CN1649590A - Therapeutic agent comprising lafutidine - Google Patents
Therapeutic agent comprising lafutidine Download PDFInfo
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- CN1649590A CN1649590A CNA038095386A CN03809538A CN1649590A CN 1649590 A CN1649590 A CN 1649590A CN A038095386 A CNA038095386 A CN A038095386A CN 03809538 A CN03809538 A CN 03809538A CN 1649590 A CN1649590 A CN 1649590A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- 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
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- 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
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/443—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with oxygen as a ring hetero atom
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- A—HUMAN NECESSITIES
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- 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
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4525—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with oxygen as a ring hetero atom
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
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Abstract
The present invention provides a safer therapeutic agent for anti-inflammatory bowel disease that has minimal adverse side-effects.The present invention discloses a therapeutic agent for inflammatory bowel disease that contains as its active ingredient lafutidine, its optical isomer, lafutidine derivative, or pharmaceutically acceptable salt thereof.
Description
The present invention relates to a kind of therapeutic agent that is used to handle inflammatory bowel, the generation of ulcer enteropathy, ulcerative colitis and segmental enteritis (Crohn ' s disease).
Inflammatory bowel (IBD) is a common name about the disease of the unknown cause that causes large intestine and mucous membrane of small intestine chronic inflammatory disease or ulcer.This inflammatory bowel comprises for example ulcerative colitis and the such disease of segmental enteritis.
In these diseases, ulcerative colitis is a kind of disease that causes the unknown cause of diffuse inflammation in the big intestinal mucosa, and its cardinal symptom comprises diarrhoea, hemafecia (it also contains mucus usually) and abdominal pain.The theory that has various likely causes about ulcerative colitis, they comprise family/heredity, immunity and infective agent.In ulcerative colitis, the diffusion difference of inflamed areas, symptomatology is also from heating and other General Symptoms occurring to being to change in the scope of slight symptom, and known colitis has high cancer complication ratio.
In the past, the processing of ulcerative colitis comprises the application of sulfasalazine, 5-aminosalicylic acid (it self is called as mesalazine) or derivatives thereof.
In these medicines, when oral, because 5-aminosalicylic acid almost completely is absorbed in upper digestive tract, it tends to not reach effective concentration at infection site when direct.
Yet the pharmacological action of 5-aminosalicylic acid (5ASA) in this disease (ulcerative colitis) is antiinflammatory action, and to producing the inhibition of leukotriene B4, free radical scavenging has proposed the immunologic mechanism about its mechanism.Though contain the medicine inflammation-inhibiting of 5ASA, they do not promote healing strongly.
Except that above-mentioned, in treatment of inflammatory bowel disease, though also immunosuppressant and steroid are used for inflammation-inhibiting, these immunosuppressant and steroid have the problem of disadvantageous side effect aspect.
So, need to develop the medicine that is used for inflammatory bowel, has minimal adverse side effects strongly.
The purpose of this invention is to provide a kind of preventive or therapeutic agent that is used for inflammatory bowel, it has eliminated the problems referred to above of prior art.
Another object of the present invention provides a kind of safer prophylactic or therapeutic agent that has minimal adverse side effects, is used for inflammatory bowel.
Another object of the present invention provides and a kind ofly not only can act on the inflammation that is confined to big enteral, also acts on the medicine of whole lower digestive tract.
Therapeutic agent for inflammatory bowel disease of the present invention comprises as the lafutidine of its active component, its optical isomer, lafutidine derivative or its pharmaceutically acceptable salt.
In first embodiment, the present invention relates to a kind of therapeutic agent that is used for generation of ulcer enteropathy and/or inflammatory bowel, it comprises the lafutidine as active component, its optical isomer or its pharmaceutically acceptable salt.
In second embodiment, the present invention relates to lafutidine, its optical isomer or the application that is used for handling the medicament of inflammatory bowel, the generation of ulcer enteropathy, ulcerative colitis and/or segmental enteritis in production of its pharmaceutically acceptable salt.
In another embodiment, the present invention relates to a kind of processing and suffer from the patient's of generation of ulcer enteropathy and/or inflammatory bowel method, this method is the reactive compound by group under being selected from that gives effective dose: lafutidine, its optical isomer, its pharmaceutically acceptable salt or its pharmaceutically acceptable derivant.
In another embodiment, the present invention relates to a kind of processing and suffer from the patient's of ulcerative colitis and/or segmental enteritis method, this method is the reactive compound by group under being selected from that gives effective dose: lafutidine, its optical isomer, its pharmaceutically acceptable salt or its pharmaceutically acceptable derivant.
In another embodiment, the present invention relates to a kind of pharmaceutical composition of handling the generation of ulcer enteropathy, inflammatory bowel, ulcerative colitis and/or segmental enteritis, it comprise a kind of treat effective dose be selected from lafutidine, its reactive compound and a kind of pharmaceutically acceptable carrier of optical isomer, its pharmaceutically acceptable salt or its pharmaceutically acceptable derivant.
Be used for representing the term " part " of weight ratio and " % " in hereinafter describing all based on weight, otherwise other explanation.
We are interpreted as inflammatory bowel and it is characterized in that (unknown etiology) intestinal obstacle of chronic functional, the spastic abdominal pain of recurrent, flatulence and diarrhoea, or constipation or follow secretion and discharge the alternative diarrhoea and the constipation of a large amount of mucus (not having blood).
We are interpreted as the ulcer sexual disorders of intestinal or the generation of disease, for example ulcerative colitis and segmental enteritis with the ulcer enteropathy.
We are interpreted as the colon of unknown etiology and the nonspecific inflammation of rectum with ulcerative colitis, it is characterized in that the diarrhoea with the discharge of mucus and blood, spastic abdominal pain and inflammation and edema with mucosa of ulceration.
The chronic inflammatory autoimmune disease of (comprise heredity with reason environment) that we are interpreted as that the cause of disease not too understands with segmental enteritis relates to the gastrointestinal arbitrary portion, but normally terminal ileum intestinal wall occurs and scabs and thicken.It usually causes intestinal obstruction and forms fistula and abscess, and has high relapse rate after processing.Inflammation spreads to the depths and causes spastic abdominal pain and with the diarrhoea of hemorrhage of rectum, follow reducing of appetite and body weight.
We will handle the processing that also is interpreted as acute attack and the maintenance of alleviation.It also comprises the processing of adventurous patient before seizure of disease.
Be used for lafutidine of the present invention, i.e. (±)-2-(furfuryl group sulfenyl)-N-[4-[4-(piperidino methyl)-2-pyridine radicals) the oxygen base-(Z)-crotyl] acetamide is the chemical compound with following structural formula (formula 1).
Formula 1
This lafutidine is a kind of known compound, and its production method is had no particular limits.Lafutidine can be according to disclosed method production in for example European patent EP 0 282 077 or the European patent EP 0 582 304.
In the present invention, though can use (±) form (that is, racemate), can increase a kind of content of optical isomer and/or can separate a kind of optical isomer by optical resolution or other conventional method.
More particularly, its expression, described active substance comprises a kind of optical isomer of 90wt% at least, the preferred lafutidine of 95wt% at least and 10wt%, the preferred another kind of optical isomer of the lafutidine of 5wt% at the most at the most.Each optical isomer can obtain by conventional method, that is, obtain from corresponding racemic mixture or by asymmetric synthesis.Each optical isomer can be used the racemic mixture acquisition of conventional method from it.
The adduct of not only representing and mineral acid sour herein as the term of using " pharmaceutically acceptable salt " with pharmaceutically acceptable non-toxic organic.
Lafutidine is sold as a kind of medicine usually in Japan, has peptic ulcer (gastric ulcer, duodenal ulcer) and gastritis as its indication.
In the present invention, though can use the lafutidine of the free state that is it, also can be pharmaceutically acceptable salt form as required and use it.Though be not particularly limited for the method that forms this class salt, but pharmaceutically acceptable salt can obtain by for example handling in suitable solvent with suitable acid.Applicable examples of solvents comprised water, methanol, ethanol, ether, oxolane (THF) was with diox this moment.The example of applicable acid comprises hydrochloric acid, hydrobromic acid, hydroiodic acid, sulphuric acid, nitric acid, phosphoric acid, acetic acid, maleic acid, fumaric acid, benzoic acid, citric acid, oxalic acid, succinic acid, tartaric acid, malic acid, mandelic acid, methanesulfonic acid, benzenesulfonic acid, p-methyl benzenesulfonic acid and 10-camphorsulfonic acid in the salt formation process.
Be not particularly limited can be used for lafutidine derivative of the present invention, only needing them is pharmaceutically acceptable derivants.The instantiation of this analog derivative comprises the Chemical ﹠amp; Pharmaceutical Bulletin Vol.46 (1998), the chemical compound 6,7,8,9,11,12,14,16,19,20,21 and 22 in the chemical compound of describing in the table 1 of pp.610～615; The Chemical ﹠amp; Pharmaceutical Bulletin Vol.46 (1998), the chemical compound of describing in the table 2 of pp.616～622 15, and European patent discloses the chemical compound of describing among the embodiment 1,2,3,12 and 21 contained in the table of describing among No.0282 077 B1 3 (pyridine radicals oxygen radical derivative) (chemical compound of embodiment 2 is a lafutidine self).Preferred chemical compound as lafutidine derivative is 2-furfuryl group sulfenyl-N-[4-[4-(piperidino methyl)-2-pyridine radicals oxygen base]-(Z)-and crotyl] acetamide.
In the present invention, lafutidine, its optical isomer, its derivant or the suitable therapeutic agent of making inflammatory bowel of its pharmaceutically acceptable salt hereinafter will be described.
Known lafutidine, its derivant or the protective effect of the gastric injury (ulcer) of its pharmaceutically acceptable salt with anti-artificial induction.
The mechanism of having reported the above-mentioned protective effect of lafutidine is to be mediated by the neural stimulation that is called as capsaicin-sensitive neurons in the sensory neuron that exists in the gastrointestinal mucosal.Learn that from the drug test that lafutidine is carried out described protective effect is the effect mediation by the reparation of acceleration loss injured tissue at least in part, and this effect is different from observed antiinflammatory action in steroid and 5-aminosalicylic acid.
Known capsaicin-sensitive neurons not only distributes under one's belt, also is dispersed throughout in the whole digestive tract.
Lafutidine shows the inhibition to the mucosa injury that occurs in the small intestinal, or its healing that promotes to rise by non-steroids analgesic antiphlogistic guiding drug, and owing to this effect of capsaicin is mediated by capsaicin-sensitive neurons, and capsaicin-sensitive neurons also is distributed in big enteral, the present inventor has studied the anti-effect that causes the inductive colitis of material of inflammation of lafutidine, thereby confirmed lafutidine acts and suppress the inflammation of large intestine or promote healing, so cause of the present invention finishing.
Segmental enteritis is a kind of mainly observed patient's condition in Young Adults, and it causes starting from digestive tract and spreads to the ulcer of anus from digestive tract, and follows generation abdominal pain, diarrhoea and hemafecia.Environmental factors and dietary habit are to its appreciable impact that has, and the intake of animal protein and fat is bigger and living standard is higher, and its incidence rate is just higher.
The clinical symptoms of segmental enteritis sharply changes according to the patient, and, though they are also different because of the damage location (little visible peristalsis visible intestinal peristalsis, big visible peristalsis visible intestinal peristalsis or small intestinal/big visible peristalsis visible intestinal peristalsis) of invasion and attack, observe the distinctive especially symptom of abdominal pain and diarrheal in most of patient.In addition, other usually observed symptom comprise heating, hemorrhage of rectum, abdominal tumor, by losing weight of causing of malabsorption, general malaise and anemia.In addition, in the course of disease of segmental enteritis, complication may occur partly, comprise fistulization, narrow, abscess, anal lesions, and the outer complication of intestinal, for example arthritis, iritis, erythema nodosum, also whether the existence of with good grounds these complication shows various symptoms.
Lafutidine as its active component, its also anti-effectively segmental enteritis of the therapeutic agent that is used for inflammatory bowel of optical isomer, lafutidine derivative or its pharmaceutically acceptable salt of comprising of the present invention.
But lafutidine as its active component, its therapeutic agent per os or the parenteral applications that are used for inflammatory bowel of optical isomer, lafutidine derivative or its pharmaceutically acceptable salt of comprising of the present invention, and can by for example suck, rectum inserts or topical use.Be not particularly limited for lafutidine of the present invention, its medicament forms of optical isomer, lafutidine derivative or its pharmaceutically acceptable salt.Lafutidine of the present invention, its optical isomer, lafutidine derivative or its pharmaceutically acceptable salt can be the form (for example powder, granule, tablet, pill, capsule, injection, syrup, emulsion, elixir, suspension or solution) of pharmaceutical composition for example or preparation and use.Consider distribution, be selected from oral formulations, suppository and be preferred through one or more medicament forms of Enteral formulations to damage location.
These compositionss or preparation can be by according to a conventional method with lafutidine of the present invention, its separately preparations or mixes the back as required with pharmaceutically acceptable carrier (for example adjuvant, medium, carrier and/or diluent) and prepare and obtain of optical isomer, lafutidine derivative or its pharmaceutically acceptable salt.
In the present invention, parenteral comprises for example subcutaneous injection, intravenous injection, intramuscular injection, peritoneal injection or intravenous drip.
Ejection preparation, for example waterborne suspension or the oily suspensions used of aseptic injection can utilize the preparation of suitable dispersant or humidizer by the known method in the association area.The preparation that aseptic injection is used can be solution or suspension, they can be in can be by the pharmaceutically acceptable diluent of parenteral or solvent (for example aqueous solution) aseptic injection.Suitable medium and acceptable solvent example comprise water, Ringer's mixture and isotonic saline solution.
In addition, sterile non-volatile oils also can be used as conventional solvent or suspended solvents.These nonvolatile oils comprise any nonvolatile oil, fatty acid, natural, synthetic or semisynthetic fatty oil or fatty acid, and natural, synthetic or semisynthetic monoglyceride, diglyceride or triglyceride.
Can prepare by medicine is mixed with suitable low irritant carrier for the suppository of rectally, described carrier for example is cocoa butter or Polyethylene Glycol, and it at room temperature is a solid, but is that liquid and it are in the internal rectum thawing and the release medicine under the temperature of intestinal.
The example of oral solid-state form of medication comprises powder, granule, tablet, pill and capsule.In so solid-state form of medication, active constituent compound can be mixed with at least a additive.This moment, applicable example additives comprised sucrose, lactose, cellulose sugar, mannitol, maltose alcohol, glucosan, starch, agar, alginate, chitin, chitosan, pectin, Tragacanth, Radix Acaciae senegalis, gelatin, collagen, casein, albumin, synthetic or semisynthetic polymer and glyceride.
Similar to the conventional medicine form, above-mentioned solid-state form of medication also can comprise other additive.The example of these other additives comprises inert diluent, magnesium stearate and other lubricant, parabens (parabenzenes), sorbic acid and other antiseptic, ascorbic acid, alpha-tocopherol, cysteine and other antioxidant, disintegrating agent, binding agent, thickening agent, buffer agent, sweetener, flavoring agent and spice.Tablet and pill also can wrap casing.
The example of liquid oral comprises pharmaceutically acceptable syrup, emulsion, elixir, suspension and solution.These liquid also can comprise the inert diluent (for example water) that is usually used in the association area.
The dosage form of therapeutic agent of the present invention is at least a form that is selected from peroral dosage form, suppository and parenteral dosage forms.
The patient dose of medicine of the present invention can and be considered those and other factors decides according to the degree of patient's age, body weight, general physical condition, sex, diet, administration time, medication, drainage rate, drug regimen and the patient who was subject to processing the at that time patient's condition.Because lafutidine, its optical isomer, lafutidine derivative or its pharmaceutically acceptable salt have hypotoxicity, so it can be used safely.
Though have such situation: wherein, the daily dose of described chemical compound is according to changes such as patient's situation, body weight, route of administration, but, for example under the situation of therapeutic agent administration as adult's ulcerative colitis, oral daily dose is about 10～60mg, preferably 10～40mg (and especially preferably 10～20mg), and the intravenous injection daily dose is about 0.1～3mg, preferably 0.1～1.5mg (and especially preferably 0.1～1mg), preferably with single-dose or be divided into twice or three administrations.
In addition, under the situation of therapeutic agent administration as adult's segmental enteritis, oral daily dose is about 10～60mg, preferably 10～40mg (and especially preferably 10～20mg), and the intravenous injection daily dose is about 0.1～3mg, preferably 0.1～1.5mg (and especially preferably 0.1～1mg), preferably with single-dose or be divided into twice or three administrations.
Though illustrated effect of the present invention by following experimental example, the present invention is subjected to the restriction of these embodiment never in any form.
Embodiment 1
Produced lafutidine (racemate) according to disclosed method in the European patent EP 0 282 077.
In addition, prepared optical isomer by the lafutidine that this racemate is separated to obtain (+) and (-) form respectively.
Utilize the lafutidine (racemate) and its (+) and (-) form of producing by this way to compare gastric mucosal protective effect separately.
The S.D. male rat (160～190g, Japan Charles River) in six ages in week is used for this test, before beginning test, closes foster 1 week in advance with these animal housing.
Will be as the lafutidine (racemate) of above-mentioned production, (+)-lafutidine and (-)-lafutidine are used for test after being suspended in 5% Arabic gum aqueous solution.
Fasting gave each medicine of 10mg/kg to animal (stipulating that every group of N only) per os after 18 hours, then gave 1% ammonia with the 5ml/kg per os after 30 minutes.Add information for matched group.Give ammonia after one hour,, excise stomach subsequently by making the cervical vertebra kill animals of offing normal.By injection 10ml formlinata aquae concentratac (about 2%) with the gastric distension of excision and fixing after, cut along greater gastric curvature.Utilize stero microscope to measure the surface area of gastric mucosa injury, and should be worth as ulcer coefficient.
In surface area test process, whether the part that shows gastric mucosa injury is differentiated with normal part according to the existence of petechia to gastric mucosal damage.
All results represent with mean+/-standard error, utilize Dunnett ' s check (reference: Dunnett, C.W. (1955), " A Multiple Comparisons Procedure forComparing Several Treatments with a Control ", U.S. statistical institution magazine (Journal of the American Statistical Association), 50,1096～1121) (SAS Institute Tokyo) is judged to be those results under the situation of P＜0.05 significantly.
As shown in following table 1 and Fig. 1, the racemic form of lafutidine, (+) form and (-) form all show the inhibitory action of the equal gastric mucosa injury that ammonia is caused.
Table 1
| Medicine | Dosage (mg/kg) | Injured surface amasss (mm 2) | Suppress (%) |
| Contrast | ????-- | ????42.2±5.4 | ????-- |
| (±)-lafutidine | ????10 | ????14.0±3.4 ** | ????66.8 |
| (+)-lafutidine | ????10 | ????16.3±5.2 ** | ????61.4 |
| (-)-lafutidine | ????10 | ????16.5±2.4 ** | ????60.9 |
*: significant difference compared with the control (Dunnett ' s t check, P＜0.01).
Embodiment 2
Used for seven ages in week, the normal male F144 rat of closing support clear-headed and not having fasting (body weight: 160～200g), otherwise explanation in addition.In addition, before the previous day that begins to test, normal the closing of animal supported, in the previous day that begins one's study animal is transferred in the Rotating Stainless Steel Cage, several groups that animal are divided into 4～8 every group then in the experiment that begins next day are used.
Dextran sodium sulfate [dextran sodium sulfate (DSS)], lafutidine, cimetidine and capsaicin are used for this experiment.
Prepare above-mentioned DSS with distilled water with the form of 3% solution, inject the suction dispenser and during support the pass of animal, allow animal arbitrarily drink.
Lafutidine, cimetidine and capsaicin are suspended in 0.5% sodium carboxymethyl cellulose (CMC), simultaneously SOD (superoxide dismutase) and azovan blue (Evan ' s blue) are dissolved in the concentration of normal saline to 1%.
Each medicine of preparation before application just, and with the amount oral administration of every 100g body weight 0.5ml.With identical amount with give matched group solvent separately by identical route of administration.
Colitis be by make animal freely accept 3% dextran sodium sulfate solution (DSS, molecular weight: 5,000, sulfur content: 15.0～20.0%) reach 7 days and inductive, also allow animal freely accept food.In addition, allow control animals freely accept distilled water similarly.
From experiment beginning, twice dosage per os with 5ml/kg gave lafutidine (3～30mg/kg) reached 6 days every day.Increase is about the information of cimetidine.
With identical amount with give control animals CMC and normal saline by identical route of administration.
Beginning to test the last fortnight carried out sensory neuron in continuous three days by the capsaicin of the subcutaneous 100mg/kg of total with independent dosage denervation.
Begin under etherization to give rat intravenous injection 1% azovan blue solution with after the DSS solution-treated 7 days, and after 1 hour under etherization by after heart total body perfusion normal saline kills rat, the excision large intestine.By 2% formalin solution being injected large intestine and large intestine is immersed this identical solution reaching 10 minutes in addition from the fixing large intestine of mucosa side and serosa side.
After in large intestine, making an otch along mesentery, use NIH Image 1.61 (freeware is downloaded from http://rsb.info.nih.gov/nih-image/download.html) and measured the surface area that damages colon and the rectum and colon length to rectum.
According to hereinafter based on to the method for Krawisz etc. (reference: gastroenterology (Gastroenterology) 1984, December, 87 (6): the program determination of improvement 1344～50) myeloperoxidase (MPO) (MPO) activity in the big intestinal mucosa.
After beginning to handle 7 days, by under etherization from heart total body perfusion normal saline and kill animals is then excised large intestine with 3%DSS and each medicine.
Big enteral in excision cuts along mesentery, after the cold saline washing, to the about 100mg of site sampling that damages in the distal colon.
Ratio with every 50mg 1ml of tissue weight adds extraction buffer (pH6.0,0.50mM phosphoric acid+0.5% cetyl trimethyl ammonium bromide (HTAB)), after with homogenization of glass device (Iuchi) homogenize, repeat freezing and melt three times, then in 2000rpm and cooling (0～4 ℃) centrifugalize 10 minutes down.
The centrifuged supernatant and the 1.9ml phosphate buffer (pH6.0,10mM phosphoric acid) of the above-mentioned acquisition of 0.1ml are added in 3.0～4.0ml glass cell, fully mix subsequently.Adding 1ml hydrogen peroxide-dianisidine reactant liquor (0.88mM hydrogen peroxide: 20mM 3,3'-dimethoxy-4,4'-diaminobiphenyl .=1: 200), use the variation of the absorbance at spectrophotometric determination 450nm wavelength place.
Utilize BCA protein analysis box (Pease) to measure the protein content of each sample.By adding hydrogen peroxide-dianisidine reactant liquor (0.88mM hydrogen peroxide: 20mM 3,3'-dimethoxy-4,4'-diaminobiphenyl .=1: 100 of the various concentration of 1ml in the 5 μ g/ml peroxidase reference materials that are determined at 0.1ml, 1: 200,1: 400,1: 800 and 1: 1600) during the variation of absorbance made standard curve, utilize following formula to calculate the MPO activity then.
Specific activity (μ mol H
2O
2/ min/ protein)=(OD/min)/(OD/1 μ mol H
2O
2* mg protein).
Total data is all represented with the mean+/-standard error of the value that obtains from every group of 4～8 animal.Tested statistical significance according to student t-check or Dunnett ' s multiple comparison test, under the situation of the significance level of P＜0.05, the result has been judged to be significantly.
Reduced to the lafutidine dose interdependence surface area of the big damage of intestines that DSS causes.Cimetidine not performance reduces effect.
Show that the injured surface similar to lafutidine is long-pending to reduce effect (as aforementioned) though observe capsaicin, this acts under the high dose (10mg/kg) and has disappeared.
Although have sign, after inducing inflammation, observe the active increase of MPO by DSS to the effect of MPO activity (indicators of phagocyte invasion and attack).Otherwise the lafutidine of 30mg/kg and the capsaicin of 3mg/kg (they have damaged area reduce effect) have caused that MPO is active and have reduced, and obviously suppressed inflammation.
Influence to large intestine (colon-rectum) length is another indication of big damage of intestines.DSS has caused reducing of large intestine length.Lafutidine shows dose-dependent length and reduces, and cimetidine does not show this effect.Though lafutidine act on the sensory neuron denervation after disappeared, this effect that lafutidine has been described is mediated by the capsaicin-sensitive sensory neuron.These medicines have produced and they similar results of effect to the surface area of damage the effect of large intestine length.
As previously mentioned, according to the present invention, provide to have therapeutic agent for inflammatory bowel disease minimal adverse side effects, safer.
Claims (9)
1. one kind is used for that the ulcer enteropathy takes place or the therapeutic agent of inflammatory bowel, and it comprises the lafutidine as active component, its optical isomer, its pharmaceutically acceptable salt or its pharmaceutically acceptable derivant.
2. the therapeutic agent of claim 1, wherein, described ulcer enteropathy comprises at least a disease that is selected from down group: ulcerative colitis and segmental enteritis.
3. claim 1 or 2 therapeutic agent, wherein, dosage form is at least a form that is selected from down group: peroral dosage form, suppository and parenteral dosage forms.
4. lafutidine, its optical isomer, its pharmaceutically acceptable salt or its pharmaceutically acceptable derivant are used for handling the application of the medicament of inflammatory bowel in production.
5. lafutidine, its optical isomer, its pharmaceutically acceptable salt or its pharmaceutically acceptable derivant are used for handling the application of the enteropathogenic medicament of ulcer in production.
6. lafutidine, its optical isomer, its pharmaceutically acceptable salt or its pharmaceutically acceptable derivant are used for handling the application of the medicament of ulcerative colitis in production.
7. lafutidine, its optical isomer, its pharmaceutically acceptable salt or its pharmaceutically acceptable derivant are used for handling the application of the medicament of segmental enteritis in production.
8. handle that ulcer enteropathy among the patient takes place or the method for inflammatory bowel, this method is the reactive compound of organizing by being selected from that gives effective dose under: lafutidine, its optical isomer, its pharmaceutically acceptable salt or its pharmaceutically acceptable derivant.
9. handle that the ulcer enteropathy takes place or the pharmaceutical composition of inflammatory bowel for one kind, what it comprised that treatment goes up effective dose is selected from lafutidine, its reactive compound and a kind of pharmaceutically acceptable carrier of optical isomer, its pharmaceutically acceptable salt or its pharmaceutically acceptable derivant.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2002129007A JP2003321366A (en) | 2002-04-30 | 2002-04-30 | Prophylactic or treating agent for inflammatory enteropathy |
| JP129007/2002 | 2002-04-30 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1649590A true CN1649590A (en) | 2005-08-03 |
Family
ID=29397289
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA038095386A Pending CN1649590A (en) | 2002-04-30 | 2003-04-28 | Therapeutic agent comprising lafutidine |
Country Status (5)
| Country | Link |
|---|---|
| JP (1) | JP2003321366A (en) |
| KR (1) | KR20040104658A (en) |
| CN (1) | CN1649590A (en) |
| AU (1) | AU2003229741A1 (en) |
| WO (1) | WO2003092692A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101199527B (en) * | 2007-12-20 | 2010-09-15 | 江苏奥赛康药业有限公司 | Lafutidine lyophilized powder injection and preparing method thereof |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR100703340B1 (en) * | 2004-12-11 | 2007-04-03 | 삼성전자주식회사 | Apparatus and method for providing broadcasting channel information in a digital broadcasting system based on internet protocol |
| JP5120875B2 (en) * | 2007-07-27 | 2013-01-16 | 大鵬薬品工業株式会社 | Preventive or therapeutic agent for stomatitis |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IE58373B1 (en) * | 1986-06-18 | 1993-09-08 | Bloomfield Frederick Jacob | 5-Lipoxygenase pathway inhibitors |
| US5294433A (en) * | 1992-04-15 | 1994-03-15 | The Procter & Gamble Company | Use of H-2 antagonists for treatment of gingivitis |
| EP0582304B1 (en) * | 1992-08-07 | 1998-04-01 | FUJIREBIO Inc. | Methods of producing amino butene derivatives |
| EP0954294A1 (en) * | 1996-06-12 | 1999-11-10 | The Procter & Gamble Company | Use of h2-antagonists for the manufacture of a topical composition for the treatment of colds |
-
2002
- 2002-04-30 JP JP2002129007A patent/JP2003321366A/en active Pending
-
2003
- 2003-04-28 CN CNA038095386A patent/CN1649590A/en active Pending
- 2003-04-28 AU AU2003229741A patent/AU2003229741A1/en not_active Abandoned
- 2003-04-28 KR KR10-2004-7017362A patent/KR20040104658A/en not_active Application Discontinuation
- 2003-04-28 WO PCT/EP2003/004415 patent/WO2003092692A1/en active Application Filing
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101199527B (en) * | 2007-12-20 | 2010-09-15 | 江苏奥赛康药业有限公司 | Lafutidine lyophilized powder injection and preparing method thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| AU2003229741A1 (en) | 2003-11-17 |
| JP2003321366A (en) | 2003-11-11 |
| WO2003092692A1 (en) | 2003-11-13 |
| KR20040104658A (en) | 2004-12-10 |
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