CN100448442C - Use of elastic protease inhibitor for preparing medicine for protecting cerebral hemorrhage - Google Patents
Use of elastic protease inhibitor for preparing medicine for protecting cerebral hemorrhage Download PDFInfo
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- CN100448442C CN100448442C CNB200510057405XA CN200510057405A CN100448442C CN 100448442 C CN100448442 C CN 100448442C CN B200510057405X A CNB200510057405X A CN B200510057405XA CN 200510057405 A CN200510057405 A CN 200510057405A CN 100448442 C CN100448442 C CN 100448442C
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Abstract
The present invention relates to new medical purposes of an elastic proteinase inhibitor and particularly relates to applications of a neutrophil elastic proteinase inhibitor of sivelestat during preparing medicines for preventing or / and treating cerebral hemorrhage. The sivelestat is in an injection form and is mainly selected from a freeze-dried injection and injection liquid. Animal research shows that the sivelestat has protective action on the cerebral hemorrhage.
Description
Technical field
(neutrophil elastase, NE) the new medical usage of inhibitor more specifically relate to neutrophil elastase inhibitor sivelestat and prevent or/and the utilization in the treatment cerebral hemorrhage medicine in preparation to the present invention relates to elastoser.
Background technology
Cerebral hemorrhage (intracerebral hemorrhage, ICH) mean non-traumatic brain intraparenchymal hemorrhage, behind the cerebral hemorrhage except the space occupying lesion of hematoma itself, decline, metabolism disorder, inflammatory reaction of surrouding brain tissue disturbance of blood circulation, local cerebral hemorrhage flow etc. are still arranged, thereby cause the damage and the cerebral edema of peripheral cell, cause the damaged of function of nervous system.
Apoplexy is clinical common emergency case, is more common in middle-older patient, and along with becoming clear day by day of aged tendency of population, the sickness rate of primary disease is also soaring day by day, and hemorrhagic apoplexy accounts for the 10%-20% of patients with cerebral apoplexy.It is anxious that cerebral hemorrhage has onset, changes soon, causes the high characteristics of disability rate and case fatality rate, has a strong impact on patient's existence quality of life.In addition, it is clinical common emergency case that craniocerebral trauma causes cerebral hemorrhage, very common at the craniocerebral trauma that industrial injury, vehicle accident cause at ordinary times, and in wartime, various weapons and abominable battlefield surroundings all might cause intracranial hemorrhage.In China, the incidence rate of annual cerebral trauma is 2/1000ths, intracranial hematoma is to see at most and the most dangerous secondary affection in the craniocerebral injury, its incidence rate accounts for 10% of closed trauma of head, but the concurrent intracranial hematoma of half patient is almost arranged in Heavy craniocerebral injury, often threaten patient's life because of diagnostic process is untimely.Though craniocerebral trauma causes cerebral hemorrhage and hemorrhagic apoplexy has certain difference, the treatment of the two has a lot of similarities.(intracerebral hemorrhage, ICH) deterioration of the state of an illness is often relevant with the damage of cerebral edema, inflammatory reaction, the energy metabolism disorder of hematoma surrounding tissue and oxygen-derived free radicals of secondary behind the ICH for cerebral hemorrhage.There is the scholar also to observe in the process of elastoser (NE) brain injury behind ICH that leukocyte in the inflammatory reaction discharges and has tangible effect.The about 10-40% of hematoma treated that modern medicine causes hemorrhagic apoplexy and the wound treatment that can undergo surgery, other can only carry out the internal medicine Comprehensive Treatment mostly.Wherein, inflammatory mediator that produces for inflammatory reaction such as cytokine, free radical, elastoser, can impel inflammation to continue, thereby further injured brain tissue, cell and nerve, wherein increasing of elastoser causes that the reduction of elastin laminin, proteoglycan and collagen causes tissue, cell and basement membrane of blood vessel damage.Therefore, how to control elastoser in case brain cell, tissue further impaired also be one of people's method of actively seeking.Discover that through us elastase inhibitor can suppress the generation and the activity thereof of elastoser when cerebral ischemia or cerebral hemorrhage, have the effect of protection cerebral tissue, cell, can avoid inflammation to continue development and cause brain damage.
The neutral elastoser of people (hereinafter abbreviating elastoser sometimes as) is a large amount of a kind of serine proteases that discharge of neutrophil granule that occur under infection or inflammatory diseases situation. elastoser is a kind of enzyme of hydrolyzed protein, the albumen of described hydrolysis for example is elastin laminin, collagen protein, proteoglycan, fibronectin etc., matter between the live body connective tissue of these albumen configuration examples such as lung, cartilage, blood vessel wall, skin etc. in addition, illustrated elastoser and also acted on other protein or cell.
In vivo, elastoser keeps live body dynamic equilibrium, and its activity is controlled by endogenous Profilin matter, for example Prolastin, α simultaneously
2-macroglobulin, excretory leukocyte protease inhibitor etc. still, when because the inflammation part elastoser excessively discharges or the inhibitor level reduces when causing between elastoser and the endogenous inhibitor disequilibrium, can not control elastase activity, thereby cause tissue injury.
The disease that elastoser (NE) may participate in has for example emphysema, adult respiratory distress syndrome (ARDS), idiopathic interstitial pneumonia (IIP), the capsule pulmonary fibrosis, the chronic interstitial pneumonia, chronic bronchitis, chronic hole pulmonary infection, the dispersivity panbronchiolitis, bronchiectasis, asthma, pancreatitis, nephritis, liver failure, chronic rheumatoid arthritis, arthrosclerosis, osteoarthritis, psoriasis, periodontitis, arteriosclerosis, organ transplant rejection, premature infant's amniorrhexis, the bulla dermatosis, shock, sepsis, systemic lupus erythematosus (SLE), Crohn disease, disseminated inravascular coagulation (DIC), the damage of ischemia reperfusion sex organization, corneal injury etc.
Elastase inhibitor suppresses the active of elastoser and produces; at present, elastase inhibitor especially the neutrophil elastase inhibitor in injury of lung, pancreatitis, nephritis, ischemia reperfusion sex organization Study on Damage, demonstrated organization protection effect.But elastase inhibitor especially neutrophil elastase inhibitor is used for the treatment of damage of cerebral tissue that cerebral hemorrhage causes and brain cell and the research of prevention does not have bibliographical information.The inventor finds that after deliberation the neutrophil elastase inhibitor has protective effect to cerebral hemorrhage, and especially the tissue injury that elastoser is caused has good protection effect.For this reason, finish the present invention.
Summary of the invention
The object of the present invention is to provide a kind of new method that prevents and/or treats cerebral hemorrhage; specifically provide the especially new purposes of neutrophil elastase inhibitor of elastase inhibitor, i.e. the utilization of neutrophil elastase inhibitor in protection cerebral hemorrhage medicine.More specifically be meant sivelestat or its officinal salt or its medicinal derivative, the preferred sivelestat sodium of its pharmaceutical salts, said here sivelestat sodium is the tetrahydrate form.
Said protection cerebral hemorrhage be meant be used for the treatment of and (or) prevention of cerebral hemorrhage, reduces the hemorrhage and hemorrhage Secondary cases cerebral tissue of initiation afterwards and the damage of brain cell.
The said utilization of the present invention is meant the form of sivelestat sodium with injection, preferred freeze-dried powder and injection.Preferred freeze-dried powder, every single agent contain sivelestat sodium 50-500mg, preferred 100-300mg.
The daily dose scope of sivelestat sodium is 5-1500mg, preferred 10-1000mg, more preferably 10-500mg.
Above-mentioned said injection also comprises pharmaceutic adjuvant, as excipient, solubilizing agent, cosolvent, PH regulator, antioxidant etc.
Excipient: lactose, glucose, sucrose, trehalose, mannitol, sorbitol, gelatin hydrolysate, glycine, glutamic acid, dextran, sodium chloride etc. are one or more mixture wherein, 0.01%～50% (w/v).
Hydrotropy solubilizing agent: polyvinylpyrrolidone, poloxamer, beta-schardinger dextrin-, HP-beta-schardinger dextrin-, glycerol, 0.001%～30% (w/v).
PH regulator agent: phosphoric acid and phosphate (sodium dihydrogen phosphate, sodium hydrogen phosphate, tertiary sodium phosphate, dipotassium hydrogen phosphate, potassium phosphate), carbonic acid and carbonate (sodium bicarbonate, sodium carbonate), citric acid and citrate (disodium citrate, sodium citrate), hydrochloric acid, sodium hydroxide, potassium hydroxide, glycine, Glycine sodium, deoxycholic acid, sodium deoxycholate, ammonium hydroxide, acetic acid and sodium acetate, 0.001%～30% (w/v).
Antioxidant: sodium sulfite, sodium sulfite, sodium pyrosulfite, sodium thiosulfate, thiourea, vitamin C, 0.001%～20% (w/v).
Chelating agent: EDTA-CaNa, EDTA-2Na, 0.001%～20% (w/v).
Solvent: one or more mixed solvents such as water, ethanol, propylene glycol, polyhydric alcohol.
The above neutrophil elastase inhibitor also comprises tifacogin (tifacogin), people's Prolastin (human alpha-1-proteinase inhibitor), AE-3763, depelestat, erdosteine (erdosteine), elafin, ABT-491, SLAPI, TAPI, FK-706, ICI-200880, ZD-0982, ZD-8321, BI-L-45XX, BI-RA-260, ONO-6818, DF-1283, GW-311616, ALP-242, eglin, lodelaben (lodelaben), SSR-69071, FR-134043, FR-901451, AAPbV, CE-0137, AN-090, NX-21909, Ro-31-3537, midesteine (midesteine), L-658758, L-659286, L-680833, L-683845, orazipone, FCE-28204, PBI-1101, MDL-100948A, MDL-104238, MDL-27324, SR-26831, SR-268794, LEX-001, LEX-032, TEI-8362, SPAAT or its pharmaceutically useful derivant.
Preferred sivelestat sodium or its pharmaceutically useful derivant in the property granulocyte elastase inhibitor are in these used the tetrahydrate form of sivelestat sodium usually.
The molecular formula of sivelestat sodium (sivelestat sodium) is C
20H
21N
2O
7Na.4H
2O is a kind of neutrophil elastase inhibitor by Japanese firm's exploitation, is used for the treatment of acute lung injury in Japan's listing.
Sivelestat sodium is that (neutrophilic polymorphonuchearleukocytes, PMN) NE (elastoser) inhibitor can reversibility and suppress NE competitively for a micromolecule polymorphonuclear granulocyte.Clinical research confirmation, sivelestat sodium improves the respiratory function with acute lung injury (ALI) patient of systemic inflammatory reaction syndrome (SIRS) by suppressing the elastoser that neutrophilic granulocyte discharges.Its main mechanism may be: directly suppress the synthetic and release of NE, reduce the alveolar epithelial cells and the vascular endothelial cell damage of activatory neutrophilic granulocyte mediation; Reduce the permeability of pulmonary vascular endothelial cell, reduce the release of thrombomodulin, reduce the permeability of pulmonary artery pressure and lung; Suppress person monocytic cell's the generation that causes inflammatory factor such as IL-β, IL-6, tumor necrosis factor (TNF-α) etc.External existing report sivelestat sodium can improve cerebral edema, brain injury and the inflammatory reaction that Cerebral Ischemia causes.
The present invention mainly realizes by following scheme:
The present invention is mainly from neural biochemical, three aspects of neuro pathology and behavioristics, observe and research sivelestat sodium to collagenase the protective effect of inductive rat cerebral hemorrhage mold.
The present invention selects for use and induces the rat brain internal hemorrhage model of generation by collagenase is object of study, and medicine Ni Lisu (nimodipine) commonly used is the contrast reference with present clinical treatment cerebral hemorrhage, has studied the protective effect of sivelestat sodium to cerebral hemorrhage.Learn variation, pathology, brain water content change by ICH rat behavior after the paired observation administration, proved that sivelestat sodium has protective effect to cerebral hemorrhage.
The Mus cerebral hemorrhage mold that the present invention selects for use is the collagenase guidance model, and this model is one of cerebral hemorrhage mold the most commonly used both at home and abroad at present.The collagenase that adopts in this model (collagenase) is a kind of metalloproteases, matter and basement membrane collagen between degradable, be injected in the brain after, the collagen of the blood vessel wall of degrading, thus cause hemorrhage.This model in some aspects pathology such as cerebral edema, histology and behavioristics etc. with clinical very approaching, and the amount of liquid that this mould injects in brain is less, does not almost have the compressing occupy-place effect of medicinal liquid itself.
The present invention adopts the rat model that the collagenase injection is made in tail shell (shape) nuclear.It is nuclear group maximum in the Mus brain that the tail shell is examined, and is easy to the location, and tail shell nuclear genus ganglion basal, is that the position is preferably sent out in human hypertensive cerebral hemorrhage.Model group animal tail shell nuclear all forms typical hematoma behind the stereotactic injection 0.5U collagenase in brain, occurs the neurologic defect sign simultaneously, goodish clinical sign of having simulated with the position cerebral hemorrhage.This model modeling success rate height (the hemorrhage incidence rate of rat brain that the present invention is used for modeling is 100%), good reproducibility is comparatively ideal study model.
Conclusion:
The ICH rat behavior that sivelestat sodium (150mg/kg) can promote collagenase to cause is learned the recovering process that changes; Alleviate the generation of cerebral edema and be dose dependent; Reduce the activity of cerebral tissue NE and the content of NO, sivelestat sodium can alleviate the pathology damage of the hemorrhage side brain cell of ICH rat simultaneously.Show that sivelestat sodium has protective effect to the caused rat ICH of collagenase.
Result of the test proves; sivelestat sodium can effectively reduce the scoring of the hemorrhage back of rat brain function of nervous system, and the increase that can significantly alleviate brain water content can obviously alleviate pathological change; the activity of the NE of reduction cerebral tissue and the content of NO have significant protective effect to cerebral hemorrhage.Protective effect and the nimodipine hemorrhage to rat brain are suitable.
The other animal test results of the present invention shows that also sivelestat sodium (150mg/kg) can reduce the increase degree of the hemorrhage side brain of the caused ICH rat of collagenase BBB permeability; Can stop the reduction of SOD content in the hemorrhage side brain of the caused ICH rat of collagenase and the rising of MDA content; Can reduce the increase of interior TNF-alpha expression of the hemorrhage side brain of the caused ICH rat of collagenase and MPO content.Show sivelestat sodium may be by rat BBB behind the protection ICH, improve tissue and remove the gathering of the ability of free radical and anti-polymorphonuclear granulocyte, discharge the rat ICH that mechanism realization such as inflammatory mediator causes collagenase and have protective effect.
Description of drawings
Fig. 1
Sivelestat sodium is to the influence of the hemorrhage back of rat brain 4h, 8h, 12h, 24h neurological scoring
* p＜0.05VS model; △ p＜0.05VS sivelestat sodium-l; * p＜0.01VS model; △ △ p＜0.01VS sivelestat sodium-l
Fig. 2
Sivelestat sodium is to the influence of the hemorrhage back of rat brain 4h, 8h, 12h, 24h brain water content
* p＜0.05VS model; * p＜0.01VS model; △ p＜0.05VS sham; △ △ p＜0.001VS sham
The specific embodiment
Embodiment 1 sivelestat sodium is to the hemorrhage protective effect of rat brain
Material and method
Experiment material:
Laboratory animal:
The Wistar rat, male and female half and half, body weight 180-250g is provided by Medical University Of Chongqing's Experimental Animal Center.12h fasting before the art is freely drunk water.
Main agents and medicine:
Collagenase VII type U.S. Sigma company
Positive Xinghua, chloral hydrate Suzhou factory
Sivelestat sodium Chongqing Medicine Industry Academe Co.,Ltd
Nimodipine (Ni Lisu) Tai'an, Shandong pharmaceutical factory
Key instrument:
Optical instrument factory, stereotaxic instrument northwest
Microsyringe Shanghai Bao Xi glass apparatus factory
Thermostatic drying chamber Chongqing experimental apparatus factory
Electronic analytical balance Sartorius, Germany
Microscope H-2 Japan Ou Lin Bath company (OLYMPUS)
Experimental technique:
1, laboratory animal grouping:
Animal is divided into five groups promptly at random: sham-operation (sham) 24h group; ICH+ normal saline group (model); ICH+ sivelestat sodium (150mg/kg) group is called high dose group (h); ICH+ sivelestat sodium (75mg/kg) group is called low dose group (1); ICH+ nimodipine (50 μ g/100g) group.Four groups in back are divided into 4h again, 8h, 12h, four time point subgroups of 24h.Normal saline, sivelestat sodium and nimodipine before the ICH modeling 30min through the rat tail vein administration, once a day.Slowly injection, the medicinal liquid overall control is in the 1ml/200g body weight; Normal saline also gives by the 1ml/200g body weight.7 of every group of Wistar rats.
2, the foundation of rat ICH model:
This paper is with reference to reported method such as Rosenberg.The concrete operations step is as follows: experimental mouse is after chloral hydrate (350mg/kg) intraperitoneal anesthesia, dorsal position is fixed on the stereotaxic instrument, and wait the localization method of reports to make according to the bag new people and call the hook plane than the low 2.4mm in biauricular line plane, rat bregma and posterior are on same plane like this.Use iodine tincture partly sterilised, the scalp median incision is cut off periosteum, exposes bregma, and 1mm behind bregma, center line be other left to be opened the 3mm place and be approximately the aperture of 1mm with No. five pin drill one diameters, reaches cerebral dura mater deeply.Be fixed on the stereotaxic instrument microsyringe along boring inserting needle, depth of needle is 5.8mm (being the caudatum position), slowly injects collagenase VII0.5U (being mixed with 1U/ μ l with normal saline).Be 3min inject time, the 5min withdraw of the needle again that let the acupuncture needle remain at a certain point after having injected, and skin suture steams again and raises then.A sham operated rats contact pin, injectable drug not, all the other operations are the same.
Statistical procedures: each organizes measured value, and (x ± SD) expression does one factor analysis of variance (one-way ANOVA), significance level p＜0.05 with the SPSS statistical software with mean ± standard deviation.
3, observation index:
(1), sivelestat sodium is to the influence of ICH rat neurological scoring
After animal revived, each group was all carried out neurological deficit immediately according to the neurologic defect rank scores standard (improving a little) of Bederson etc. and is marked.Standard is as follows: (seeing Table 1)
Table 1 ICH rat model neurological standards of grading
3 minutes and above animal go into the anthology experiment, postoperative animal sub-cage rearing, normal feed water inlet.Room temperature is controlled at 20-25 ℃, and 4h, 8h, 12h, 24h mark after modeling later on.
The result: each time point neurological deficits score of sham operated rats is 0 fen; Scoring immediately was 3 fens or 4 minutes after the model group Animal Anesthesia was clear-headed, and ICH rat modeling success is described on the one hand, illustrated that on the other hand ICH has caused very significantly rat neurologic impairment.As time goes on we observe simultaneously, and each organizes ICH rat function of nervous system scoring decline gradually, and the decline of administration group scoring is faster than model group.The neurologic defect scoring of the heavy dose of sivelestat sodium of 12h, 24h administration group and model group, the corresponding time point of low dose of sivelestat sodium group is than there being significant difference (p＜0.05) behind ICH, and marks than there not being significance with the nimodipine group neurologic defect of corresponding time point.12h, 24h time point behind ICH, the nimodipine group is marked than significant difference (p＜0.05) is arranged with the neurologic defect of model group, the corresponding time point of low dose of sivelestat sodium.Though low dose of sivelestat sodium group has also reduced the neurologic defect scoring of corresponding time point to a certain extent, mark than not having significant difference with the neurologic defect of the corresponding time point of model group.Neurologic defect was marked after above-mentioned observation prompting sivelestat sodium 150mg/kg intravenously administrable can improve ICH, and its effect is similar in appearance to the effect of the nimodipine generation of 50 μ g/100g.(see Table 2, Fig. 1)
The influence that table 2 sivelestat sodium is marked to the hemorrhage back of rat brain 4h, 8h, 12h, 24h neurological (x ± SD, n=7)
Annotate: * p＜0.05VS model; △ p＜0.05VS sivelestat sodium-l
* p＜0.01VS model; △ △ p＜0.01VS sivelestat sodium-l
(2), brain water content (BWC) is measured:
Observe of the influence of sivelestat sodium to the hemorrhage back of rat brain 4h, 8h, 12h, 24h brain water content, each treated animal is at the preset time point, and after chloral hydrate anesthesia, broken end is got brain rapidly, the cerebral tissue that takes out is placed on the filter paper of using the moistening mistake of normal saline, divides evaporation to prevent water.Removing pia mater encephali and bloodstain, is the center with the inserting needle hole, cuts the first half cerebral tissue, precision weigh (being accurate to 0.1mg).Get brain to having claimed the weight time to be controlled in the 5min.Place 95 ℃ of constant temperature oven 24h then, take by weighing dry weight again.Press the Blliot formula and calculate brain water content:
BWC=(weight in wet base-dry weight)/weight in wet base * 100%.
The result: analytical table 3 can be found, its brain water content of the hemorrhage back of rat brain rises than obvious with sham operated rats at 4h, 8h, 12h, 24h time point, and has a significant difference (p＜0.05), and brain water content is along with the process of time constantly increases, and reaches a peak behind cerebral hemorrhage in 24 hours.Treatment group ICH rat brain water content and model group ratio, each time point all reduce in various degree.Wherein, heavy dose of sivelestat sodium administration group and model group, low dose of sivelestat sodium group have significance (p＜0.05) at its brain water content reduction degree difference of four corresponding time point comparisons, though more do not have significance (p＞0.05) with the nimodipine group than reducing degree at its brain water content of four corresponding time points.The nimodipine group reduces degree at its brain water content of four corresponding time points also has significant difference (p＜0.05) with the model group ratio.Though low dose of sivelestat sodium group also can reduce ICH rat brain water content in various degree, with model group ratio and there was no significant difference (p＞0.05).These results show, the order of severity of rat brain edema behind sivelestat sodium 150mg/kg administration can the reduction ICH, and its therapeutic effect is similar to the effect of the nimodipine of 50 μ g/100g.(see Table 3, Fig. 2)
Table 3 sivelestat sodium to the influence of the hemorrhage back of rat brain 4h, 8h, 12h, 24h brain water content (± SD, n=6)
* p＜0.05VS model; * p＜0.01VS model;
△p＜0.05VS?sham；△△p＜0.001VS?sham；
(3), pathological study:
Observe of the influence of sivelestat sodium to the hemorrhage pathomorphism of rat brain.Each treated animal of picked at random, with the chloral hydrate deep anaesthesia, broken end is got brain rapidly, cuts the cerebral tissue sheet (about 5mm) that contains hematoma in preset time point, put into 10% formalin immediately, fixedly 24h is after the ethanol gradient is dewatered, and dimethylbenzene is transparent, waxdip, embedding, section (5 μ m), HE dyeing, mounting.Om observation diseased region and near brain tissue pathology change.
The result: tangible pathological change appears in rat cerebral tissue behind the cerebral hemorrhage, and the 4th, 8,12 hour section can be seen tangible hemorrhagic focus, and the focus surrounding tissue edema of loosening is with a little inflammatory cell infiltration; The 24th hour section can be seen the still loose edema of focus surrounding tissue, and inflammatory cell infiltration is even more serious.
Give heavy dose of sivelestat sodium treatment ICH rat in advance and can obviously alleviate tissue edema and inflammatory cell infiltration behind the cerebral hemorrhage; And give low dose of sivelestat sodium in advance or Ni Lisu also can alleviate above-mentioned pathological changes in various degree.
(4), to the influence of NE in the cerebral tissue
Each organizes rat after chloral hydrate anesthesia, and fast broken end is got brain, cuts the pin hole surrouding brain tissue, after precision is weighed, as the homogenate medium, makes 10% tissue homogenate with normal saline with glass homogenizer in the ice bath environment.Get supernatant and measure the NE activity with double antibodies sandwich ELISA method.
Result: compare cerebral tissue NE active obviously increase (P＜0.01) in the hemorrhage back of rat brain with sham operated rats; Sivelestat sodium high and low dose all can significantly reduce the NE activity (p＜0.01) (seeing Table 4) of the hemorrhage back of rat brain cerebral tissue.
Table 4 sivelestat sodium is to the influence of the NE of ICH rat cerebral tissue content
Annotate: △ P p＜0.01VS model
(5), to the influence of NO in the cerebral tissue
Each organizes rat after chloral hydrate anesthesia, and broken end is got brain fast, cuts the pin hole surrouding brain tissue, after precision is weighed, as the homogenate medium, in the ice bath environment, make 10% tissue homogenate with normal saline, get supernatant and measure NO content with nitrate reductase method with glass homogenizer.
The result: compare with sham operated rats, the hemorrhage back of rat brain cerebral tissue NO content obviously increases (p＜0.01), and sivelestat sodium high and low dose all can reduce the content (p＜0.01) (seeing Table 5) of the hemorrhage back of rat brain cerebral tissue NO.
Table 5 sivelestat sodium is to the influence of the NO of ICH rat cerebral tissue content
Annotate: △ P p＜0.01VS model
Embodiment 2 sivelestat sodium freeze-drying powders
Sivelestat sodium 100g
Mannitol 300g
Polyvinylpyrrolidone 100g
Sodium carbonate is an amount of
Water for injection is diluted to 51
Make 1000 bottles
Preparation technology:
Sodium carbonate is mixed with 4% solution for standby; Sivelestat sodium, mannitol, polyvinylpyrrolidone mix the back and add a certain amount of water for injection, after being stirred well to dissolving, transfer pH to 6.5～8.5, use the water for injection standardize solution then with sodium carbonate liquor, through just being distributed into the 5ml/ bottle after filter, the aseptic filtration, lyophilization promptly.
Embodiment 3 sivelestat sodium injections
Sivelestat sodium 100g
HP-beta-schardinger dextrin-100g
EDTA-CaNa 1g
Sodium pyrosulfite 1g
Sodium phosphate is an amount of
Water for injection is diluted to 5L
Make 1000 bottles
Preparation technology
Sodium phosphate is mixed with 4% solution for standby; After sivelestat sodium, HP-beta-schardinger dextrin-, EDTA-CaNa, sodium pyrosulfite mixing, add a certain amount of water for injection, fully stir and make its dissolving, transfer pH to 6.5～8.5 with sodium radio-phosphate,P-32 solution then, the water for injection standardize solution, packing promptly after filter, aseptic filtration just.
Using method:
For patients with cerebral hemorrhage, freeze-dried powder dilutes with normal saline, presses 0.2-0.5mg/kg/ hour infusion, can administration in 24 hours.
List of references:
1、Rosenberg?GA.Mun-bryce?S.Wesley?M，et?al.Collagenase-induced?intracerebral?hemorrhagein?rats.Stroke，21(5)：801-807，1990
2, bag new people, Shu Siyun.The rat brain stereotaxic atlas.Beijing: People's Health Publisher, 1991
3、Bederson，JB，Pitts?LH，Nishimura?MC，et?al.Rat?middle?cerebral?artery?occlusion：evalutionofthe?model?and?development?ofa?neurologic?examination.Stroke，1986；17(13)：472-476
Claims (9)
1, sivelestat or its officinal salt prevent and/or treat application in the cerebral hemorrhage medicine in preparation.
2, the application of claim 1, the officinal salt of said sivelestat are sivelestat sodium.
3, the application of claim 2, said sivelestat sodium is the tetrahydrate form.
4, the arbitrary described application of claim 1～3, said sivelestat sodium is the injection form.
5, the application of claim 4, said sivelestat sodium injection form is selected from freeze-dried powder and injection.
6, the application of claim 4, said injection also comprises pharmaceutic adjuvant.
7, the application of claim 6, said pharmaceutic adjuvant comprise excipient, solubilizing agent, cosolvent or pH value regulator.
8, the application of claim 2, the daily dose scope of said sivelestat sodium is 5-1500mg.
9, the application of claim 8, the daily dose scope of said sivelestat sodium is 10-500mg.
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|---|---|---|---|---|
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Non-Patent Citations (2)
| Title |
|---|
| 炎性细胞因子在脑出血继发性脑损害中的应用. 吴万福等.国外医学脑血管疾病分册，第13卷第4期. 2005 |
| 炎性细胞因子在脑出血继发性脑损害中的应用. 吴万福等.国外医学脑血管疾病分册，第13卷第4期. 2005 * |
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