CN101450048B - Acute hypoxia injury resistance use of teprenone - Google Patents
Acute hypoxia injury resistance use of teprenone Download PDFInfo
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- CN101450048B CN101450048B CN2007101958431A CN200710195843A CN101450048B CN 101450048 B CN101450048 B CN 101450048B CN 2007101958431 A CN2007101958431 A CN 2007101958431A CN 200710195843 A CN200710195843 A CN 200710195843A CN 101450048 B CN101450048 B CN 101450048B
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Abstract
The invention relates to the action of anti-acute hypoxia injury of teprenone, under the condition of oral administration of the teprenone, the survival ratio of chmice under the acute hypoxia condition can be obviously improved, the survival time can be prolonged. The invention pours the teprenone with different concentrations into the stomach of the adult chmice, after four hours, the chmice isarranged in the acute hypoxia environment, the survival ratio and the survival time are observed, so that the survival ratio of the animal can be improved and the survival time of the animal can be prolonged under acute hypoxia condition by pouring the teprenone with certain concentration into the stomach in advance, the anti-acute hypoxia injury capability of the chmice can be improved. According to the method of the invention, the teprenone is administrated at suitable time with suitable dose, which can improve the anti-acute hypoxia injury capability of the chmice, powerful evidences can be provided for the human body experiment, if the teprenone can be popularized for human body application, good economic benefit and social benefit can be generated.
Description
Technical field
The present invention relates to a kind of anti-acute hypoxia injury purposes of teprenone (two hold together the cattle benzylacetone).Teprenone can obviously improve the survival rate of mice under the acute hypoxia condition under peroral administration condition, prolong its time-to-live.
Background technology
If the human area that rises to rapidly more than the 2500m without abundant adaptation tends to take place acute high altitude reaction, show as headache, anorexia, feel sick, vomiting, tired, dizzy, insomnia etc., clinical acute mountain sickness (the acute mountain sickness that is called, AMS), if do not treat, part patient then may develop into plateau pneumochysis (high-altitude pulmonary oedema, HAPE) or high altitude cerebral adema (high-altitude cerebral oedema, HACE).AMS and HACE are the brain syndromes of altitude sickness (high-alti-tude illness), it is generally acknowledged that HACE is the late stage of AMS, ataxia, consciousness changing are its Clinical symptoms, may because of cerebral hernia make progress for stupor in addition dead (Xie Yonghong. acute mountain sickness and high altitude cerebral adema progress. plateau medicine magazine .2004; 14 (1): 61-64.).The main cause that causes AMS is the acute hypoxia injury that the plateau hypobaric hypoxia environment is caused.
The preventive measure of acute hypoxia injury at first comprises enhancing mountaineer adaptive capacity.Most scholars thinks that the reasonable adaptation back the most effective definite speed of ascending a height is to reduce the correct method of this harm.The most recommendable method is that the ladder of minimum physiological stress is ascended a height.Its principle comprises: 1. 2500～3000m level, continue to ascend a height after stopping 2～3d; 2. more than the height above sea level 3000m, every rising 600m stops 1d (sleeping for two nights in same height above sea level), and the back of ascending a height daytime get back to night the lowland sleep adapt to strengthen (Gu Youquan, Shi Xiangqun. the high altitude cerebral adema progress. medical science summary .2005; 11 (11): 1009-1012.).But such rising speed is often very slow, can not satisfy military combat and some climber's needs.And, determine that an ideal rate of climb is very difficult, often varies with each individual.Can take the chemoprophylaxis measure under some situation.Recommend acetazolamide clinically, but do not determine ideal dosage.In addition, the generation that dexamethasone also can the prophylaxis of acute hypoxia injury.
The treatment measure of acute hypoxia injury has two kinds of non-drug therapy and Drug therapys.Non-drug therapy is meant oxygen uptake and is sent to the low altitude area immediately.But it is just effective to need to reduce height above sea level 500～1000m usually, and the reduction of HACE needs of patients is more.In the Drug therapy, first-elected acetazolamide of classical medicine and dexamethasone.But acetazolamide can cause metabolic acidosis and hyperventilation.In addition, still there are report other drug such as clonidine, hypoxanthine, propranolol, nimodipine, phenytoin Sodium etc. that the effect of prophylaxis of acute hypoxia injury is all arranged, but its mechanism still among inquiring into (Gu Youquan, stone is to group's high altitude cerebral adema progress. medical science summary .2005; 11 (11): 009-1012.).
In sum, up to the present, still do not have the satisfied medicine of preventing and treating altitude sickness and come out.Therefore, seeking effectively, the novel drugs of antagonism acute hypoxia injury has become a urgent problem.
(geranylgeranylacetone, GGA), promptly two hold together the cattle benzylacetone (geranylgeranylacetone GGA), are a kind of non-annularity isoprenoid complex, now has been widely used in the treatment of digestive tract ulcer teprenone.People such as Tsuruma T in 1999 find that first it can induce in the rat small intestine HSP70 family to express (TsurumaT, Yagihashi A, Koide S, Araya J, Tarumi K, Watanabe N, Hirata K.Geranylgeranylacetone inducesheat shock protein-73 in rat small intestine.Transplant Proc.Feb-Mar; 1999.31 (1-2): 572-573.).After this, constantly have and studies confirm that GGA is a kind of safe, stable HSP70 derivant.
HSP extensively is present in microorganism and the intravital a kind of stress protein of animals and plants.It synthetic can be improved organism to all kinds of harmful factors () toleration for example: ischemia, anoxia, heavy metal and ethanol etc.; make cell be in stress state; suppress synthetic and the quick active and the antitoxin proteins associated plasmagene of some normal proteins, thereby play the effect of protection cell and organism.HSP70 family is the most conservative and topmost stress protein (Ning Fan among the HSPs, Guang-Shun Yang, Jun-Hua Lu, Ning Yang, Hai-Bin Zhang.Oral administration of geranylgeranylacetone plus local somatothermalstimulation:A simple, effective, safe and operable preconditioning combination for conferringtolerance against ischemia-reperfusion injury in rat livers.World J Gastroenterol2005; 11 (36): 5725-5731.).Teprenone can alleviate the cytotoxicity (BaiJ that chemical substance causes by inducing HSP70, Nakamura H, Hattori I, Tanito M, Yodoi J.Thioredoxin suppresses1-methyl-4-pHenylpyridinium-induced neurotoxicity in rat PC12 cells.Neurosci Lett 2002; 321:81-84.) and neuronal damage (Kikuchi S, Shinpo K, Takeuchi M, Tsuji S, Yabe I, Niino M, Tashiro K.Effect of geranylgeranylaceton on cellular damage induced by proteasome inhibition in culturedspinal neurons.J Neurosci Res.2002; 69:373-81.); It is also by inducing HSP70 to ischemic renal failure (SuzukiS, Maruyama S, Sato W, Morita Y, Sato F, Miki Y, Kato S, Katsuno M, Sobue G, Yuzawa Y, Matsuo S.Geranylgeranylacetone ameliorates ischemic acute renal failure via induction of Hsp70.Kidney Int 2005; 67:2210-20.), gentamycin the vestibule cell injury (Takumida M, the Anniko M.Heatshock protein 70 delays gentamicin-induced vestibular hair cell death.Acta Otolaryngol.2005 that cause; 125:23-8.), epilepsy (Fujiki M, Kobayashi H, Inoue R, Tatsuya R, Ishii K.Single oral dose ofgeranylgeranylacetone for protection against delayed neuronal death induced by transient ischemia.Brain Res 2004; 1020:210-213.), cerebral infarction (Yasuda H, Shichinohe H, Kuroda S, Ishikawa T, IwasakiY.Neuroprotective effect of a heat shock protein inducer, geranylgeranylacetone in permanent focalcerebral ischemia.Brain Res 2005; 1032:176-182.) etc. have a protective effect.Whether teprenone can not appear in the newspapers as yet by inducing HSP70 to express to resist acute hypoxia injury.
Summary of the invention
(Geranylgeranylacetone, new purposes GGA) promptly prevent and/or treat application in the acute hypoxia injury in preparation to the purpose of this invention is to provide teprenone.
Application of the present invention is, and to be active component with GGA prevent and/or treat application in the acute hypoxia injury medicine in preparation.
When needing, can also add one or more acceptable accessories in the application of the present invention, described adjuvant comprises diluent, excipient, filler, binding agent, wetting agent, absorption enhancer, surfactant, lubricant, stabilizing agent of pharmaceutical field routine etc., also can add flavouring agent, sweeting agent and pigment etc. in case of necessity.
Application of the present invention except that making capsule, can also make tablet, powder, granule, oral liquid, injection, etc. multiple medicament forms.The medicine of above-mentioned various dosage forms all can be according to the conventional method preparation of pharmaceutical field.
The oral consumption of the adult of this medicine is generally 50mg/ time, 3 times/day.
The invention provides the new purposes of a kind of GGA, promptly prevent and/or treat application in the acute hypoxia injury in preparation.Zoopery result: after (1) oral GGA4 hour, mice is placed the acute hypoxia environment, observe its survival rate.Find oral in advance certain density teprenone, can obviously improve the survival rate of mice under the acute hypoxia condition.(2) after oral GGA4 hour, mice is placed the acute hypoxia environment, observe its time-to-live.Find oral in advance certain density teprenone, can obviously prolong the time-to-live of mice under the acute hypoxia condition.Above-mentioned experimental result shows that oral GGA can resist acute hypoxia injury, plays a protective role to the mice under the acute hypoxia condition.Therefore can GGA be that active component is prepared into the medicine that prevents and/or treats acute hypoxia injury.Compare with the medicine of the anti-acute hypoxia injury of using always clinically at present, medicine of the present invention has the following advantages: 1) curative effect is obvious; 2) safe; 3) main route of administration is oral, and medication is convenient; 4) GGA is cheap, and the cost for preparing this medicine is lower, thereby can alleviate patient's financial burden.
By method of the present invention, adopt suitable time to take the common drug of suitable dose---teprenone, just can improve the ability of animal antagonism acute hypoxia injuries such as mice,, also provide strong evidence for human experimentation for the control acute hypoxia injury provides a new way.Use if can be generalized to human body, favorable economic benefit and social benefit will be arranged.
Below in conjunction with specific embodiment the present invention is described in further detail.
The specific embodiment
Method therefor is conventional method if no special instructions among the following embodiment.
Embodiment one teprenone is to the protective effect research of acute hypoxia injury mice
Laboratory animal: cleaning level kunming mice, male, in 7-8 week, body weight 30 ± 5g is provided by Military Medical Science Institute's Experimental Animal Center.Take back the single cage isolated rearing of mice 24h, the special feed of feeding, drinking public water supply allows free diet.Before irritating stomach, animal fasting 12h, but can freely drink water.This experiment is divided into 2 groups at random with mice, normal control group (n=20) and 200mg/kgGGA administration group (n=12).
Teprenone (GGA): Japanese Wei Cai company produces, and molecular weight 330.55 is white powder.After the dissolving of 5% arabic gum, 1ml packing ,-20 ℃ of preservations.
Medication: according to the mice body weight, normal control group and 200mg/kgGGA administration group irritate respectively that stomach gives 5% arabic gum and whole dosage is the GGA suspension of 200mg/kg, irritate that body of stomach is long-pending to be 0.1ml/10g body weight (10ml/Kg body weight).GGA begins to carry out the acute hypoxia experiment after irritating stomach 4h.
Acute hypoxia injury is handled: mice is placed the transparent animal experimental chamber of hypobaric hypoxia, extract air in the cabin out with pump, simulation height above sea level raises with the even speed of 2700m/min in the cabin, 3min30 rises to 9500m second, keep this height, the opening entry time, cease breathing until animal, still have breathing as animal behind the 15min, then be survival.In the experiment, write down two indexs, i.e. time-to-live and survival rate.Time-to-live: the death time (be accurate to second) of animal in 15min.Survival mice is calculated the time-to-live (statistical method reference literature: Shelley X.L.Zhang and James J.Miller.Whole-body hypoxicpreconditioning protects mice against acute hypoxia by improving lung function.J Appl Physiol2004 according to 15min; 96:392-397.).Survival rate: the sum of the survival quantity/animal of animal behind 15min.
Date processing:, carry out statistical analysis with SPSS11.5 software at last according to survival rate and time-to-live.With the survival rate difference of each treated animal of fisher Precision Test method comparison, with each treated animal time-to-live difference of T method of inspection comparison of independent sample.
Result: when being elevated to 9500 meters of height above sea level (oxygen content is 5.29%) in the 2700m/min speed 3min30s rapidly, have 40% control group mice all dead in 15min mice.The oxygen environment of 9500 meters height above sea levels of this phenomenon explanation is fatal low-oxygen environment for mice.Different with matched group, after mice is irritated stomach 4h with 200mg/kgGGA, carry out the acute hypoxia experiment of height above sea level 9500m again, mice all survives in the 15min, compares significant difference (n with matched group
Contrast=20, n
200mg/kg=12, P＜0.05VS matched group).Above results suggest, the GGA that the preceding 4h of acute hypoxia gives 200mg/kg concentration can significantly improve the survival rate of animal under the acute hypoxia condition.Mice to be increased to 9500 meters of height above sea level in the 2700m/min speed 3min30s rapidly, is kept 15min.The mean survival time of control group mice is 11.29 ± 5.73min (n
Contrast=20), the mean survival time of 200mg/kgGGA filling stomach group mice reaches 15min (n
200mg/kg=12), compare difference extremely significantly (P＜0.01VS matched group) with matched group.Above results suggest, the GGA that the preceding 4h of acute hypoxia gives 200mg/kg concentration can obviously prolong the time-to-live of animal under the acute hypoxia condition.
Table 1. mice various dose GGA irritates the protective effect of stomach acute hypoxia
| Group | N | Time-to-live (min) | Survival rate (%) |
| Matched group 200mg/kgGGA group | 20 12 | 11.29±5.73 15 ** | 60 100 * |
Compare with matched group,
*P＜0.05
*P＜0.01
Claims (1)
1. teprenone prevents and/or treats application in the medicine of acute hypoxia injury in preparation.
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| CN103751208B (en) * | 2010-11-08 | 2016-06-08 | 中国人民解放军军事医学科学院放射与辐射医学研究所 | The new purposes of sodium sulfite |
| CN110870866A (en) * | 2018-09-03 | 2020-03-10 | 浙江医药股份有限公司新昌制药厂 | Application of pyrroloquinoline quinone in preparation of medicine for preventing and treating acute altitude reaction and acute altitude hypoxia injury |
| CN115671107B (en) * | 2022-12-29 | 2023-04-04 | 文韬创新药物研究（北京）有限责任公司 | Compound medicinal composition for relieving alcoholism |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1575166A (en) * | 2001-10-25 | 2005-02-02 | 卫材株式会社 | Preventive and/or therapeutic agent for viral infection |
| CN1954806A (en) * | 2005-10-27 | 2007-05-02 | 汕头大学医学院 | Teprenone orally disintegrating tablet prescription and its preparation method |
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- 2007-11-30 CN CN2007101958431A patent/CN101450048B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1575166A (en) * | 2001-10-25 | 2005-02-02 | 卫材株式会社 | Preventive and/or therapeutic agent for viral infection |
| CN1954806A (en) * | 2005-10-27 | 2007-05-02 | 汕头大学医学院 | Teprenone orally disintegrating tablet prescription and its preparation method |
Non-Patent Citations (3)
| Title |
|---|
| Y.Aron et al..Geranylgeranylacetone protects human monocytes frommitochondrial menbrane depolarization independently ofHsp70 expression.Cellular and Molecular life Sciences58.2001,581522-1527. * |
| 刘鹏.胃溃疡治疗药Teprenone.国外药学-合成药、生化药、制剂分册7 5.1986,7(5),第314-315页. |
| 刘鹏.胃溃疡治疗药Teprenone.国外药学-合成药、生化药、制剂分册7 5.1986,7(5),第314-315页. * |
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