CN1526381A - Application of small dosage anticholinesterase in preparing medicine for treating digestive system diseases caused by gastrointestinal motive disorder - Google Patents
Application of small dosage anticholinesterase in preparing medicine for treating digestive system diseases caused by gastrointestinal motive disorder Download PDFInfo
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Abstract
The present invention relates to the application of small dosage anticholinesterase in preparing medicine for treating digestive system diseases caused by gastrointestinal motive disorder. The anticholinesterase of the present invention is Pyridostigmine and Neostigmine, preferably Pyridostigmine. The small dosage anticholinesterase preparation has obvious gastrointestinal motive strengthening effect and no obvious side effect.
Description
Technical field
The present invention relates to the new application of low dosage cholinesterase inhibitor, relate to the application of low dosage cholinesterase inhibitor in the digestive system disease that gastrointestinal motility disorder causes particularly.
Background technology
The normal wriggling of gastrointestinal has important function for the machinery of finishing its food, chemical digestion and absorption etc.When digestive tract power generation obstacle, will cause the gastrointestinal motility functional disorder.Gastric motility disorder disease clinically has functional dyspepsia, gastroesophageal reflux disease, stomach spasm, intestinal pseudo obstruction and irritable bowel syndrome etc.Treat this class disease clinically and adopt the motivator medicine to strengthen the nervimuscular tension force of gastrointestinal more, thereby remove abnormal symptom.Clinical common digestive tract power reinforcing medicine has cisapride, motilium (domperidone), metoclopramide (metoclopramide), erythromycin etc. at present.
Cisapride is that a kind of novel gastrointestinal is actuated medicine, also is that unique full gastrointestinal is actuated medicine.Cisapride acts on the 5-hydroxytryptamine receptor of cholinergic relay cell and myenteric nerve plexus motor neuron, causes that the acetylcholine of myenteric nerve plexus discharges increase, strengthens the gastrointestinal motive force.Because 5-hydroxy tryptamine is distributed in full gastrointestinal, so cisapride all has the motivator effect to whole gastrointestinal tract.Clinical research proves, cisapride has good efficacy to most stomach spasm, gastroesophageal reflux disease, functional dyspepsia, be the active drug of first treatment reflux esophagitis, also be proved to be to treat the unique effective dynamics-promoting medicine of intestinal pseudo obstruction simultaneously.Its clinical adverse of discovery is all lacked than metoclopramide, motilium etc. at present, and loose stool and diarrhoea are only arranged.Therefore, cisapride was once becoming the choice drug of treatment gastrointestinal motility disorder disease.(cisapride Prepulsid) with serious heart condition reaction, stops using in the U.S. from July 14th, 2000, and Canada stopped using on August 7th, 2000, and on July 28th, 2000 rose in Britain and revoked licence but because of cisapride.Make one's attitude clear separately after EU member country weighs the advantages and disadvantages, France defines its indication, but still allows to sell on market.Other member states then consider to adopt a kind of mode wherein.In Japan, it is used and also is subjected to strict restriction.
Motilium is a kind of stronger dopamine-receptor antagonist, is the more gastro-kinetic agent of present clinical practice.This medicine is coordinated pylorus and duodenal power activity by increasing stringer smooth muscle contraction frequency and amplitude, improves the gastric emptying function.Be mainly used in nauseating, vomiting that treatment stomach spasm, functional dyspepsia and a variety of causes cause clinically.But it is invalid to gastroesophageal reflux disease.This medical instrument has extrapyramidal symptoms, increases untoward reaction such as prolactin antagonist secretion, galactorrhea and gynaecomastia.Therefore, it uses and also is subjected to certain restriction.
This medicine of metoclopramide is a kind of dopamine receptor antagonist, increases the release of myenteric plexus acetylcholine, produces the choline-like effect, adds the motion of stomach strengthening and top intestinal segment, promotes small intestinal peristalsis and emptying, lax pyloric antrum and bishop's cap, thus improve the food percent of pass.Be used for the treatment of gastroesophageal reflux disease clinically, improve the gastric emptying function of sudden stomach spasm, functional dyspepsia is also had certain curative effect.Metoclopramide has certain untoward reaction, mainly shows as parkinson's syndrome, anxiety, excitement, mobility's uneasiness, dysphonia, ataxia or drowsiness, asthenia is arranged, symptoms such as dizziness; Also can cause female mammary gland tumor, galactorrhea, womanlike breast appears in the male patient.The existence of these untoward reaction has influenced metoclopramide extensive use clinically.In addition, metoclopramide should not with phenothiazines medicines such as chlorpromazine, perphenazine, drug combination such as anticholinergic agent such as atropine, Semen daturae and cimetidine.Even clinical needs are needing on medicine time at interval more than 1 hour at least.
Erythromycin is macrolide antibiotics, how to use as antibacterials.This medicine has side effect such as nausea,vomiting,diarrhea.Recent study is found, the reason that produces this class side effect is that erythromycin is the motilin receptor stimulating agent that is distributed in smooth muscle cell, stomach and duodenum there are the intensive usefulness of actuating, can cause the gastric antrum and the duodenal irregular contraction of strong and high amplitude.Because still need further promoting mutual understanding, its clinical efficacy only erythromycin is used for treatment to the invalid stomach spasm of other medicine for stomach dynamic at present.
In sum, all there is certain defective in existing digestive tract power medicine, and ideal digestive tract power reinforcing medicine should be able to be corrected the power abnormality relevant with symptom and recover normal motor function, and does not produce system's untoward reaction.But still lack in the market and can regulate the power medicine of all clinical symptoms comprehensively.
Summary of the invention
The invention provides the application of cholinesterase inhibitor in the digestive system disease that gastrointestinal motility disorder causes of low dosage.
Low dosage cholinesterase inhibitor provided by the invention can be formula I or its salt, formula II or its salt, huperzine A, tacrine (tacrine), donepezil (donepezil), sharp this bright (rivastigmine) or galantamine (galantamine) in a kind of;
Formula I formula II
Wherein, R1, R2, R3 can be alkyl, hydroxyl, formic acid ester group or mephenesin Carbamate base among the formula I, formula I salt can be with halogen (F, Cl, Br or I) or-CH
3SO
4The salt that is become; R1, R2, R3, R4 can be alkyl, hydroxyl, formic acid ester group or mephenesin Carbamate base among the formula II, formula II salt can be with halogen (F, Cl, Br or I) or-CH
3SO
4The salt that is become.
Low dosage cholinesterase inhibitor of the present invention is preferably the medicine shown in formula I or the formula II, and more preferably pyridostigmine bromide and neostigmine bromide are preferably pyridostigmine bromide again.
Acetylcholine (Ach) is neural important mediator, with cholinoceptor effect performance physiological effect.Low dose of obvious excited M cholinoceptor, exciting n receptor when dosage is big of getting final product.The digestive gland secretion can appear in m receptor excitement, digestive system, gastrointestinal smooth muscle shrinks and the enhancing etc. of moving.
(acetylcholinesterase, AchE are the cholinolytic enzymes of a class catalyzing acyl EC3.1.1.7) to acetylcholinesterase, and its physiological function mainly is catalyzing hydrolysis Ach.
Cholinesterase inhibitor (anticholinesterase drug) suppresses the hydrolysis of AChE to Ach, thereby has strengthened the effect of ACh to cholinoceptor, has realized therapeutic purposes.
The cholinesterase inhibitor that in the past used is mainly used in the treatment of myasthenia gravis, operation venter posterior flatulence and urine retention, the excessive flesh pine that causes of depolarizing relaxant, glaucoma etc. clinically, proves that in recent years it is used for alzheimer disease and has good effect.Cholinesterase inhibitor has improved the choline systemic-function that reduces under the above disease pathological state, thereby has brought into play therapeutical effect preferably by suppressing the degraded of AChE to Ach.But because the using dosage of cholinesterase inhibitor is bigger, have serious adverse effects in therefore using, maincenter shows as degradation under dizziness, dysmnesia, nightmare, the sleep quality; Periphery then mainly shows as hyperhidrosis, sialorrhea, feels sick, vomiting, abdomen are painful, diarrhoea etc.Modal untoward reaction is a digestive tract reaction, promptly feels sick, [Shanghai Sunve Pharmaceutical Co., Ltd., pyridostigmine bromide sheet (the accurate word 1995 of medicine is defended No. 002044 in Shanghai) description such as vomiting, abdomen are painful, diarrhoea; Military Medical Science Institute's medicine is developed, and the Sino-U.S. bamboo grove is pacified special medicine company limited production Huperzine A-Zhulin Antun (94) and defends the tablet description the accurate word X-152 of medicine number].
The inventor finds to give the cholinesterase inhibitor that animal is lower than clinical treatment myasthenia gravis, operation venter posterior flatulence and urine retention, the excessive flesh pine that causes of depolarizing relaxant, alzheimer disease using dosage by a large amount of animal experiments, can obviously promote the wriggling of gastric emptying, small intestinal and large intestine, significantly digestive tract power effect is promptly arranged.
The inventor finds through clinical research: the adult gives the cholinesterase inhibitor of low dosage, as pyridostigmine bromide (less than 60mg), neostigmine bromide (less than 15mg), huperzine A (less than 50 μ g), galantamine (galantamine is less than 10mg), obviously promote gastrointestinal motility, and do not have obvious adverse reaction.
Based on above discovery, cholinesterase inhibitor is prepared into the small dimension preparation, as pyridostigmine bromide less than 60mg, neostigmine bromide less than 15mg, huperzine A less than 50 μ g, tacrine tacrine less than 10mg, donepezil donepezil less than 5mg, sharp this bright rivastigmine less than 2mg, galantamine galantamine less than 10mg, low dose is administered for the treatment of the digestive system disease that gastrointestinal motility disorder causes, to provide new medicine for patient, compare with existing digestive tract power medicine, untoward reaction will obviously reduce.
When cholinesterase inhibitor is used for the treatment of the digestive system disease that gastrointestinal motility disorder causes, central action will become side effect, therefore, the cholinesterase inhibitor that preferably is difficult for the maincenter that enters is used for the treatment of the digestive system disease that gastrointestinal motility disorder causes, the medicine shown in preferred formula I or the formula II wherein, more preferably pyridostigmine bromide and neostigmine bromide are preferably pyridostigmine bromide again.
Dosage when pyridostigmine bromide is used for the treatment of the digestive system disease that gastrointestinal motility disorder causes is 1-60mg, is preferably 2-30mg, more preferably: 2-10mg.
Dosage when neostigmine bromide is used for gi system treatment of diseases that gastrointestinal motility disorder causes is 0.1-15mg, is preferably 1-10mg, more preferably 1-5mg.
Dosage when huperzine A is used for gi system treatment of diseases that gastrointestinal motility disorder causes is 1-50 μ g, and is preferred: 1-25 μ g, more preferably: 5-25 μ g.
Dosage when donepezil is used for gi system treatment of diseases that gastrointestinal motility disorder causes is 0.1-5mg, is preferably 0.1-2mg, more preferably: 0.1-1mg.
Dosage when sharp this bright is used for gi system treatment of diseases that gastrointestinal motility disorder causes is 0.1-2mg, is preferably 0.1-1mg, more preferably: 0.1-0.5mg.
Dosage when galantamine is used for gi system treatment of diseases that gastrointestinal motility disorder causes is 0.1-10mg, is preferably 0.1-5mg, and more preferably 0.5-2.5mg is preferred again: 1-2mg.
Dosage form when cholinesterase inhibitor is used for the treatment of the digestive system disease that gastrointestinal motility disorder causes can be an oral formulations, as tablet, capsule, granule, buccal tablets, it also can be preparation for external application to skin, as gel, paster etc., can also be suppository of anum administration etc., but be not limited to this.
The specific embodiment
1. the preparation of pyridostigmine bromide 10mg sheet
Prescription:
Pyridostigmine bromide 10.0g
Microcrystalline Cellulose 57.0g
Lactose 100.0g
Carboxymethyl starch sodium 10.0g
3%PVP
K30Aqueous solution is an amount of
Magnesium stearate 1.0g
Make 1000 altogether
Operation: take by weighing the abundant mix homogeneously of pyridostigmine bromide, lactose, microcrystalline Cellulose and carboxymethyl starch sodium of recipe quantity, add 3%PVP
K30Aqueous solution is made soft material in right amount, and 28 mesh sieves are granulated, 60 ℃ of dryings 3 hours, and 26 mesh sieve granulate add the magnesium stearate of recipe quantity, φ 8mm scrobicula stamping behind the mix homogeneously, the heavily about 180mg of adjustment sheet.
2. the preparation of pyridostigmine bromide 10mg bolt
Prescription
Pyridostigmine bromide 10.0g
PEG-4000 250.0g
PEG-6000 500.0g
Glycerol 50.0g
Purified water 200.0g
Make 1000 pieces altogether
Operation: PEG-4000, the PEG-6000, glycerol and the purified water that take by weighing recipe quantity are put heating and melting in 50 ℃ of water-baths, add pyridostigmine bromide 10.0g stirring and make dissolving fully, are incubated 50 ℃, irritate mould, every piece of heavily about 1.0g, and cooling, promptly.
3. the capsular preparation of neostigmine bromide 5mg
Prescription:
Neostigmine bromide 5.0g
Starch 138.0g
Dextrin 35.0g
3%PVP
K30Aqueous solution an amount of
Make 1000 altogether
Operation: take by weighing the starch of neostigmine bromide 5.0g and equivalent (5.0g), abundant mix homogeneously adds the abundant mix homogeneously of recipe quantity dextrin after adding 10.0g starch mixing again, with the PVP of adding 3% behind the starch mix homogeneously of this mixed-powder and surplus
K30Aqueous solution is made soft material in right amount, and 28 mesh sieves are granulated, about 3 hours of 60 ℃ of dryings, and 26 mesh sieve granulate are adorned capsule No. 1, regulate the about 180mg of loading amount, promptly.
4. the preparation of huperzine A 20 μ g sheets
Prescription
Huperzine A 0.02g
Microcrystalline Cellulose 67.0g
Lactose 100.0g
Carboxymethyl starch sodium 10.0g
Dehydrated alcohol 10.0ml
3%PVP
K30Aqueous solution is an amount of
Magnesium stearate 1.0g
Make 1000 altogether
Operation: the huperzine A that takes by weighing recipe quantity is dissolved in the 10.0ml dehydrated alcohol, this solution is joined in the microcrystalline Cellulose of recipe quantity, mix back 50 ℃ thoroughly and volatilize ethanol and get mixed-powder,, add 3%PVP the lactose and the abundant mix homogeneously of carboxymethyl starch sodium of this mixed-powder and recipe quantity
K30Aqueous solution is made soft material in right amount, and 28 mesh sieves are granulated, 60 ℃ of dryings 3 hours, and 26 mesh sieve granulate add the magnesium stearate of recipe quantity, φ 8mm scrobicula stamping behind the mix homogeneously, the heavily about 180mg of adjustment sheet.
5. the preparation of donepezil 1mg sheet
Prescription:
Donepezil 1.0g
Pregelatinized Starch 167.0g
Carboxymethyl starch sodium 10.0g
3%PVP
K30Aqueous solution is an amount of
Magnesium stearate 1.0g
Make 1000 altogether
Operation: take by weighing donepezil 1.0g, put in the mortar, the pregelatinized Starch that adds equivalent (1.0g) is fully ground evenly, add again equivalent (2.0g) pregelatinized Starch grind well and add 4.0,8.0 according to this respectively, the 16.0g pregelatinized Starch grind well mixed-powder.Add in this mixed-powder and add 3% PVP behind the abundant mix homogeneously of carboxymethyl starch sodium of the pregelatinized Starch of surplus and recipe quantity
K30Aqueous solution is made soft material in right amount, and 28 mesh sieves are granulated, about 3 hours of 60 ℃ of dryings, and 26 mesh sieve granulate add the 1.0g magnesium stearate, φ 8mm scrobicula stamping behind the mix homogeneously, the heavily about 180mg of adjustment sheet.
6. the preparation of galantamine 2mg sheet
Prescription:
Galantamine 2.0g
Pregelatinized Starch 166.0g
Carboxymethyl starch sodium 10.0g
3%PVP
K30Aqueous solution is an amount of
Magnesium stearate 10g
Make 1000 altogether
Operation: take by weighing galantamine 2.0g, put in the mortar, the pregelatinized Starch that adds equivalent (2.0g) is fully ground evenly, add again equivalent (4.0g) pregelatinized Starch grind well and add 8.0 according to this respectively, the 16.0g pregelatinized Starch grind well mixed-powder.Add in this mixed-powder and add 3% PVP behind the abundant mix homogeneously of carboxymethyl starch sodium of the pregelatinized Starch of surplus and recipe quantity
K30Aqueous solution is made soft material in right amount, and 28 mesh sieves are granulated, about 3 hours of 60 ℃ of dryings, and 26 mesh sieve granulate add the 1.0g magnesium stearate, φ 8mm scrobicula stamping behind the mix homogeneously, the heavily about 180mg of adjustment sheet.
7. the preparation of galantamine gel 5g (1%)
Prescription:
Galantamine 10.0g
Carbopol?940 15.0g
Propylene glycol 80.0g
Ethanol 40.0g
Azone 2.0g
20% triethanolamine solution is an amount of
Purified water adds to 1000g
Make 1000g altogether
Operation:
(1) get propylene glycol, the ethanol mix homogeneously of recipe quantity, add recipe quantity galantamine and Azone stir make dissolve medicinal liquid A;
(2) getting recipe quantity Carbopol 940 adds water and is configured to blank substrate in right amount, above-mentioned medicinal liquid A joined in the blank substrate and stir to make be uniformly dispersed, it is an amount of to add 20% triethanolamine solution under stirring condition, and it is about 6.5 to regulate pH value, add water to 1000g and stir gel B;
(3) above-mentioned gel B is sub-packed in the aluminum pipe, every loading amount 5.0g, promptly.
8. test example: to the influence of normal mouse gastric emptying
(1) test objective:
Gavaging methyl orange to normal mouse, is index with methyl orange residual rate in the stomach, observes pyridostigmine bromide and whether promotes gastric emptying 0.3, under the dosage of 1mg, 3mg/kg.
(2) content of the test
Be subjected to the reagent thing: pyridostigmine bromide (60mg/ grain, Shanghai Sunve Pharmaceutical Co., Ltd., lot number: 200111C06); Motilium (10mg/ grain, Xian-Janssen Pharmaceutical Ltd., lot number: 010214002); Methyl orange (chemical reagent station, Chinese Medicine Shanghai, lot number: 000308); Raceanisodamine (tablet, 10mg/ grain, Huanghai Pharmaceutical Plant, Qingdao, lot number: 001137); Sodium bicarbonate (Shanghai reagent four factories, lot number: 000612)
Instrument: centrifuge (DL-4000B refrigerated centrifuger, Anting Scientific Instrument Factory, Shanghai); Spectrophotometer (UV-9100 Beijing Rayleigh scientific instrument factory)
Animal: secondary Kunming kind white mice, male and female half and half, body weight 22-24g, Shandong Province's natural drug Engineering Technical Research Centre Experimental Animal Center provides the animal quality certification: (matter) word 2001003 is moved in the Shandong.
Get 55 of mices, female 28, male 27, fasting 12 hours, random packet, gavage 0.015 respectively, 0.05mg, 0.15mg/ml pyridostigmine bromide suspension, 1mg/ml motilium suspension, distilled water, be respectively the height of pyridostigmine bromide, in, low dose group, positive controls, negative control group, the administration volume is and is 0.4ml/20g, after the administration 20 minutes, gavage the 0.2ml0.1% methyl orange solution, to 20 minutes execution mices after the methyl orange, cut open the belly, get stomach, stomach is placed the l0ml cillin bottle, and the sodium bicarbonate solution that adds 8ml 0.1% is cut off stomach with little shears, and gastric content is fully washed in sodium bicarbonate solution, shake up, get supernatant, insert in the test tube, centrifugal 10 minutes of 200tpm, get supernatant and respectively manage absorption value in 420nm place mensuration, 0.1% sodium bicarbonate solution zeroising, and shake up the back with the sodium bicarbonate solution that 0.1% methyl orange solution 0.2ml adds 8ml 0.1% and survey trap as radix methyl orange optical density, be calculated as follows methyl orange stomach residual rate: methyl orange stomach residual rate (%)=stomach methyl orange optical density/radix methyl orange optical density * 100%.
Each organizes t check between methyl orange stomach residual rate employing group, carries out statistical procedures.
(3) result of the test
The influence of table 1 pair normal mouse gastric emptying
Group dosage (mg/kg) optical density methyl orange stomach residual rate (%)
Blank group 0.306 ± 0.080 50.9 ± 13.2
Motilium group 20 0.188 ± 0.056 31.3 ± 9.4
*
Pyridostigmine bromide high dose group 3 0.184 ± 0.049 30.7 ± 8.1
*
Dosage group 1 0.210 in the pyridostigmine bromide ± 0.056 34.8 ± 9.3
*
Pyridostigmine bromide low dose group 0.3 0.231 ± 0.069 38.3 ± 13.3
*
Annotate: with the blank group than P＜0.05, * * P＜0.01
As can be seen from the above table.The motilium group can significantly promote mice gastric emptying (P＜00.01), and dosage group, pyridostigmine bromide low dose group also can significantly promote mice gastric emptying (P＜0.05) in pyridostigmine bromide high dose group, the pyridostigmine bromide.Pyridostigmine bromide people's dose,equivalent is about 2-20mg/ time.
9. test example: to the influence of small intestine movement of mice wriggling
(1) test objective
Gavaging active carbon to normal mouse, is index with the propelling rate of active carbon in small intestinal, observes pyridostigmine bromide and whether promotes the mouse small intestine wriggling 0.3, under the dosage of 1mg, 3mg/kg.
(2) content of the test
Get 50 of mices, male and female half and half, fasting 12 hours, random packet, gavage respectively and gavage 0.015 respectively, 0.05mg, 0.15mg/ml pyridostigmine bromide suspension and 1mg/ml motilium suspension, distilled water, be respectively the height of pyridostigmine bromide, in, low dose group, positive controls, negative control group, the administration volume is and is 0.4ml/20g, gavaged 5% Insta-Char 0.5ml after the administration in 20 minutes, put to death mice after 20 minutes, the taking-up intestinal tube of cutting open the belly, measure pylorus to the distance in active carbon forward position as " advance distance in the active carbon intestinal ", measure pylorus to the distance of caecum as full intestinal length, be calculated as follows: advance distance (cm) in active carbon propelling rate=active carbon intestinal/full intestinal length (cm) * 100%
Each organizes t check between active carbon propelling rate employing group, carries out statistical procedures.
(3) result of the test
The influence of table 2 pair small intestine movement of mice wriggling
The full intestinal length of group dosage (mg/kg) active carbon advance distance active carbon propelling rate)
(cm) (cm)
Blank group 27.0 ± 4.2 41.4 ± 3.7 64.9 ± 7.1
Motilium group 20 30.6 ± 4.9 41.1 ± 3.7 74.8 ± 11.5
*
Pyridostigmine bromide high dose group 3 35.2 ± 5.9 45.1 ± 3.2 78.2 ± 12.4
*
Dosage group 1 33.5 ± 5.3 43.6 ± 3.6 76.9 ± 11.6 in the pyridostigmine bromide
*
Pyridostigmine bromide low dose group 0.3 31.9 ± 4.7 43.6 ± 3.6 74.2 ± 10.1
*
Annotate: with the blank group than P＜0.05, * * P＜0.01
As can be seen from the above table.The motilium group can significantly promote mouse small intestine wriggling (P＜0.05), and dosage group, pyridostigmine bromide low dose group also can significantly promote mouse small intestine wriggling (P＜0.05) in pyridostigmine bromide high dose group, the pyridostigmine bromide.
10. test example: to the slow down influence of mouse small intestine wriggling of enterokinesia
(1) test objective
To the small intestinal peristalsis mouse gavaging active carbon that slows down, be index with the propelling rate of active carbon in small intestinal, observe pyridostigmine bromide and whether promote the mouse small intestine wriggling 0.3, under the dosage of 1mg, 3mg/kg.
(2) content of the test
Get 60 of mices, male and female half and half, random packet, divide 6 groups, wherein 5 groups every gavages 1.5mg/ml raceanisodamine suspension 0.5ml, makes the enterokinesia model that slows down, and 1 group is the blank group in addition, modeling group administration every day 1 time, successive administration 3 days after giving the raceanisodamine suspension 1 hour, gavages pyridostigmine bromide suspension and motilium suspension, pyridostigmine bromide suspension concentration is 0.015,0.05,0.15mg/ml, is respectively the high, medium and low dosage group of pyridostigmine bromide; Motilium suspension concentration is 1mg/ml, positive matched group, and model group and blank group gavage distilled water, and the administration volume is and is 0.4ml/20g.Fasting (can't help water) after administration in second day, gave in the 3rd day and revolved behind the Anisodamine suspension 1 hour, gavage respectively and gavage 0.015 respectively, 0.05mg, 0.15mg/ml pyridostigmine bromide suspension and 1mg/ml motilium suspension, distilled water, the administration volume is and is 0.4ml/20g, gavaged 5% Insta-Char 0.5ml after the administration in 20 minutes, put to death mice after 20 minutes, the taking-up intestinal tube of cutting open the belly, measure the distance conduct " active carbon intestinal in advance distance " of pylorus to the active carbon forward position, measure the distance conduct full intestinal length of pylorus, be calculated as follows: advance distance (cm) in active carbon propelling rate=active carbon intestinal/full intestinal length (cm) * 100% to caecum.Each organizes t check between active carbon propelling rate employing group, carries out statistical procedures.
(3) result of the test:
The slow down influence of mouse small intestine wriggling of table 3 pair enterokinesia
Group dosage (mg/kg) active carbon advances apart from full intestinal length active carbon propelling rate
From (cm) (cm) (%)
Blank group 27.9 ± 4.4 41.6 ± 4.1 67.0 ± 6.4
Model group 20.7 ± 4.9 44.0 ± 1.8 47.1 ± 11.3
Motilium group 20 25.4 ± 2.8 41.1 ± 2.8 62.1 ± 8.1
*
Pyridostigmine bromide high dose group 3 29.6 ± 6.0 43.7 ± 3.4 67.6 ± 11.3
*
Dosage group 1 26.3 ± 5.4 41.1 ± 3.6 63.9 ± 12.4 in the pyridostigmine bromide
*
Pyridostigmine bromide low dose group 0.3 28.9 ± 7.6 45.5 ± 3.5 63.7 ± 17.5
*
Annotate: administration group and model group be than P＜0.05, * * P＜0.01
The result shows (table 3), and dosage group, pyridostigmine bromide low dose group can significantly promote mouse small intestine wriggling (P＜0.05) in motilium group, pyridostigmine bromide high dose group, the pyridostigmine bromide.
Test with neostigmine bromide.The result shows (table 4), and the mouse small intestine wriggling that the smaller dose neostigmine bromide slows down to enterokinesia also has obvious facilitation.
The high low dosage neostigmine bromide of table 4 is to the slow down influence of mouse small intestine wriggling of enterokinesia
The full intestinal length of group dosage active carbon advance distance active carbon propelling rate
(mg/kg) (cm) (cm) (％)
Blank group 27.9 ± 4.4 41.6 ± 4.1 67.0 ± 6.4
Model group 20.7 ± 4.9 44.0 ± 1.8 47.1 ± 11.3
Motilium group 20 25.4 ± 2.8 41.1 ± 2.8 62.1 ± 8.1
*
Neostigmine bromide high dose group 1.5 27.3 ± 3.8 42.1 ± 2.9 64.8 ± 9.2
*
Neostigmine bromide low dose group 0.5 26.3 ± 2.7 41.9 ± 2.5 62.8 ± 8.7
*
11. test example: the administration of cholinesterase inhibitor human oral is to the influence of gastric emptying and intestinal promotion
Call up the volunteer, the male in age 18-60 year, is divided into normal control group, pyridostigmine bromide group 5mg, neostigmine bromide group 2mg, huperzine A group 10 μ g and galantamine group 2mg, with relative medicine and digestive tract examining barium meal mixing, oral back X checks and observes gastric emptying and intestinal propelling respectively.
The result shows, pyridostigmine bromide, neostigmine bromide, huperzine A and galantamine, all but the propelling of accelerate gastric emptying and intestinal contents shows that the above medicine that is lower than conventional therapy dosage (pyridostigmine bromide 60mg, neostigmine bromide 1mg 5 huperzine As 100 μ g galantamine 10mg) has gastrointestinal progradation preferably.
Claims (9)
1. the application of the cholinesterase inhibitor of low dosage in the digestive system disease that preparation treatment gastrointestinal motility disorder causes.
2. application according to claim 1, it is characterized by cholinesterase inhibitor and can be formula I or its salt, formula II or its salt, huperzine A, tacrine (tacrine), donepezil (donepezil), sharp this bright (rivastigmine) or galantamine (galantamine) in a kind of;
Formula I formula II
Wherein, R1, R2, R3 can be alkyl, hydroxyl, formic acid ester group or mephenesin Carbamate base among the formula I, formula I salt can be with halogen (F, Cl, Br or I) or-CH
3SO
4The salt that is become; R1, R2, R3, R4 can be alkyl, hydroxyl, formic acid ester group or mephenesin Carbamate base among the formula II, formula II salt can be with halogen (F, Cl, Br or I) or-CH
3SO
4The salt that is become.
3. application according to claim 1 and 2, cholinesterase inhibitor is preferably pyridostigmine bromide or neostigmine bromide, and wherein the application dose of pyridostigmine bromide is 1-60mg, and the application dose of neostigmine bromide is 0.1-15mg.
4. application according to claim 3, the bright range of application that it is characterized by the bromine pyrrole phase is preferably 2-30mg.
5. application according to claim 4, the bright range of application that it is characterized by the bromine pyrrole phase is 5-15mg more preferably.
6. application according to claim 3, the application dose scope that it is characterized by neostigmine bromide is preferably 1-10mg.
7. application according to claim 6, the more preferably dosage range that it is characterized by neostigmine bromide is 1-5mg.
8. application according to claim 1 and 2, when it is characterized by cholinesterase inhibitor and being huperzine A, its dosage range is 1-50 μ g; When being tacrine, its dosage range is 0.1-10mg; When being donepezil, its dosage range is 0.1-5mg; When being sharp this bright, its dosage range is 0.1-2mg; When being galantamine, its dosage range is 0.1-10mg.
9. application according to claim 1 and 2 is characterized by cholinesterase inhibitor and exists with forms such as oral formulations, aerosol, preparation for external application to skin or suppositorys.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA031071694A CN1526381A (en) | 2003-03-06 | 2003-03-06 | Application of small dosage anticholinesterase in preparing medicine for treating digestive system diseases caused by gastrointestinal motive disorder |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA031071694A CN1526381A (en) | 2003-03-06 | 2003-03-06 | Application of small dosage anticholinesterase in preparing medicine for treating digestive system diseases caused by gastrointestinal motive disorder |
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| Publication Number | Publication Date |
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| CN1526381A true CN1526381A (en) | 2004-09-08 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA031071694A Pending CN1526381A (en) | 2003-03-06 | 2003-03-06 | Application of small dosage anticholinesterase in preparing medicine for treating digestive system diseases caused by gastrointestinal motive disorder |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105853370A (en) * | 2016-06-15 | 2016-08-17 | 安徽省逸欣铭医药科技有限公司 | Neostigmine Bromide powder and preparation method thereof |
| WO2020030089A1 (en) * | 2018-08-10 | 2020-02-13 | 浙江海正药业股份有限公司 | Use of benzodioxole derivative in treatment of disease related to gastrointestinal motility disorder |
-
2003
- 2003-03-06 CN CNA031071694A patent/CN1526381A/en active Pending
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105853370A (en) * | 2016-06-15 | 2016-08-17 | 安徽省逸欣铭医药科技有限公司 | Neostigmine Bromide powder and preparation method thereof |
| WO2020030089A1 (en) * | 2018-08-10 | 2020-02-13 | 浙江海正药业股份有限公司 | Use of benzodioxole derivative in treatment of disease related to gastrointestinal motility disorder |
| CN110812358A (en) * | 2018-08-10 | 2020-02-21 | 浙江海正药业股份有限公司 | Application of compound AD-35 in treating diseases related to gastrointestinal motility disorder |
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