical commonly used drug, and securely and reliably, preparation is easy.
2, rapamycin is short-term, low concentration acts on has significant small intestine radiation injury protective action.
3, rapamycin uses no apparent toxic side effect in Rational Dosage.
The present invention uses standard and conventional technique, by acceptable solid or liquid on rapamycin or multiple and galenic pharmacy
Body carrier combines, and is allowed to arbitrarily be prepared into various preparations in conjunction with adjuvant acceptable on galenic pharmacy and excipient.
These dosage forms include oral solution, injection, suspension, pill, tablet, capsule, powder, granule or pill.It is described
Pharmaceutically acceptable solid or liquid-carrier, including diluent conventional in preparation, filler (such as lactose, poly- second two
Alcohol), adhesive (starch, microcrystalline cellulose), disintegrating agent (such as carboxymethyl cellulose, low substituted hydroxypropyl cellulose), lubrication
Agent (such as talcum powder, magnesium stearate), wetting agent (such as propylene glycol, ethyl alcohol), stabilizer (EDTA-2Na, sodium thiosulfate, burnt sulfurous
Sour sodium, sodium sulfite, ethanol amine, sodium bicarbonate, niacinamide) etc..Wherein solid dosage forms include tablet, discrete particles, capsule,
Sustained release tablets, sustained release pellet etc..Solid carrier can be at least one substance, can serve as diluent, flavouring agent, solubilising
Agent, lubricant, suspending agent, adhesive, disintegrating agent and coating agent.Inert solid carrier includes magnesium phosphate, magnesium stearate, smoothers
Sugar, lactose, pectin, propylene glycol, dried starch, Tween-80, dextrin, starch, gelatin, cellulose substances such as methyl are fine
Tie up element, microcrystalline cellulose, low melt point paraffin, polyethylene glycol, mannitol, cocoa butter etc..Liquid dosage form includes solvent, suspension example
Such as injection, pulvis.
The amount of pharmaceutical preparation of the present invention can specifically be answered according to the case where state of an illness, diagnosis of patient
With the amount or concentration of (active component of active constituent) used are adjusted in a wider range, in general, active constituent has
The amount range for imitating position is 0.5%~90%(weight of composition).Another preferred range is 0.5%-70%.
Detailed description of the invention
Fig. 1 is the chemical structural formula of rapamycin；
Fig. 2 is influence of the rapamycin to Irradiated Mice survival rate.
Specific embodiment
The present invention is described below by specific embodiment.Unless stated otherwise, technological means used in the present invention
It is method known in those skilled in the art.In addition, embodiment is interpreted as illustrative, it is not intended to limit the present invention
Range, the spirit and scope of the invention are limited only by the claims that follow.To those skilled in the art, without departing substantially from this
Under the premise of invention spirit and scope, to the various changes or change of material component and dosage progress in these embodiments
It belongs to the scope of protection of the present invention.The raw materials used in the present invention and reagent are commercially available.For purposes of simplicity and clarity, hereafter just
When the description that well-known technique is omitted, to avoid unnecessary details affecting the description of the technical solution.Below in conjunction with
Example is described further to animal model constructing method of the present invention and as model progress mechanism.
Embodiment 1
(1) main agents and experimental animal
Rapamycin buying is configured to the mother liquor packing storage of 0.1M after Sigma Co., USA, addition DMSO, and -20 DEG C are protected from light
It saves, when experiment is diluted to aimed concn.Ki67 antibody (article No. ab66155), Claudin-1 antibody (article No. ab15098),
ZO-1 antibody (article No. ab96587), cleaved caspase-3(article No. ab2302) it purchases in abcam company, the U.S..Bush
Element, Yihong, immunohistochemical staining kit (secondary antibody, DAB etc.) are mountain gold bridge product in Beijing.Cell counting
Kit-8 kit is purchased from Japanese colleague company.It orders for (SPF grades) of C57BL/6 male mice and is studied in Chinese food drug assay
Institute, quality certification number [SCXK (capital) 2014-0013].
Experimental animal feeding is in Tianjin Union Medicine Centre animal experimental center cleaning animal house, and 41 cages, drinking water is unlimited,
Padding is regularly replaced, mouse cage is cleaned.Mucous membrane of small intestine IEC-6 cell line is bought in Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences
Resource center's (resource number: 3111C0001CCC000110).
(2) cytologic experiment
IEC-6 cell culture condition, condition of culture: 37 DEG C, 5% CO2, DMEM-H culture medium (Dulbecco ' s Modified
Eagle ' s Medium+5%FBS+0.01mg/ml Insulin).Logarithmic growth phase IEC-6 cell, pancreatin digestion system
Cell suspensions, cell count are inoculated in 96 orifice plates after equal proportion diluting cells suspension, and every hole is inoculated with 2500 cells, if
5 multiple holes are set, in 5% CO2, cultivate in 37 DEG C of cell incubator, be added in various concentration processing 100 μ L of drug and incubate by design
It educates 30min to be followed by being irradiated by various dose high energy x-ray, linear accelerator is the U.S. Varian Clinic 21ES(Varian
Company), dosage rate 0.76Gy/min.37oC incubator culture 48h is placed in after irradiation.Culture plate is taken out, discards culture solution, addition contains
Absorbance of the microplate reader measurement in 450 nm after culture solution 100 the μ L, 37 DEG C of 2 h of incubation of 10% CCK-8 solution.
(3) animal packet and processing
Mouse radiation lethal effect experiment takes 8 week old C57BL/6 male mices, and weight 20-22g is square at random by weight by mouse
Method is divided into control group, simple administration group, simple irradiation group and irradiation administration group, and every group 15, control group, simple administration group are given
Vacation irradiation, simple irradiation group and irradiation administration group mouse web portion receive 9Gy irradiation, and linear accelerator is Varian Clinic
21ES(VARIAN Oncology Systems), dosage rate 0.76Gy/min.Simple administration group and irradiation administration group irradiate first 3 days to after irradiating
Same amount carrier is given in daily intraperitoneal administration rapamycin (1mg/kg) on the 3.5th, control and the daily abdominal cavity of simple irradiation group.Survival assay
In every group of 15 mouse, exposure dose 11Gy, after irradiation observe 30 d survival rate of each group mouse；Injury of small intestine Protection
In, every group of 8 mouse, 3.5 d sacrifice mouse after irradiation, harvest small intestine's row subsequent experimental.
(4) histologic examination
Part small intestine is taken to make paraffin mass, cross section cuts 5 μm of slices, row H&E dyeing.With Nikon D90 microscope row shape
State observation, observation index include that intestinal villi length, Surviving crypts quantity, every survival crypts of small intestine cell quantity, small intestine are hidden
Nest apoptotic cell.Every small intestine cross section counts 10 intestinal villi length of longest, intestinal villi length Image-Pro Plus
The analysis of 5.1 softwares；Complete crypts standard: section is at crypts center, it is seen that clear, complete crypts chamber, crypts bottom have 4~6
A secretory cell, secretory cell to every side at least 10 Crypt Cells in crypts top.
(5) immunohistochemical assay
Small intestine's paraffin mass is taken, cross section cuts 4 μm of slices.The conventional dewaxing of slice, inactivates Endogenous peroxidase, repairs anti-
Original, with Ki67 primary antibody (1:2000), Cleaved Caspase-3 primary antibody (1:400) is incubated for, the dyeing of PV6001 kit, Soviet Union
Lignin is redyed.The micro- sem observation staining conditions of Olympus BX51 are used after mounting, every mouse at least counts 50 crypts of small intestine,
It counts Cleaved Caspase-3 positive cell and analyzes crypts of small intestine Apoptosis, count crypts of small intestine cell Ki67 and express feelings
Condition analyzes crypts of small intestine cell proliferative conditions.
(6) western blot detects GAP-associated protein GAP
Small intestine's total protein is extracted after taking fresh 100 mg of small intestine to be homogenized.Protein concentration is measured using BCA method, in equivalent
Sample is separated by electrophoresis with 10% and 15% PAGE gel respectively, on albumen transferring film to Kynoar (PVDF) film, 5% degreasing
Optium concentration primary antibody (Claudin-1,1:200 are chosen after milk closing；ZO-1,1:100；GAPDH, 1:1000；Beclin 1,
1:1000) 4 DEG C of overnight incubations wash after film and are incubated for 2 h with the secondary antibody (1:3000) that horseradish marks, wash ECL chemoluminescence method after film
Development, the development of Bio-rad full automatic gel imaging system is taken pictures, using 1.4 software (National of Image J
Institutes of Health company, the U.S.) to strip analysis.
(7) statistical procedures
With SPSS16.0 software package analyze data, survival assay data line Kaplan-Meier survival analysis, remainder data with
± s is indicated, significant difference between carrying out multiple groups is analyzed using Student-Newman-Keuls and is analyzed, P < 0.05 is that difference has system
Meter learns meaning.
Embodiment 2
Experimental result and discussion
(1) to small intestinal mucosa cytotoxicity
In vitro culture IEC-6 cell, adjustment cell concentration to 2 × 106/ml.The rapamycin extract culture medium of various concentration
It is prepared.It takes 100 μ L of cell suspension and various concentration to handle drug and 96 well culture plates is added, after being incubated for 18 hours, CCK-8 method
Carry out cell viability measurement.As a result, it has been found that rapamycin is lower than 10 in concentration-8Apparent cytotoxicity is not found when mol/L
Effect.It the results are shown in Table 1, table 2；
Influence of 1 rapamycin of table to small intestinal mucosa cell viability
Influence of 2 rapamycin of table to small intestinal mucosa cell viability
(2) to the protective effect of mouse small intestine mucosa cells external radiation damage
In vitro culture IEC-6 cell after the drug of various concentration is added, is incubated for 30min, is irradiated.Continue to be incubated for after irradiation
18h carries out cell viability measurement.As a result, it has been found that: the cell viability of 1Gy dosage irradiation group compared with control group decline 19.1% (p <
0.05), rapamycin has no protective action；The cell viability of 4Gy dosage irradiation group compared with control group decline 38.8% (p <
0.05), rapamycin group improves 22.5%(10-10Mol/L, p < 0.05).
Influence (OD 450nm × 1000) of 3 rapamycin of table to exposure small intestinal mucosa cell viability
Influence (%) of 4 rapamycin of table to exposure small intestinal mucosa cell viability
The experimental results showed that (table 3, table 4), small intestinal cell vigor 1,4Gy decline 19.1%, 38.8% respectively after irradiation, mention
Show that irradiation can cause small intestinal mucosa cell function vigor to decline.Compared with irradiation group, rapamycin is to by thin according to small intestinal mucosa
Born of the same parents' vigor has certain protective effect；Effective protection concentration is 10-9 -10-10Mol/L, the 1/ of the smallest cell toxicity dose
100 still have protective effect, and rapamycin is prompted to have good safety when being used for drug or health care product.
(3) influence of the rapamycin to irradiation mouse life rate
Shown in Fig. 2,14 d after irradiation, control group, simple administration group, simple irradiation group and irradiation administration group mouse survival rate difference
It is 100.0%, 100.0%, 13.3% and 46.7%；Control group, simple administration group, simple irradiation group and irradiation 30 d of administration group existence
Rate is respectively 100%, 100%, 0%(0/15) and 33.3%(5/15)；Simple irradiation group and irradiation administration group death mouse are averagely raw
Depositing number of days is respectively 9.0d and 14.0d.Simple irradiation group compared with irradiating administration group, difference it is statistically significant (χ 2 =6.338, p=0.0118), prompt rapamycin that the survival rate of abdomen high dose x-ray irradiation mouse can be improved.
(4) rapamycin is influenced to by according to mouse small intestine mucous membrane
Intestinal villi is the basic unit of Small Intestinal, the length and quantitative response Small Intestine of intestinal villi；Small intestine is hidden
Nest is the position of intestinal villi hair tonic, the proliferative capacity again of quantity and crypts inner cell quantitative response intestinal villi.We are right
Small intestine cross-sectional slices carry out H&E staining analysis.The result shows that irradiation can substantially reduce small intestine compared with simple irradiation group
The quantity and length of villus reduce the quantity of crypts of small intestine and the quantity of every crypts of small intestine inner cell, have statistical significance (P <
0.05), rapamycin intervention can be improved by according to mouse small intestine villus length and quantity, increase survival crypts of small intestine quantity and
Cell number, detailed data are shown in Table 5.The experimental result prompts rapamycin to have protective effect to by according to mouse mucosal function.
5. each group mouse small intestine mucous membrane of table and crypts of small intestine situation (n=8)
(5) rapamycin is influenced to by according to mouse small intestine pit cell apoptosis
It can detect each apoptosis period cell, the simple each crypts mean apoptotic cell of irradiation group in crypts of small intestine cell H&E dyeing
Quantity is increased than control group, and difference is statistically significant (P < 0.05).Compared with simple irradiation group, each crypts of administration group is irradiated
Mean apoptotic cell quantity decline 47.7%, difference is statistically significant (P < 0.05).Cleaved caspase-3 expression is thin
Born of the same parents' early apoptosis index, in immunohistochemical staining result, each group crypts of small intestine cells staining positive cell withers compared with H&E dyeing
It is few for dying cell.The simple each crypts mean apoptotic cell quantity of irradiation group has statistics meaning than control group apparent increase, difference
Adopted (P < 0.05).Compared with irradiation group, each crypts mean apoptotic cell quantity decline 45.8% of irradiation administration group, significant difference
(P < 0.05), is shown in Table 6.
The case where different colouring methods of table 6 show each group mouse small intestine pit cell apoptosis (every crypts apoptotic cell)
(6) rapamycin is influenced on by according to mouse small intestine pit cell expanding capacity
Normal control, simple administration group, irradiation control and each crypts of small intestine of the administration group Ki67 positive cell number that is averaged are respectively
17.35 ± 0.26,16.51 ± 0.18,5.36 ± 0.91 and 8.31 ± 1.17；Compared with Normal group, irradiation group is each hidden
Nest Ki67 positive cell number is substantially reduced 69.1%(P<0.05)；Compared with irradiation group, the irradiation each crypts of administration group is averaged Ki67
Positive cell number apparent increase 55.0%(P<0.05), prompt rapamycin that can significantly improve by the increasing according to mouse pit cell
Grow ability.
(7) rapamycin is influenced on by according to mouse small intestine barrier function
Normal bowel has perfect barrier function, prevents harmful substance and pathogen in enteron aisle from entering body, is environment in maintaining
Stable important barrier.Mucous membrane of small intestine is impaired can to destroy barrier function, lead to bacteremia, toxaemia, diarrhea etc., and it is strong to jeopardize patient
Health and life.Studies have shown that the expression of Claudin-1 and ZO-1 albumen and small intestinal barrier function are positively correlated.Simple irradiation group
Compared with control group decline 39% and 64%, difference is statistically significant (P < 0.05) for Claudin-1 and ZO-1 expression；With simple irradiation group
It compares, irradiation administration group Claudin-1 and ZO-1 expression improves 46.0% and 59.0%, and difference is statistically significant (P < 0.05),
It is shown in Table 7.This prompt, rapamycin intervention can be effectively improved by according to mouse small intestine function of shielding.
7 each group mouse small intestine mucosal barrier function (relative expression quantity) of table
We conducted cytotoxicity experiment, the experiment of small intestinal mucosa cell viability, mouse survival experiment, histology experiment, it is immunized
Groupization experiment and protein blot experiment.The discovery of in vitro and in vivo experimental result, rapamycin have radiation-induced injury of small intestine
There is certain protective effect, prompts preventive administration that can prevent and treat radiation-induced injury of small intestine；Experimental result also shows rapamycin
Toxic side effect is low, can be used as clinical application or health treatment and radiates personnel for radiotherapy group and Exposed and provide protection.
Embodiment 3
Active constituent rapamycin 8mg, dried starch 382mg, magnesium stearate 10mg, after mentioned component is mixed, with 400mg
It is packed into hard gelatin capsule.
Embodiment 4
Active constituent rapamycin 2mg, starch 45mg, Sodium carboxymethyl starch 4.5mg, magnesium stearate 0.5mg, talcum powder
1mg.Supplementary material is pre-dried, is sieved with 100 mesh sieve spare.First the auxiliary material of recipe quantity is mixed well.Bulk pharmaceutical chemicals are dilute to be incremented by
Interpretation of the law is added in auxiliary material, and each added-time mixes well 2-3 times, is guaranteed that medicine is mixed well with auxiliary material, is crossed 20 meshes, logical at 55 DEG C
Dry 2h in wind baking oven, dry particl cross the arrangement of 16 meshes, measure intermediates content, be uniformly mixed, the tabletting on tablet press machine.
Embodiment 5
The preparation of injection
Active constituent rapamycin 5mg, propylene glycol 50mg, poly- sorb 300ml.It takes active constituent to be added to and has dissolved sorbierite
In the water for injection of propylene glycol, addition medicinal basic adjusting pH value to 4-8 is made it dissolve.Active carbon is added, stirring and adsorbing 30 is divided
Clock, carbon removal, refined filtration, encapsulating, sterilizing.
Embodiment 6
Active constituent rapamycin 2mg, medicinal basic 1-7%, mannitol 55-85%.Take active constituent that water for injection, medication is added
It is made it dissolve with alkali adjusting pH value to 4-8.Mannitol is added, high pressure sterilization is carried out by the requirement of injection, active carbon is added,
Using filtering with microporous membrane, filtrate is dispensed, and using freeze-drying, loose block is made, seals to obtain the final product.
Claims (5)
1. rapamycin prevents and treats the application in radiation-induced injury of small intestine drug in preparation.
2. claim 1 or the application, injury of small intestine therein include intestinal villi damage, crypts of small intestine cellular damage,
The decline of small intestine function of shielding.
3. application described in claim 1, wherein the radiation-induced injury of small intestine, the tumour including receiving radiotherapy is suffered from
The personnel that person, the staff of radioactive exposure, accidental exposure isotope expose.
4. application described in claim 1, wherein the drug include the therapeutic agents of clinical various dosage forms, prophylactic agent or
Health food.
5. application described in claim 1, wherein the drug is tablet, capsule, granule, pill, pre- emulsion, micro emulsion
Agent, suspension, syrup, enteric coated preparations or injection.
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| CN104815014A (en) * | 2015-05-28 | 2015-08-05 | 天津市人民医院 | Application of polygonum cuspidatum in preparation for medicine for preventing and treating ionization radiation-induced intestinal injuries |
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2019
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| CN104815014A (en) * | 2015-05-28 | 2015-08-05 | 天津市人民医院 | Application of polygonum cuspidatum in preparation for medicine for preventing and treating ionization radiation-induced intestinal injuries |
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| KAMAL DATTA等: "Radiation persistently promoted oxidative stress, activated mTOR viaPI3K/Akt, and downregulated autophagy pathway in mouse intestine", 《THE INTERNATIONAL JOURNAL OF BIOCHEMISTRY & CELL BIOLOGY》 * |
| 程井军等: "《与瘤共存-中西医肿瘤治疗》", 31 January 2018, 世界图书出版公司 * |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN110101701A (en) * | 2019-06-18 | 2019-08-09 | 天津市人民医院 | Application of the BEZ-235 in preparation prevention and treatment radiation enteritis drug |
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