CN1277533C - Use of archin and extracts containing archin in recovery of enterogastric functions after operation and prevention of intestinal edhension - Google Patents
Use of archin and extracts containing archin in recovery of enterogastric functions after operation and prevention of intestinal edhension Download PDFInfo
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- CN1277533C CN1277533C CN 02146279 CN02146279A CN1277533C CN 1277533 C CN1277533 C CN 1277533C CN 02146279 CN02146279 CN 02146279 CN 02146279 A CN02146279 A CN 02146279A CN 1277533 C CN1277533 C CN 1277533C
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Abstract
The present invention discloses rheum emodin for injections and the new application of extract containing the rheum emodin in preparing medicines for promoting postoperative gastrointestinal functional recovery and preventing intestinal adhesions. The present invention has the advantages of good curative effect and less side effect, and a defect that the postoperative short-term oral dosing is adverse to the gastrointestinal functional recovery is overcome.
Description
Technical field
The present invention relates to a kind of injection emodin and contain the new application of extract in pharmaceutical field of emodin, be specifically related to its new application in the medicine of preparation treatment operation back restoration of gastrointestinal function and prevention intestinal adhesion.
Background technology
Abdominal operation is the modal operation of surgery, and the gastrointestinal function of general patients after surgery is relatively weaker, and the recovery of operation back gastrointestinal function comprises the recovery from illness of disease to patient's rehabilitation, reduces complication such as intestinal adhesion, and is all significant.
Recovering postoperative gastrointestinal function, mainly is the gastrointestinal peristalsis that recovers certain intensity.But,, can not cause epigastric discomfort because of gastric has food if make the too early wriggling of stomach because patients after surgery can not be taken food.
According to the literature, the ratio of intestinal adhesion in various degree takes place up to 80-90% (Menies D in abdominal postoperative, Ellis H.Intestinal obstruction from adhesion howbig is the problem.Ann R Coll Surg Engl, 1990,72:60), the fibrin that oozes out after the operation, play in 10 hours begin to form fiber adhesion [Jin Zhuhua etc. emodin is to the influence of guinea pig in vitro intestinal tube effect." Chinese combination of Chinese and Western medicine magazine ", 1994,14 (7): 429～431]; And the generation of intestinal adhesion is oozed out with postoperative abdominal cavity and enterokinesia is crossed weak relevantly, reduces and oozes out or improve wriggling, can reduce the generation of adhesion.
At present, the digestive tract power medicine, particularly the effect of stomach is strong excessively to gastrointestinal, easily causes epigastric discomfort and vomiting, though can promote the enterokinesia medicine can promote enterokinesia, can not alleviate inflammatory reaction, reduces inflammatory material and fibrin and oozes out; And be oral administration substantially, because of the back fasting of performing the operation can not be used, therefore, the recovery of gastrointestinal function after being unsuitable for performing the operation.
Can reduce the intestinal adhesion medicine nonsteroidal antiinflammatory drug and steroidal anti-inflammatory drugs are arranged.Steroidal anti-inflammatory drugs such as dexamethasone can alleviate inflammatory reaction, reduce inflammatory material and fibrin and ooze out, but when suppressing intestinal adhesion and take place, also have a strong impact on the healing of intraperitoneal operative site and incision of abdominal wall; NSAID (non-steroidal anti-inflammatory drug) can reduce oozes out, but present clinical using dosage usually causes gastrointestinal side effect; The medicine that promotes fibrinolysis to absorb has DF-521 etc., and side effect such as bleeding tendency are arranged during application.
Summary of the invention
At above-mentioned technological deficiency, technical problem to be solved by this invention provides a kind of injection emodin recovers the medicine of gastrointestinal function and prevention intestinal adhesion in the preparation treatment new purposes.
Wherein, emodin can adopt prior art to carry out chemosynthesis or extract from plant among the present invention, but preferably extracts from plant.
Content of the present invention is further treated restoration of gastrointestinal function and is prevented the new medicine use of intestinal adhesion in preparation for the plant extract that contains emodin, and the extract that wherein contains emodin preferably extracts from Radix Et Rhizoma Rhei, Rhizoma Polygoni Cuspidati, Radix Polygoni Multiflori or Semen Cassiae and obtains; When extracting from the Radix Et Rhizoma Rhei plant, the plant extract that contains emodin among the present invention is the anthraquinones extract that contains emodin; Be preferably the free type anthraquinones extract that contains emodin.
In the middle of the above-mentioned in the present invention plant extract that contains emodin, the weight percent content of emodin in extract is 22%-99%, and preferred weight percent is 60-99%.
When from the Radix Et Rhizoma Rhei plant, extracting, the free anthraquinones extract that more preferably contains emodin and aloe-emodin that contains emodin among the present invention, wherein emodin and the aloe-emodin weight percent content in extract is 22%-99%, and preferred weight percent is 60-99%.
Emodin of the present invention and the plant extract that contains emodin are in the application of the medicine of preparation treatment restoration of gastrointestinal function and prevention intestinal adhesion, the emodin of the present invention and the administering mode of plant extract that contains emodin are for the injection system administration, as intramuscular injection, lumbar injection, intravenous injection, subcutaneous injection etc., wherein preferred intravenous injection;
Among the present invention, emodin and the plant extract that contains emodin can adopt conventional preparation technology make injection or freeze-dried powder injection with intravenous mode administration with the conventional pharmaceutic adjuvant in this area.
Among the present invention, emodin or contain the emodin plant extract and emodin salt is made in alkaline matter such as reactions such as potassium hydroxide, sodium hydroxide, sodium carbonate, sodium bicarbonate or amine more preferably, then separately or and the pharmaceutic adjuvant combination make injection or lyophilized injectable powder with the administration of intravenous injection mode; Preferably make the emodin amine salt with amine reaction, then separately or and the pharmaceutic adjuvant combination make injection or lyophilized injectable powder with the administration of intravenous injection mode.
Further be preferably and get in emodin adding methanol, ethanol, propanol, isopropyl alcohol or the acetone soln, heating makes it dissolving; Other gets the meglumine solution of methanol, ethanol, propanol, isopropyl alcohol or acetone solution, under agitation it is added drop-wise in the emodin solution, stirs, and filters, and removes solvent under reduced pressure, and drying promptly gets the emodin meglumine salt; Adopt then conventional preparation technology with its separately or and the pharmaceutic adjuvant combination make injection or lyophilized injectable powder with the administration of intravenous injection mode.
Emodin of the present invention and the extract that contains emodin are in the medicinal application of preparation treatment restoration of gastrointestinal function and prevention intestinal adhesion, and its dosage scope with respect to the adult is: 100～200mg/ day (calculating with emodin); Its dosage scope with respect to rat is: 10～20mg/kg (calculating with emodin).
The present invention is through experimental studies have found that, operation back early stage (operation back 1-3 days) intravenous administration emodin or contain the extract of emodin, an intravenously administrable 10mg/kg (calculating with emodin) has tangible impetus to rat colon prepared Chinese ink, obviously increases rat in body ileum tension force and energy; One time intravenously administrable 5mg/kg obviously suppresses the mice capillary permeability; Intravenously administrable 10mg/kg obviously suppressed rat cotton balls granuloma in 7 days and forms; Medication obviously suppressed the formation of rat intestine adhesion in 5 days, showed that emodin can alleviate inflammatory reaction, reduced inflammatory material and fibrin and oozed out, and promoted the gastrointestinal peristalsis medicine.
Injection emodin of the present invention and the plant extract that contains emodin are newly used at the medicine of preparation treatment restoration of gastrointestinal function and prevention intestinal adhesion, have good effect, and side effect is low; And overcome after the operation (operation back 1-3 day) oral administration in a short time and be unfavorable for the defective of restoration of gastrointestinal function.
The specific embodiment
The present invention is further elaborated below in conjunction with experimental example and experimental example, but be not limited to this.
The preparation of embodiment 1, emodin
Get Rhizoma Polygoni Cuspidati coarse powder 100g, add 3 times of amount 95% alcohol heating reflux 3 times, each 1 hour, merge extractive liquid,, concentrating under reduced pressure becomes extractum, use a small amount of 95% ethanol heating for dissolving then, add 10 times of water gaging dilutions afterwards, transfer to PH=2 with acid, stir, leave standstill, sucking filtration gets the brown ceramic powder precipitation, add ethyl alcohol recrystallization with pyridine then, promptly get emodin, be orange-yellow crystal.
Embodiment 2, contain the free property anthraquinones extract preparation of emodin.
Radix Et Rhizoma Rhei coarse powder 100g, add 5 times of amounts, 70% alcohol heating reflux hydrolysis 1 hour, sucking filtration, clean with 2 times of amount 70% ethanol, merging filtrate also is evaporated to 30% of stock solution volume, gets rare syrup, adding dense HCL (1 volume concentrated hydrochloric acid/10 times amount medical material) while hot stirs more than the 10min, add toluene (2 volumes/1 times amount medical material) reflux then more than 1 hour, separatory, the Na of toluene layer (upper strata liquid) with 5%
2CO
3Solution extraction is toward Na
2CO
3Adding hydrochloric acid accent pH value in the extract is 2, filters, is washed to neutrality, is drying to obtain, brown ceramic powder.
The preparation of embodiment 3, emodin meglumine salt
Take by weighing the 2.7g emodin, add 300ml ethanol, heating makes it dissolving; Other gets the 1.95g meglumine, with 100ml ethanol ultrasonic dissolution, under agitation, meglumine ethanol drop is added in the emodin ethanol liquid, finishes, and continues to stir 30 minutes, and filtrate decompression is steamed and desolventized, and is dissolved in water, and filters, and lyophilization promptly.
The preparation of embodiment 4, emodin meglumine salt
Take by weighing the 2.7g emodin, add 300ml acetone, heating makes it dissolving; Other gets the 1.95g meglumine, with 100ml acetone heating for dissolving, makes the meglumine methanol solution, stirs down the meglumine acetone solution is added drop-wise in the emodin acetone solution, finishes, and continues to stir 30 minutes, filters, and filtrate decompression is steamed and desolventized, and is drying to obtain.
The preparation of embodiment 5, emodin injection
Get emodin meglumine 10g, be dissolved to 1000ml, regulate pH value with water for injection, filtration, depyrogenation, packing promptly gets the emodin injection after the sterilization.
The preparation of embodiment 6, emodin lyophilized injectable powder
Get emodin meglumine 10g, 5% mannitol is dissolved to the 1000ml dissolving with water for injection, filtration, depyrogenation, and packing adopts conventional freeze-dry process to make lyophilized injectable powder.
Used emodin is and obtains by the preparation of the method for the embodiment of the invention 5 among the following experimental example 1-5.
The influence that test example 1, emodin promote rat colon
Get 50 of rats, male, body weight 180～220g, divide 5 groups, the anesthesia of 20% urethane, anesthesia volume 0.5mg/100g, cut off along the rat ventrimeson, find out back cecum, return cecum middle part injection prepared Chinese ink, volume injected: 0.5ml/ only, intravenously administrable immediately, administration volume 0.4ml/100g, model group gives the NS with volume, put to death rat after 2 hours, with prepared Chinese ink in colon advance distance and the ratio of colon length overall be index, organize t check.Result of the test following (table 1):
Table 1 emodin is to the propelling influence of rat colon prepared Chinese ink
| Group | Dosage | Advance distance | Colon length | Propelling rate (%) |
| NS | 2.5±2.1 | 14.3±0.9 | 17.2±14.8 | |
| The sulphuric acid neostigmine | 0.10mg/kg | 5.9±1.1 | 15.6±0.58 | 37.5±5.9 △△ |
| The emodin high dose group | 20mg/kg | 4.9±2.7 | 14.5±0.8 | 33.6±18.7 △ |
| Dosage group in the emodin | 10mg/kg | 4.4±1.9 | 14.5±0.7 | 30.2±13.9 △ |
| The emodin low dose group | 5mg/kg | 3.6±2.0 | 13.8±0.7 | 26.6±15.6 |
△△：P＜0.01；
△：P＜0.05
Result of the test shows emodin high dose group, middle dosage group and model group relatively, and rat colon prepared Chinese ink is advanced obvious effect, P＜0.05; The emodin low dose group advances rat colon prepared Chinese ink does not have the significance effect, but certain trend is arranged.
Test example 2, emodin are to the influence of mice capillary permeability
Get 60 of mices, male, body weight 19～21g is divided into 5 groups at random, and 12 every group, administration volume: 0.20ml/20g gives mouse mainline 0.5% azovan blue solution, administration volume: 0.20ml/20g immediately after the administration.The acetic acid 0.20ml of lumbar injection 1.0% put to death mice after 20 minutes immediately, drew the 6.0ml normal saline, injected the abdominal cavity, gently rubbed abdominal part, drew peritoneal fluid, and centrifugal (3000rpm 10min), measures absorption value in 590nm wavelength place, organizes a t check.Result of the test following (table 2):
Table 2 emodin is to the influence of mice capillary permeability
| Group | Dosage | ODS |
| NS | 0.603±0.159 | |
| Diclofenac sodium | 5mg/kg | 0.301±0.102 △△ |
| The emodin high dose group | 20mg/kg | 0.469±0.103 △ |
| Dosage group in the emodin | 10mg/kg | 0.487±0.099 △ |
| The emodin low dose group | 5mg/kg | 0.579±0.134 |
△：p＜0.05；
△△：p＜0.01
Result of the test shows emodin high dose group, middle dosage group and model group relatively, obvious effect is arranged, P＜0.05 to suppressing the mice capillary permeability.
Test example 3, emodin are to the influence of rat intestine adhesion
Animal fasting 16h anaesthetizes with 10% chloral hydrate intraperitoneal.Anesthesia volume: 0.35ml/100g after the anesthesia lies on the back rat and is fixed on the operation plate abdominal part depilation, sterilization skin, the shop aseptic towel is taken off the abdominal part center and is about the 2cm otch, proposes caecum, placed on the dry gauze about 5 minutes, make the serous coat drying, gently scrape whole caecum serous coat 10 times, cause slight oozing of blood with scalpel blade, press from both sides small intestinal twice with mosquito forceps with same dynamics, splash into anhydrous alcohol again on wound surface.Divide two-layer with 1-0 silk thread pass abdomen, random packet, administration immediately, sub-cage rearing.Be administered once every day, administration volume 0.4ml/100g, and model group gives the NS with volume, and positive controls gives dexamethasone, administration every other day, dosage: 10mg/kg, the administration volume is with the administration group.Postoperative 7d puts to death, and abdominal part is got " n " shape otch and opened abdomen, carries out the scoring of adhesion grading respectively.Observation index adhesion grading criterion is with reference to Nair
[1]5 grades of classification method formulating are determined grade scale, see attached list 1, and result of the test is organized a rank test, result of the test following (table 3,4):
Table 3 intestinal adhesion grading evaluation criteria
| Score value | Grade adhesion situation |
| 0 | There is not adhesion fully |
| 1 | 1 adhesive band between internal organs or between internal organs and stomach wall |
| 2 | 2 adhesive bands between internal organs or between internal organs and stomach wall |
| 3 | Internal organs directly are not attached to stomach wall more than 2 adhesive bands |
| 4 | Internal organs directly adhere to stomach wall, no matter adhesive band what |
Table 4iv emodin is to the influence of rat intestine adhesion
Result of the test shows emodin high dose group, middle dosage group and model group relatively, obvious effect is arranged, P＜0.05 to suppressing the rat intestine adhesion.
Test example 4, emodin cause the influence that the rat granuloma forms to cotton balls
Rat is divided into 5 groups of (normal saline groups at random, the positive drug group, the large, medium and small dosage group of EMD), 10 every group, etherization, the skin iodine tincture sterilization of omoplate portion, ethanol takes off iodine, cuts the otch of a 1cm between omoplate, and the mosquito forceps passivity is separated both sides skin and subcutaneous tissue, subcutaneous one of the sterilized cotton ball of respectively implanting in otch both sides (weighs 19.8～20.2mg), sews up the incision.Perform the operation and began administration the same day.The next day of positive controls the im drug administration by injection once, dosage 10mg/kg, administration volume: 0.4ml/100g; Normal saline group and EMD administration group, each administration volume: 0.4ml/100g.Dislocation is put to death after one week, takes out cotton balls, rejects fatty tissue, and 70 ℃ were dried by the fire 24 hours, weighed, and deducted the cotton balls original weight, were granuloma weight, organizes a t check.Result of the test following (table 5):
The influence that table 5 emodin forms rat cotton balls granuloma
| Group | Dosage (mg/kg) | Granuloma heavy (mg) |
| The normal saline group | 42.2±12.5 | |
| Dexamethasone group | 10 | 13.6±4.8 △△ |
| The emodin low dose group | 5 | 37.2±6.9 |
| Dosage group in the emodin | 10 | 27.8±7.0 △△ |
| The emodin high dose group | 20 | 21.0±5.2 △△ |
△ △: P＜0.01, compare with the normal saline group.
Result of the test shows iv emodin high dose group, middle dosage group and model group relatively, is formed with obvious effect, P＜0.01 to suppressing rat cotton balls granuloma.
Test example 5, emodin is to getting 30 of rats in the tensile influence of body rat small intestine, body weight 180～220g, male and female half and half, the anesthesia of 20% urethane, anesthesia volume 0.5mg/l00g cuts off along the rat ventrimeson, find out ileum apart from ileocecus 3cm place, two is fixed, and intestinal mid point perforation seam one cotton thread is connected with transducer, and tension force is 2g, behind one section normal contraction curve of Powerlab record, intravenously administrable, administration group dosage is 10mg/kg, administration volume: 0.4ml/100g, it is 0.10mg/kg that positive controls gives im neostigmine dosage, administration volume: 0.4ml/100g, model group gives NS, gives volume with the administration group.Observe after the administration small intestinal tension force and contraction frequency after 1 hour, organize a t check.Result of the test following (table 6):
Table 6 iv emodin is to the influence in body rat small intestine tension force, frequency, energy
| Group | Dosage (mg/kg) | Before the administration | After the administration | ||||
| Frequency (inferior/min) | Tension force (g) | Energy | Frequency (inferior/min) | Tension force (g) | Energy | ||
| The normal saline group | 29±4 | 2.0±0.3 | 58±5 | 28±5 | 2.2±0.5 | 62±9 | |
| The neostigmine methylsulfate group | 0.10 | 31±5 | 2.1±0.2 | 65±7 | 45±8 | 4.3±1.5 △△ | 195±42 △△ |
| The emodin group | 10 | 30±5 | 2.2±0.4 | 66±8 | 31±5 | 3.5±0.8 △△ | 109±18 △△ |
△ △: P＜0.01, compare with the normal saline group
Result of the test shows iv emodin 10mg/kg and model group relatively, and rat small intestine tension force and energy are had tangible rising effect, P＜0.01.
Claims (7)
1. the application of injection emodin in the medicine of preparation promotion operation back restoration of gastrointestinal function and prevention intestinal adhesion.
2. application according to claim 1 is characterized by described emodin and extracts from Radix Et Rhizoma Rhei and obtain.
3. application according to claim 1, described emodin are extracted from Rhizoma Polygoni Cuspidati, Radix Polygoni Multiflori or Semen Cassiae and are obtained.
4. according to the arbitrary described application of claim 1-3, emodin and pharmaceutic adjuvant combination are with the administration of intravenous injection mode.
5. application according to claim 4 is characterized in that emodin and alkali substance reaction make the combination of emodin salt and pharmaceutic adjuvant and make injection or lyophilized injectable powder with the administration of intravenous injection mode.
6. application according to claim 5 is characterized in that emodin and amine makes the combination of emodin amine salt and pharmaceutic adjuvant and make injection or lyophilized injectable powder with the administration of intravenous injection mode.
7. application according to claim 6 is characterized in that getting emodin and adds in methanol, ethanol, propanol, isopropyl alcohol or the acetone solution, and heating makes it dissolving; Other get methanol, ethanol, propanol, isopropyl alcohol or acetone solution meglumine solution, under the restir it is added drop-wise in the emodin solution, stir, filter, decompression steams solvent, drying, the emodin meglumine salt; Adopt then conventional preparation technology with its separately or and the pharmaceutic adjuvant combination make injection or lyophilized injectable powder with the administration of intravenous injection mode.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 02146279 CN1277533C (en) | 2002-10-18 | 2002-10-18 | Use of archin and extracts containing archin in recovery of enterogastric functions after operation and prevention of intestinal edhension |
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|---|---|---|---|
| CN 02146279 CN1277533C (en) | 2002-10-18 | 2002-10-18 | Use of archin and extracts containing archin in recovery of enterogastric functions after operation and prevention of intestinal edhension |
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| CN1277533C true CN1277533C (en) | 2006-10-04 |
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