CN102266312B - Application of geranylgeranylacetone to preparation of medicament for preventing and/or treating opiates drug addiction - Google Patents
Application of geranylgeranylacetone to preparation of medicament for preventing and/or treating opiates drug addiction Download PDFInfo
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Abstract
The invention discloses application of geranylgeranylacetone to the preparation of a medicament for preventing and/or treating opiates drug addiction, relating to the technical field of medicines. Geranylgeranylacetone is taken as a medicament for preventing and treating the opiates drug addiction or is used for preparing a medicament for preventing and treating the opiates drug addiction. One or more medicinally acceptable conventional medicinal auxiliary materials can also be added into geranylgeranylacetone to prepare capsules, pills, powder, tablets, granules, oral liquids, injections and the like. Geranylgeranylacetone has the effects of antagonizing conditioned place preference behaviors caused by morphine and increase in autonomic activities induced by morphine and relieving the function of abstinence symptom action, is used for preventing and treating the opiates drug addiction, and has the advantages of remarkable curative effect, high safety, addiction resistance, low price, capability of lowering the economic burden of a patient, and the like.
Description
Technical field
The present invention relates to a kind of purposes of teprenone, particularly teprenone and prevent and/or treat the novel medical use in the opium drug dependence producing drug, belong to medical technical field in preparation.
Background technology
The opium drug abuse is one of social effects of pollution in the world today.Common opium drug comprises morphine, heroin and Opium etc.The opium drug addiction can form drug dependence and drug dependence after being meant that repeated multiple times is used opium drug, and serious withdrawal symptom can occur after the drug withdrawal, is a kind of chronic recurrent disease of brain.Therapeutic Method to the opium drug addiction is drug rehabilitation, and its link by three organic connections such as detoxification, anti-recurrence and recurrence societies constitutes.Detoxification is the basis of drug addiction treatment, refers in particular to alleviating junkie and cuts off the withdrawal symptom that occurs behind the drugs, gives drug abstainer with Drug therapy or control the process of the abstinence reaction of its appearance.At present, anti-additive medicament mainly contains and comprises: opioid receptor agonist, and like methadone, real is the opioid drug alternative medicine; Non-opioid receptor agonist like clonidine, is alleviated withdrawal symptom; Opiate receptor antagonist like naltrexone, is used for preventing suction again after the detoxification; Chinese medicine class drug-breaking medicine.Though these medicines are given up different therapeutical effect to the opium drug addiction, cost is high, side effect is big.Research can prevent and treat the opium drug drugs of addiction to have become one of new drug development focus effectively, safely, at low cost.
Teprenone (geranylgeranylacetone, GGA), promptly 6,10,14,18-tetramethyl-5,9,13, single cis of 17-nonadecane tetraene-2-ketone and alltrans mixture of isomers have been widely used in the treatment of digestive tract ulcer at present.Research confirm GGA can induce heat shock protein 70 (heat shock protein 70, HSP70) and thioredoxin (thioredoxin, (the Tsuruma T of expression Trx); Yagihashi A; Koide S, Araya J, Tarumi K; Watanabe N, Hirata K. Geranylgeranylacetone induces heat shock protein-73 in rat small intestine. Transplant Proc. Feb-Mar; 1999.31 (1-2): 572-573; Hirota K; Nakamura H, Arai T, Ishii H; Bai J; Itoh T, Fukuda K, Yodoi J. Geranylgeranylacetone enhances expression of thioredoxin and suppresses ethanol-induced cytotoxicity in cultured hepatocytes. Biochem.Biophys. Res. Commun 2000; 275:825-830).HSP70 is a kind of stress protein of extensive existence; It synthesizes can provide the toleration of organism to all kinds of harmful factors (for example: ischemia, anoxia and heavy metal etc.); Make cell be in stress state; Quick active and antitoxin proteins associated plasmagene, thus play the effect of protecting cell and organism.Trx is a kind of effective anti-oxidants in the cell, can protect cell, alleviate the damage due to the oxidative stress.Trx can suppress the activity of p38 MAPK and apoptosis signal regulating kinase 1, strengthens anti-apoptosis capacity (Saito M., Nishitoh, H., the Fujii of cell; M., Takeda, K., Tobiume, K.; Sawada, Y., Kawabata, M.; Miyazono, K., and Ichijyo, H. Mammalian thioredoxin is a direct inhibitor of apoptosis signal-regulating kinase (ASK) is EMBO 1998 1.; 17:2596-2606; Hashimoto S., Matsumoto K., Gon Y.; Furuichi S.; Maruoka S., Takeshita I., Hirota K.; Yodoi J., and Horie T. Thioredoxin negatively regulates p38 MAP kinase activation and IL-6 production by tumor necrosis factor-alpha. Biochem.Biophys. Res. Commun 1999; 258:443-447).Cytotoxicity (the Bai J that GGA causes through inducing HSP70 and Trx can alleviate chemical substance; Nakamura H; Hattori I; Tanito M, Yodoi J. Thioredoxin suppresses 1-methyl-4-phenylpyridinium-induced neurotoxicity in rat PC12 cells, Neurosci Lett 2002; 321,81-4; Takumida M, Anniko M. Heat shock protein 70 delays gentamicin-induced vestibular hair cell death. Acta Otolaryngol. 2005; 125:23-8).Simultaneously, GGA has effect (Tanito M, the Kwon Y.W of protection, improvement to photic damage, ischemic renal failure, epilepsy and cerebral infarction etc.; Kondo N, Bai J, Masutani H; Nakamura H, Fujii J, Ohira A; Yodoi J. Cytoprotective effects of geranylgeranylacetone against retinal photooxidative damage, J Neurosci 2005; 25,2396-404; Suzuki S, 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; Fujiki M; Kobayashi H; Inoue R; Tatsuya R, Ishii K. Single oral dose of geranylgeranylacetone for protection against delayed neuronal death induced by transient ischemia. Brain Res 2004; 1020:210-213; Yasuda H; Shichinohe H; Kuroda S; Ishikawa T, Iwasaki Y. Neuroprotective effect of a heat shock protein inducer, geranylgeranylacetone in permanent focal cerebral ischemia. Brain Res 2005; 1032:176-182).Teprenone whether can, or be used to prevent and/or treat the opium drug addiction and do not appear in the newspapers as yet.
Summary of the invention
(promptly teprenone prevents and/or treats the application in the opium drug dependence producing drug in preparation for geranylgeranylacetone, new purposes GGA) to the purpose of this invention is to provide a kind of teprenone.
The purposes of teprenone of the present invention; Be as prevention and treatment opium drug drugs of addiction with teprenone; Or be used for the preparation prevention and treat the opium drug drugs of addiction; Promptly be active component with the teprenone, the application in preparation prevention and treatment opium drug dependence producing drug.
The composition (or effective ingredient) of prevention of the present invention and treatment opium drug drugs of addiction is a teprenone, can also add one or more pharmaceutically acceptable adjuvants, to improve the drug absorption effect or to be convenient to take.As process capsule or pill, powder, tablet, granule, oral liquid and injection etc.
Adjuvant of the present invention comprises filler, diluent, binding agent, excipient, absorption enhancer, surfactant and the stabilizing agent etc. that pharmaceutical field is conventional, also can add flavouring agent, pigment and sweeting agent etc. in case of necessity.
The invention provides a kind of new purposes of teprenone (GGA), promptly prevent and/or treat the application in the opium drug dependence producing drug in preparation.The zoopery result: (1) oral GGA is after 7 days, and (morphine Mor), observes its autonomic movement situation to injection of morphine.Find oral in advance certain density GGA, the autonomic activities that can the antagonism morphine brings out increases.(2) after oral GGA7 days, mice is carried out the condition place preference.Find oral in advance certain density GGA, can the preference behavior of the caused position of antagonism morphine.(3) before injection of morphine, oral in advance GGA after continuous 6 days, urges with Allylnoroxymorphone and to give up, and observes the withdrawal symptom (jumping with upright) of mice.Find oral in advance certain density GGA, can reduce number of skips and upright number of times that Allylnoroxymorphone is induced the morphine addiction mice.Above-mentioned experimental result shows can be resisted morphine by oral GGA (morphine, Mor) addiction have mitigation to the withdrawal symptom of morphine addiction mice.Therefore, teprenone can be used for the prevention and the treatment of opium drug addiction.
Compare with anti-dependence producing drug commonly used clinically at present, medicine of the present invention has the following advantages: (1) is evident in efficacy; (2) safe, no addiction property; (3) cheap, can alleviate patient's financial burden.
Because belonging to first, the application of teprenone in preparation prevention and treatment opium drug dependence producing drug find; Therefore; No matter be that GGA processes the medicament use as active component separately; Still utilize effect and other active component of GGA prevention and treatment opium drug addiction to be used the application of processing medicament, all within protection scope of the present invention.
Description of drawings
Fig. 1 is the experiment analysis results figure that the autonomic activities that brings out of teprenone antagonism morphine of the present invention increases.
Fig. 2 is the experiment analysis results figure of the caused position of teprenone antagonism morphine of the present invention preference behavior.
Fig. 3 is that teprenone reduction Allylnoroxymorphone of the present invention is induced the experiment analysis results figure of the number of skips of morphine addiction mice.
Fig. 4 is that teprenone reduction Allylnoroxymorphone of the present invention is induced the experiment analysis results figure of the upright number of times of morphine addiction mice.
The specific embodiment
Below in conjunction with accompanying drawing and embodiment the present invention is done further explain, but said content should not regarded limitation of the present invention as.
The present invention is conventional method if no special instructions.
Embodiment 1: the autonomic activities that teprenone antagonism morphine brings out increases experiment
The laboratory animal that adopts in the experiment is: SPF level C57BL/6 mice, male, in age in 6-7 week, body weight 22-25g is provided by Medical University Of Chongqing's Experimental Animal Center.The single cage isolated rearing of mice, the special feed of feeding, free diet and drinking-water.
The medicine that adopts in the experiment is: teprenone (Japanese Wei Cai company produces, molecular weight 330.55), morphine hydrochloride injection (Shenyang No.1 Pharmaceutical Factory, Dongbei Pharmaceutical Group Co.).
Adopt toy autonomic activities detection means measure.Mice is divided into 3 groups, every group of 6 mices.Matched group (saline) was irritated stomach in continuous 7 days and is given normal saline; Morphine group (Mor) was irritated stomach in continuous 7 days and is given normal saline; GGA and morphine group (GGA+Mor) were irritated stomach in continuous 7 days and are given GGA (800 mg/kg).The 8th day, the saline group was irritated stomach and is given normal saline, and the Mor group is irritated stomach and given normal saline; The GGA+Mor group is irritated stomach and is given GGA (800 mg/kg); Behind the 2h, saline organizes intraperitoneal injection of saline, after Mor group and the GGA+Mor group lumbar injection morphine (20 mg/kg); Put into the autonomic activities checkout gear, measure the autonomic activities number of every mice 30 min.The result shows (see figure 1), and Mor group mice is behind injection of morphia, and autonomic activities strengthens (*
p＜0.05, with the contrast of saline group mice); And GGA+Mor group mice is after GGA pours in advance, and the autonomic activities that can the antagonism morphine brings out increases (#
p＜0.05, with the contrast of Mor group mice).
Embodiment 2: the caused position of teprenone antagonism morphine preference behavioral experiment
Laboratory animal that adopts in the experiment and medicine are with example 1.
The place preference device is formed (each box size is 15 * 15 * 30 cm) by two identical boxes of size, and there is a closable hole centre.Two boxes are respectively white, smooth floor and black, the coarse floor of granule.Mice is divided into 4 groups (6 every group): matched group (saline), morphine group (Mor), GGA and morphine group (GGA+Mor) GGA group.Saline group and Mor group were irritated stomach in continuous in advance 7 days and are given normal saline, and GGA+Mor group and GGA group were irritated stomach in continuous in advance 7 days and given GGA (800 mg/kg).Wherein mice after the injection of filling stomach, was put into the place preference device at the 5th day and the 6th day, and is free movable between two boxes, adapts to 2 days; The 7th day, mice was write down the time of mice in flight data recorder in 20 min after irritating the stomach injection.The 8th, 10,12; 14 days, Saline group and Mor group were irritated stomach and are given normal saline, and GGA+Mor group and GGA group are irritated stomach and given GGA (800 mg/kg); Behind 2 h; Saline group and GGA group intraperitoneal injection of saline after Mor group and the GGA+Mor group lumbar injection morphine (20 mg/kg), are put into flight data recorder 20 min.The 9th, 11,13,15 days, Saline group and Mor group were irritated stomach and are given normal saline, and GGA+Mor group and GGA group are irritated stomach and given GGA (800 mg/kg), behind 2 h, after each organizes the mouse peritoneal injecting normal saline, put into clear box 20 min.The 16th day, open the hole, make the mice freely-movable, write down the time of mice in flight data recorder in 20 min.The result shows (see figure 2), and Mor group mice can produce preference behavior (* to flight data recorder behind injection of morphia
p＜0.05, with the contrast of saline group mice); And GGA+Mor organizes mice after GGA pours in advance, the caused position of antagonism morphine preference behavior (#
p＜0.05, with the contrast of Mor group mice).
Embodiment 3: teprenone is alleviated the withdrawal symptom that Allylnoroxymorphone is induced the morphine addiction mice
Laboratory animal that adopts in the experiment and medicine are with example 1.
Mice is divided into 4 groups (6 every group): matched group (saline), morphine group (Mor), GGA and morphine group (GGA+Mor) GGA group.Saline group and Mor group were irritated stomach in continuous in advance 7 days and are given normal saline, and GGA+Mor group and GGA group were irritated stomach in continuous in advance 7 days and given GGA (800 mg/kg).From the 8th day to 14 days, Saline group and Mor group were irritated stomach and are given normal saline, and GGA+Mor group and GGA group are irritated stomach and given GGA (800 mg/kg); Behind 2 h, Saline group and GGA group intraperitoneal injection of saline, (every day, the dosage of injection was: 10 for Mor group and GGA+Mor group lumbar injection morphine; 20; 40,60,80 and, 100 mg/kg).The last time behind injection of morphia 2 h, each is organized mouse peritoneal and injects 2 mg/kg Allylnoroxymorphones and urge and giving up, and writes down that mouse jumps and axial number of times in 20 min.The result shows (see figure 3), pours into GGA in advance and can reduce the number of skips (* that Allylnoroxymorphone is induced the morphine addiction mice
p＜0.05, with the contrast of saline group mice; #
p＜0.05, with the contrast of Mor group mice).Fig. 4 result shows, pours into GGA in advance and can reduce the upright number of times (* that Allylnoroxymorphone is induced the morphine addiction mice
p＜0.05, with the contrast of saline group mice; #
p＜0.05, with the contrast of Mor group mice).
Claims (1)
1. teprenone prevents and/or treats the application in the opium drug drugs of addiction in preparation.
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| CN102764248A (en) * | 2012-07-12 | 2012-11-07 | 昆明理工大学 | Application of teprenone in prevention and treatment of morphine-induced liver injury |
| CN104922097A (en) * | 2015-05-26 | 2015-09-23 | 昆明理工大学 | Application of Teprenone in preparing drug for preventing and/or treating readdiction in opiates narcotics |
| CN104958281A (en) * | 2015-05-26 | 2015-10-07 | 昆明理工大学 | New application of teprenone |
| CN108159032A (en) * | 2018-01-24 | 2018-06-15 | 昆明理工大学 | Application and drug and preparation method of the melbine in prevention and/or treatment opium drug dependence producing drug is prepared |
| CN110893180A (en) * | 2018-09-12 | 2020-03-20 | 厦门信力康生物技术有限公司 | Application of teprenone and derivatives thereof in preparing drugs for treating drug addiction and preventing relapse |
| CN115645411B (en) * | 2022-12-27 | 2023-03-10 | 文韬创新药物研究（北京）有限责任公司 | Compound medicine composition for giving up drug |
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| CN1903188A (en) * | 2006-08-03 | 2007-01-31 | 首都医科大学附属北京同仁医院 | Application of teprenone for preparing medicine for treating and/or preventing glaucoma |
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