CN101444520A - Application of progesterones in preparing medicament for curing severe stroke and brain injury - Google Patents
Application of progesterones in preparing medicament for curing severe stroke and brain injury Download PDFInfo
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Abstract
The invention provides an application of progesterones in preparing medicament for curing severe stroke and brain injury. The medicament can be prepared into intravenous injection, muscle injection or implant according to the conventional method in the field. Continuously feeding injection or implant of the medicament is needed within 8 hours after severe stroke and brain injury occur. The application mainly has the beneficial effects that a new application of progesterones in preparing medicament for curing severe stroke and brain injury is provided, acute cerebral necrosis caused by severe stroke and brain injury can be effectively prevented, nerve function recovery of patients with ischemic brain injury can be promoted, the death rate can be reduced, therefore, the application has good clinical application prospect.
Description
(1) technical field
The present invention relates to the application of Progesterone in the medicine of preparation treatment serious symptom apoplexy and brain injury.A kind of neurological functional recovery that prevents the acute brain tissue necrosis and promote brain injury patients is provided, and reduces the medicine approach of mortality rate.
(2) background technology
In acute serious symptom hemorrhagic and ischemic brain injury, apoplexy and cerebral trauma are the most common, be to threaten human life's important illness and the major reason that disables clinically, the national coroner's inquest result that Ministry of Public Health is announced shows, cerebrovascular has become the first cause of death of China urban and rural residents, accounts for 22.45% of dead sum.According to investigations, about 2,000,000 people of national annual New Development apoplexy die from about 1,500,000 people of cerebrovascular every year.Traumatic brain injury, in recent years by vehicle accident, fall, sickness rate that motion and natural disaster etc. are caused rises very soon, according to statistics, in developed country, the annual morbidity of department of pediatrics TBI is at 124,89/,100,000 populations.In China, traumatic brain injury accounts for second in each position damage of whole body, and case fatality rate occupies first especially up to 35～50%.
Acute serious symptom apoplexy and brain injury are because morbidity is anxious, the state of an illness is heavy, it is very complicated to hinder the back pathological process, has very high case fatality rate, the still high certificate of case fatality rate of acute in the world serious symptom apoplexy and brain injury is not down at present, treat very difficult, integrative therapy does not have the medicine of desirable effect at present, yet there is not the cranial nerve function recovery after a kind of effective Therapeutic Method can obviously improve acute serious symptom apoplexy and brain injury, maybe can reduce mortality rate, the huge especially financial burden concerning society and Health care system of its long term body obstacle that is brought of acute serious symptom apoplexy and brain injury, and become world-famous puzzle.Therefore find a kind of suitable acute serious symptom apoplexy of treatment and the method for brain injury to have very important social meaning.
After acute serious symptom apoplexy and brain injury took place, a series of reaction was as inflammation immunoreation, acetylcholine, GABA
ACan cause neuronic minimizing with destruction of nmda receptor system etc.And cerebral edema, cerebrovascular destruction and enhanced inflammation immunoreation cause further neuronal degeneration through regular meeting, thereby cause serious secondary injury.Therefore, the purpose for the treatment of acute serious symptom apoplexy and brain injury is to prevent and treat neurological deficit and apoptosis in the brain injury, the neuronic secondary injury of protection residue, and recover normal physiological environment in the brain.
The clinical method that is used for the treatment of acute serious symptom apoplexy and brain injury mainly comprises clinical monitoring at present, suits the medicine to the illness and supports and operative treatment.But in the acute serious symptom apoplexy and the brain injury patients that are caused in the face of cerebrovascular, vehicle accident and the natural disaster that takes place frequently, traditional medicine can not reduce acute patient with severe symptoms's case fatality rate, always lacks a kind of simple and effective medicine.
(3) summary of the invention
The object of the invention provides the application of Progesterone in the medicine of preparation treatment serious symptom apoplexy and brain injury, and the medicine of the relevant cerebrovascular class disease of a kind of effective treatment is provided.
The technical solution used in the present invention is:
The application of Progesterone in the medicine of preparation treatment serious symptom apoplexy and brain injury.Concrete, described apoplexy comprises: cerebral infarction, cerebral hemorrhage or subarachnoid hemorrhage.Described brain injury is cerebral tissue necrosis or the disordered brain function that acute traumatic brain injury, cerebral ischemia cause.
Described medicine can be prepared into intravenous injection, intramuscular dose or skin and bury agent by this area conventional method.Described medicine needs in serious symptom apoplexy and brain injury 8 hours, carries out administration by giving the route of administration that injection or skin bury agent continuously.
When described medicine was intravenous injection, described intravenous injection effective dose was per 12 hours of 0.5mg～1.5mg/kg body weight, and after administration for the first time, administration needs to continue 7 days at least.
When described medicine was intramuscular dose, described intramuscular dose effective dose was per 12 hours of 1.0mg～3.0mg/kg body weight, and after administration for the first time, administration needs to continue 7 days at least.
Described medicine is a skin when burying agent, and it is per 72 hours of 5.0mg～12.0mg/kg body weight that described skin buries the agent effective dose, and after administration for the first time, administration needs to continue 21 days at least.
Progesterone (structure is formula as follows) is a kind of estrogen in the oral contraceptive, is produced by ovary and Placenta Hominis, generally is used to regulate the relevant function of reproduction clinically.
The method Therapeutic Method different from the past of acute serious symptom apoplexy of the treatment that the application provides and brain injury has been broken through the limitation that traditional Progesterone only is used for obstetrical and gynecological disease, has opened up the new mode and the route of administration of acute serious symptom apoplexy and brain injury treatment.A series of animal experiment and clinical trial prove that this method can be prevented and treated the secondary injury of neurological deficit, apoptosis and brain in acute serious symptom apoplexy and the brain injury effectively, and promote the recovery of interior normal physiological environment of brain and function.
Consider and to adhere to that the treatment of longer Progesterone needs the very strong compliance of patient that for the people and traumatic brain injury infant at advanced age of apoplexy, medicine of the present invention preferentially adopts intramuscular injection, intravenous injection and skin to bury the mode administration of agent especially.
It is that a class can import subcutaneous controlled release preparation through syringe needle that skin buries agent, claiming subcutaneous controlled release form again. it continues to discharge medicine with the zero order kinetics rate of release, the medicine that discharges directly enters blood circulation and brings into play its effect after subcutaneous absorption, high bioavailability and long administration time are arranged, be particularly suitable for being applied to the not high patient of compliance; This crust bury agent also have many other advantage as: eliminate the peak valley phenomenon that produces because of the administration at intermittence; Can continue to discharge medicine with constant relatively speed at specific site of action, and keep the treatment concentration of medicine.
The present invention is the application of Progesterone in the medicine of preparation treatment treatment serious symptom apoplexy and brain injury.Progesterone has confirmed it is a kind of maincenter and peripheral nervous system of being present in, need not rely on " the neurosteroid hormone " of endocrine body of gland, is that raw material is synthetic with the cholesterol under the effect of the corresponding enzyme of glial cell that can be in brain.Experiment confirm: active steroid hormone can combine with intracellular receptor, and the growth and the manhood brain function of brain produced secular effect, and participates in stress.
The mechanism of Progesterone treatment brain injury is not illustrated as yet fully, the zoopery prompting, and Progesterone has protective effect to brain injury, and it may be by retardance and Na
+-K
+The Na of-ATP enzyme mediation
+Enter cerebrovascular and cerebral tissue and alleviate cerebral edema; Progesterone receptor is distributed in the central nervous system widely, and zoopery shows the death that gives the progesterone treatment and can prevent neurocyte behind brain injury, the recovery that improves function of nervous system.In addition, Progesterone can be regulated nitric oxide production formation by the cerebrovascular regulatory function of protection, and mechanism such as anti-apoptosis play a role.Studies show that in central nervous tissue, the Progesterone treatment can reduce production of cytokines and weaken immunoreation, thus neuroprotective unit.
Beneficial effect of the present invention is mainly reflected in: the new purposes of Progesterone in the medicine of preparation treatment serious symptom apoplexy and brain injury is provided, can effectively prevent the acute brain tissue necrosis that serious symptom apoplexy and brain injury cause, promote the neurological functional recovery of brain injury patients, and the reduction mortality rate, have great potential applicability in clinical practice.
(4) description of drawings
Figure 1A is cerebral ischemia group postoperative 3 days, the neurocyte necrosis, and cell space shrinks, the neuron loss phenomenon;
Figure 1B is Progesterone group treatment 3 days, and cell and intercellular substance swelling degree are light, and visible structure is recovered good neurocyte.
Fig. 2 A is that after 7 days extensive non-structure district around cell and the blood vessel for wound; Fig. 2 B is wound Progesterone treatment group, as seen neuronal structure maintenance and recovery after 7 days.
Fig. 3 is a clinical trial flow chart of the present invention;
Fig. 4 is Progesterone group and the acute patient with severe symptoms's intracranial pressure of placebo treatment group comparative result.
(5) specific embodiment
The present invention is described further below in conjunction with specific embodiment, but protection scope of the present invention is not limited in this:
Injection and skin used in the experiment bury agent:
Injection is the sterilization oil solution of Progesterone, containing the Progesterone labelled amount is 93.0～107.0% (production product men: Tianjin pharmaceutical factory, specification 10mg/mL), be that the Progesterone with natural or conventional synthetic is a raw material, the injection that makes through the galenic pharmacy routine techniques.
Skin buries agent: be that Progesterone is added normal saline to 100mL, stir evenly,, filter with 10wt% sodium hydroxide solution adjust pH to 7.0, being concentrated into progesterone concentrations is 5mg/mL, sterilization is that carrier (is produced and produced house: Finland Leiras company) with silicone rubber (long 34mm, the pipe of diameter 2.4mm), embedding, sterilization is made the skin that contains Progesterone 0.5mg, 1mg and 1.5mg specification respectively and buried agent, and is standby.
Embodiment 1: long term toxicity test
Heavy dose of dog long term toxicity test (intravenous injection: the 15mg/kg body weight, administration was 1 time in per 12 hours, administration time was 20 weeks) and the rat long term toxicity test (skin buries the agent administration: the 240mg/kg body weight, and administration was 1 time in per 72 hours, administration time was 24 weeks).
The result shows that animal subject there is no ANOMALOUS VARIATIONS, and blood parameters inspection, each main organs there is no unusually, illustrates that this medicine uses heavy dose of safety non-toxic, and clinical application is safety just relatively.Mice spirit is neural pharmaceutical research result show, performance of mice behavioral activity and balanced capacity are not had obvious inhibitory action.Index such as blood pressure, heart rate, electrocardiogram, respiratory frequency and amplitude and obviously influence of nothing to anesthetized dog cardiovascular and respiratory system.Therefore the progesterone suspension,sterile toxicologic study shows that the treatment ischemia apoplexy is safe and effective, and has clinical practice dosage safety scope preferably.
Embodiment 2: Progesterone to the rat ischemia brain injury after the neurocyte protection effect
100 of male SD rats, divide four groups at random: (1) sham operated rats, do not insert the line bolt; (2) ischemia-reperfusion group:, utilize line bolt method blocking-up middle cerebral artery (MCAO) to make rat focal ischemia and pour into brain damage model, not administration again by removing bulldog clamp after the ligation bilateral carotid arteries again; (3) ischemia-reperfusion group+normal saline injection group (normal saline group) is set up rat focal ischemia with (2) and is poured into brain damage model again, and postoperative 6h intraperitoneal injection of saline 1mL injects 2 every day, continuously 5d; (4) ischemia-reperfusion group+progesterone injection 0.5mg/kg intramuscular injection group (Progesterone group); Set up rat focal ischemia with (2) and pour into brain damage model again, postoperative 6h intramuscular injection progesterone injection, administration every day 2 times (0.5mg/kg), successive administration 5 days.
After the modeling 12,24, each group of 72h and 7d is measured brain water content respectively, observes the cerebral tissue morphological changes of various tissue components, the situation that neuronal apoptosis is observed in Hoechst dyeing.And detect rat hippocampus CA1 district's neuronal apoptosis and rat hippocampus CA1 district Bcl-2, the expression of Bax with labelling method (TUNEL).Adopt variance analysis and t check to organize a statistical.
The result shows:
Brain water content compares: cerebral ischemia group and normal saline injection group [(81.3 ± 1.21) %, (81.7 ± 1.03) %] all are significantly higher than Progesterone group (77.9 ± 0.67) %, and difference has statistical significance (being P＜0.01).
The cerebral tissue morphological changes of various tissue components compares: histochemical stain shows that impaired side and the offside of the rat of cerebral ischemia group and the performance of normal saline group all have serious cerebral edema, the cerebral tissue swelling of edema district is obvious, bright degree increases, perivascular space broadening, and visible a large amount of focal hemorrhage, neurocyte liquefaction and necrosis phenomenon (Figure 1A).The Progesterone group is then obviously lighter, and the downright bad phenomenon of neurocyte damage combination normal saline injection group obviously reduces, and especially cell and intercellular substance swelling degree are light, and many neurocyte structures are still kept well (Figure 1B).
Fluorescence Hoechst staining cell apoptosis counting (individual/high power field): cerebral ischemia group (32.20 ± 2.71) and normal saline group (28.71 ± 2.19) are significantly higher than Progesterone group (11.09 ± 1.37) and differ significantly (P＜0.001).
Sham operated rats is not seen neuronal apoptosis, Bcl-2 and Bax positive cell; The Progesterone group is hindered back 12,24 and 72h neuronal apoptosis number is respectively: 8.96 ± 1.41; 11.23 ± 1.07; 9.67 ± 1.58, be lower than damage group apoptosis several 33.67 ± 1.96; 29.28 ± 1.07; 26.78 ± 1.83, significant difference (P＜0.01).Bcl-2 positive neurons cellular expression is higher than damage group (P＜0.05, P＜0.01) in the Progesterone group rat cerebral tissue, and Bax positive neurons cellular expression is lower than damage group (P＜0.01); Progesterone group damage back 12,24,72h and 7d Bcl-2/Bax cell ratio are respectively greater than damage group Bcl-2/Bas ratio, and difference has statistical significance (P＜0.001).
The prompting of this result of study; the method of intramuscular injection Progesterone can alleviate scope and the degree that cerebrovascular disease causes cerebral ischemia effectively; by promoting the expression of Bcl-2; suppress the expression of Bax; increase Bcl-2/Bax ratio; reduce neuronal apoptosis, thereby the brain injury that cerebral ischemia causes is played the protective effect of cranial nerve cell, thereby the acute cerebral stroke patient is brought favourable therapeutic effect.
Embodiment 3: the Progesterone skin buries the therapeutical effect of agent to the rat brain edema
80 of male SD rats (4～5 ages in week are about body weight 150g) are divided into normal group, wound group, normal saline matched group, Progesterone skin at random and bury agent treatment group.1. normal group is not done any processing; 2. wound group, freely falling body (1000gcm) hits left parietal lobe and makes brain damage model, not administration; 3. 2. the normal saline group makes brain damage model together, postoperative 6h intraperitoneal injection of saline 2mL, and every 72h injects once, continuously 7d; 4. 2. the Progesterone group makes brain damage model together, and postoperative 6h subdermal implantation skin buries agent (only count 1.5mg/ with the Progesterone quality, every 72h is administered once), 7d continuously.The row observation index is measured behind wound 24h and the 7d: (1) magnetic resonance: twice intensified image edema district and offside respective area image signal value are checked and measured to Mus brain T2 picture.Every side is selected three visual field non-overlapping copies, computation of mean values at random.(2) do the weight in wet base method and measure brain water content: rat is put to death, and opens cranium, is that the center is respectively got about 3 * 3 * 4mm cerebral tissue and claimed weight in wet base with wound kitchen range and offside corresponding position.Claim dry weight behind 110 ℃ of 24h of baking box.Water content=(weight in wet base-dry weight)/weight in wet base * 100%.(3) pathological section: conventional H E dyeing is measured traumatic edema district and offside corresponding position surface density with the CMIAS image analysis system.Surface density=cerebral tissue area/visual field area.Every side is selected 10 visuals field (1 * 10 at random
4μ m
2), computation of mean values.(4) Electronic Speculum: 6% glutaraldehyde phosphate buffer is fixedly got impingement edge cerebral tissue behind the 24h.The phosphate buffer washing, osmic acid is fixed, dehydration, embedding, ultrathin section, sodium acetate citrate double staining, H600 transmission electron microscope observing.
The result shows: 1). magnetic resonance shows: behind the wound group 24h: see on the T2 picture and hinder the extensively long T2 shadow of side cortex, Hippocampus.Treatment group: on the T2 weighting picture, hinder the long T2 scope of side and obviously reduce, hinder side and offside picture signal value difference less than wound group (P＜0.01); Matched group: do not have obvious change than the wound group.Magnetic resonance signal value behind the wound 7d (weighting picture) treatment is formed and is hindered side signal value and wound group or the apparent in view decline of matched group (P＜0.01); The treatment group, the wound group, matched group is hindered the side signal value apparently higher than offside (P＜0.01).Normal group and each group offside relatively do not have significant difference; 2). the variation of brain water content: after the 24h wound as shown in table 1, in wound group, matched group and the treatment group, hinder side brain water content and offside or normal group relatively raise (P＜0.01).The progesterone skin buries agent treatment group and has compared obvious decline (P＜0.01) with the wound group.Wound and matched group are hindered the side brain water content does not have significant difference (P〉0.05).
Table 1: the variation of brain water content percentage ratio (x ± s)
| Group | n | Wound side (%) | Offside (%) |
| Normal group wound group treatment group matched |
10 10 10 10 | 77.19±0.63 81.59±1.11# 79.71±1.49#* 81.67±1.39# | ----- 77.15±1.35 77.22±0.85 77.42±0.88 |
# and normal group or offside be P＜0.01 relatively; * compare P＜0.01. with wound group or matched group
3). pathological section: the wound group is hindered the side cortex, the Hippocampus cell space shrinks, and the cell peripheral gap is strengthened, and visible neuron loss; Treatment group edema and degeneration, necrosis obviously alleviate than the wound group.Matched group: than wound group no significant difference.Behind the wound 24h, the treatment group is hindered side density apparently higher than wound group and matched group (P＜0.01); Behind the wound 7d, treatment is formed and is hindered side density and be higher than wound group or matched group (P＜0.05); And the treatment group, the wound group, matched group is hindered side density and is starkly lower than offside (P＜0.01).4). Electronic Speculum and immunohistochemical observation: extensive non-structure district (Fig. 2 .A) around wound group cell and the blood vessel.Cell heterochromatin cohesion, organelle destroys, and nuclear membrane is unclear, the nerve fiber degeneration.Microvascular endothelial is whole, red blood cell deformation, and interstice sees and is dispersed in erythrocyte and fragment.Behind the wound 7d, Progesterone ketone skin buries agent treatment group and obviously alleviates than wound group destructiveness, as seen recovers (Fig. 2 .B) than multi-neuron.Matched group: do not have obvious change than the wound group.
This result of study prompting: the Progesterone skin buries agent and has certain therapeutical effect for the brain injury cerebral edema, is expected to become slow a kind of new route of administration of preventing and treating traumatic brain edema with discharging and selects.Although it is a lot of to be used to study the zoopery for the treatment of acute serious symptom apoplexy and brain injury, up to now, does not still have any one large-scale randomized clinical trial result and show that a certain medicine has definite curative effect to acute serious symptom apoplexy and brain injury.This may be that the Secondary cases cerebral lesion is caused that by multiple factor its specific aim medicine should possess comprehensive feature simultaneously because due to acute serious symptom apoplexy and the intrinsic heterogeneity of brain injury crowd.It has been recognized that now; the medicine that is used for the treatment of acute serious symptom apoplexy and brain injury must possess at multiple impairment factor, improve on the characteristic of prognosis; and alleviate Secondary cases cerebral lesion behind acute serious symptom apoplexy and the brain injury by multiple different mechanism; reach cerebral protection, thereby the method for clinical research is to find the most effectual way of nerve protection medicine effect.
Embodiment 4: Progesterone is to patient's cranial nerve function restitution and prognosis clinical research thereof:
The present invention has carried out the science comparative study of randomized, double-blind with the method for clinical research to 120 routine acute serious symptom brain injury patients.Clinical test results finds that Progesterone can significantly promote brain injury patients short-term and longer neurological functional recovery, and obviously reduces the mortality rate behind the brain injury.Results suggest Progesterone intramuscular injection and skin bury a kind of effective method that the agent administration is the acute serious symptom brain injury of treatment.
This research is by international clinical trial registration of website, registered the clinical research of this project, and the approval of Ethics Committee and the signature of patient's Informed Consent Form have been passed through, 200 acute injury brain injury patients have been collected, age is between 18～65 years old, by international clinical score standard, patient through demutation and stable back Glasgow coma score (GCS)≤8 is dropped into research, and everyly accepts or used medicine such as progesterone or estrogenic in preceding 30 days being admitted to hospital, brain severe depletion of oxygen damage causes brain death, clinical condition instability (partial pressure of oxygen＜60mmHg or systolic pressure＜90mmHg genetic system), conceived and be in age of sucking cause the patient of chronic spinal cord lesion not adopted with those by this research eliminating.The patient who finally selects 112 Pass Test conditions carries out at random, double-blind trial (EXPERIMENTAL DESIGN is seen Fig. 1), wherein 32 routine patients carry out 1.0ml/kg progesterone injection intramuscular injection for treating (intramuscular injection group) in wound in back 8 hours, 30 routine patients give 1.0ml/kg Progesterone skin in wound in back 8 hours and bury agent (skin buries group), other 58 routine patients give placebo intramuscular injection for treating (placebo group), and the patient who accepts Progesterone treatment carried out further injection for curing every 12 hours in subsequent 7 days.
1) the demographic feature of Progesterone group and placebo patients: as shown in table 2, the group of the same age quilt between two groups is the balance there was no significant difference well, and different disposal group patient's medication history, administration and Therapeutic Method there was no significant difference.
Table 2: two groups of patients' clinical and demographic feature (in the bracket is percent of total)
| The feature of being admitted to hospital | Placebo/n=58 | Progesterone/example several 62 | The P value |
| The male | 41(71％) | 44(71％) | >0.05 |
| The women | 17(29％) | 18(29％) | >0.05 |
| Average (standard deviation) age (year) | 31(9％) | 30(11) | >0.05 |
| Injured to average (standard deviation) time of receiving treatment (hour) | 3.65(1.46％) | 3.80(2.03％) | >0.05 |
| Average (standard deviation) mark of Glasgow coma score | 6.1(1.3％) | 6.0(1.8％) | >0.05 |
| Glasgow coma score 3～5 | 14(25％) | 16(26％) | >0.05 |
| Injured reason | |||
| Traffic | 50(86％) | 53(85％) | >0.05 |
| Get injured by a fall | 6(10％) | 7(11％) | >0.05 |
| Other | 2(3％) | 2(3％) | >0.05 |
| Surgical operation therapy | 19(31％) | 18(26％) | >0.05 |
| Pupillary reaction | |||
| Bilateral is normal | 19(33％) | 20(32％) | >0.05 |
| Unusually | 39(67％) | 42(68％) | >0.05 |
| The classification of Marshall CT scan | |||
| I | 0 | 0 | |
| II | 6(10％) | 7(11％) | >0.05 |
| III | 17(28％) | 20(32％) | >0.05 |
| IV | 9(16％) | 9(15％) | >0.05 |
| V | 18(31％) | 16(26％) | >0.05 |
| VI | 8(14％) | 10(16％) | >0.05 |
2) prognosis evaluation of Glasgow prognosis marking system (the international clinical score standard of GOS): patient's final result is divided into favourable (recovering good, medium degree deformity) and does not have sharp (severe disability, vegetative state, death).Result's (seeing Table 3) shows, after treatment the 3rd and 6 months, compare with placebo group, have more patient beneficial therapeutic effect (p＜0.01) to occur in the Progesterone group, the therapeutical effect that wherein intramuscular injection group and skin bury group differs no difference of science of statistics.Intramuscular injection group and skin bury the survival rate that group all can promote 6 months, and two groups all do not develop complications and untoward reaction.
Table 3: Progesterone group and placebo group patient be international standard Glasgow prognosis scoring comparison (in the bracket is percent of total) after 3 months and 6 months
| Glasgow prognosis scoring | Progesterone group (n=62) | Placebo group (n=58) |
| 3 months | ||
| Recover good | 15(24％) | 6(10％) |
| Medium | 13(21％) | 11(19％) |
| Severe disability | 12(19％) | 9(16％) |
| Vegetative state | 9(15％) | 12(21％) |
| Dead | 13(21％) | 20(34％) |
| 6 months | ||
| Recover good | 21(34％) | 15(26％) |
| Medium | 15(24％) | 9(16％) |
| Severe disability | 6(10％) | 8(14％) |
| Vegetative state | 7(11％) | 6(10％) |
| Dead | 13(21％) | 20(34％) |
3) bivariate analysis after Glasgow prognosis scoring: the result shows, after 3 months in the Progesterone group in 45% patient and the placebo group 29% patient favourable therapeutic effect has appearred, and in the Progesterone treatment group in 55% patient and the placebo group 71% patient sharp therapeutic outcome has appearred not having, and difference all reaches significant level (p＜0.05).After 6 months in the Progesterone group in 58% patient and the placebo group 41% patient favourable therapeutic effect has appearred, and in the Progesterone treatment group in 42% patient and the placebo group 59% patient sharp treatment final result has appearred not having, difference is highly significant (p＜0.01).
4) functional independence evaluation result FIM scoring: after 3 months, the placebo group scoring is 7.35; And the scoring of Progesterone group is 8.02, two groups of facial differences significantly (p＜0.05), and placebo group is 8.95 after 6 months; Intramuscular injection group and skin bury group and reach 10.02 and 9.87 respectively, compare difference extremely significantly (p＜0.01) with placebo group, and this shows that Progesterone treatment patient has shown the excellent function recovery.
5) mortality rate: in 6 months treatment, have 33 patients (25%) death, the Progesterone group is obviously low than placebo group on 6 months mortality rate, is respectively 18% and 32%.
6) intracranial pressure detects: 35 patients to 50 patients of Progesterone group and placebo treatment group carried out the intracranial pressure detection at injured back 24 hours, 72 hours and 7 days, (see figure 2) shows two processed group patients' intracranial pressure there was no significant difference as a result, two Progesterone treatment group patients appearance that all has no adverse reaction.
To sum up result of study shows that the method that Progesterone intramuscular injection and skin bury the agent administration has the curative effect that promotes that cranial nerve function recovers in the acute injury brain injury patients, and has longer-term cranial nerve protection effect.The following conclusion of this result of study strong support: can be used for treating and promoting the functional rehabilitation of ischemic brain injury or the mortality rate after the damage of reduction heart and brain with Progesterone, perhaps treat the pathological changes of brain cell.
Personnel are conspicuous to the present technique field, and the composition of prescription changes some performances that can influence prescription.After being regulated, the concentration of putting forth effort polymer as biological slime can provide greater or lesser biological slime to put forth effort.Oil is with water relatively the time, its relative concentration can change regulate Progesterone from the delivery system rate of release.PH value is appropriate change in addition also, perhaps influences Progesterone and put forth effort from the biological slime of drug delivery system rate of release and prescription after regulating.
What more than enumerate only is several specific embodiments of the present invention, obviously the invention is not restricted to above embodiment, also many distortion and change can be arranged.All distortion that those of ordinary skill in the art can directly derive or associate from content disclosed by the invention all should be thought protection scope of the present invention.
Claims (7)
1. the application of Progesterone in the medicine of preparation treatment serious symptom apoplexy and brain injury.
2. application as claimed in claim 1 is characterized in that described apoplexy is cerebral infarction, cerebral hemorrhage or subarachnoid hemorrhage.
3. application as claimed in claim 1 is characterized in that described brain injury is cerebral tissue necrosis or the disordered brain function that acute traumatic brain injury, cerebral ischemia cause.
4. as the described application of one of claim 1～3, it is characterized in that described medication preparation becomes intravenous injection, intramuscular dose or skin to bury agent.
5. application as claimed in claim 4 is characterized in that described medicine is an intravenous injection, and described intravenous injection effective dose is per 12 hours of 0.5mg～1.5mg/kg body weight.
6. application as claimed in claim 4 is characterized in that described medicine is an intramuscular dose, and described intramuscular dose effective dose is per 12 hours of 1.0mg～3.0mg/kg body weight.
7. application as claimed in claim 4 is characterized in that described medicine is that skin buries agent, and it is per 72 hours of 5.0mg～12.0mg/kg body weight that described skin buries the agent effective dose.
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| CN200910252875XA CN101780093B (en) | 2008-12-04 | 2009-11-30 | Application of progesterone for preparing medicament for treating cerebral apoplexy |
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| CN104010644A (en) * | 2011-10-07 | 2014-08-27 | 佛罗里达州立大学研究基金有限公司 | Prophylactic and post-acute use of progesterone to better outcomes associated with concussion |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104010644A (en) * | 2011-10-07 | 2014-08-27 | 佛罗里达州立大学研究基金有限公司 | Prophylactic and post-acute use of progesterone to better outcomes associated with concussion |
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