CN103861085A - Application of Romidepsin in treatment of amphetamine drugs - Google Patents
Application of Romidepsin in treatment of amphetamine drugs Download PDFInfo
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- CN103861085A CN103861085A CN201410049095.6A CN201410049095A CN103861085A CN 103861085 A CN103861085 A CN 103861085A CN 201410049095 A CN201410049095 A CN 201410049095A CN 103861085 A CN103861085 A CN 103861085A
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Abstract
The invention provides application of Romidepsin in treatment of drug addiction of amphetamine psychotropic drugs. The pharmacology and behavioral experiments confirm that Romidepsin promotes amphetamine psychotropic drug addiction to subside, and reduces the recurrence of amphetamine psychotropic drug addiction.
Description
Technical field
The present invention relates to the application of Romidepsin, be specifically related to the application of Romidepsin in amphetamine psychotropic drugs addiction therapy.
Background technology
Amphetamine type stimulants belongs to and causes dependency material, is easy system poison, and its abuse increases very fast, and it is drugs the most widely that United Nations International Drag Control Program announces amphetamine type stimulants, as methamphetamine hydrochloride, head-shaking pill etc.Bring significant damage to individual, family and society.
Addiction is chronic, palindromic encephalopathia, the dependency outstanding behaviours that amphetamine central excitation causes is that psychic dependence is very serious, its core feature be to medicine strong crave for sense, and craving under the ordering about of sense, form mandatory medicine and seek and usage behavior.Learning and memory accounts for critical role in amphetamines addiction and recurrence process.Once addiction patient come with accepted in the past medicine (people, place or other hints relevant with medicine) in environment will show to medicine strong crave for sense and drug-seeking behavior.The memory of addiction that dependence-producing drug causes is very deep, even giving up after the several years, then the contact hint relevant with addiction (as people, thing, with pass by the relevant environment of medication etc.) can bring out and relapse.
Therefore, in amfetamine addiction therapy, in the urgent need to impelling addiction to disappear, make patient return normal society, avoid the therapeutic scheme of recurrence.Romidepsin is by the cancer therapy drug of Gloucester Pharmaceuticals company of U.S. exploitation, is approved listing by U.S. FDA on November 9th, 2009, and this medicine is used for the treatment of cutaneous T cell lymphoma.The inventor finds under study for action, the effect of Romidepsin in amphetamine psychotropic drugs addiction therapy.
Summary of the invention
The invention discloses the purposes of Romidepsin in treatment amphetamines addiction.
Specifically, the invention provides Romidepsin and promote the effect in disappearing of amfetamine addiction, and reduce the purposes of the generation that addiction reappears.
Amphetamines of the present invention is the social common drugs such as amfetamine, methamphetamine, head-shaking pill, methamphetamine hydrochloride.
Medicine Romidepsin of the present invention obtains by commercially available.
Addiction of the present invention refers to the behavior relevant with addiction, mainly comprises mandatory look for medicine and medication, is usually expressed as condition Place Preference (conditioned pIace preference, CPP) in animal model.
In the present invention, judge that with the condition Place Preference in Animal Behavior Science (conditioned pIace preference, CPP) amphetamine psychotropic drugs addiction obtains, disappears, rebuilds.
The application of Romidepsin of the present invention in treatment amphetamines psychotropic drugs addiction, the effective dosage ranges of Romidepsin is 0.1-6 mg/kg, optimal dose scope is 0.5-2 mg/kg.
The present invention has studied the effect of Romidepsin in amphetamine addictive behavior disappears, and found that Romidepsin promotes disappearing of amphetamine addiction mice condition Place Preference.
The present invention has studied the effect during Romidepsin rebuilds after amphetamine addiction disappears, and found that Romidepsin reduces the reconstruction after amphetamine addiction mice addiction disappears.
The present invention has also studied the addiction of Romidepsin, and result shows Romidepsin(0.1-6 mg/kg) itself do not cause preference or detest effect do not there is addiction.
The invention provides the new purposes of Romidepsin, i.e. the therapeutic use of Romidepsin to amphetamine psychotropic drugs addiction.
Brief description of the drawings
Fig. 1 is methamphetamine CPP Establishing process schematic diagram.Wherein MA is methamphetamine, and NS is normal saline.
Fig. 2 is that methamphetamine CPP sets up result.
Fig. 3 is the non-limiting experiment flow figure that disappears.Wherein MA is methamphetamine, and NS is normal saline, and Rom is Romidepsin.
Fig. 4 is that Romidepsin promotes the non-limiting result that disappears of CPP.
Fig. 5 is the restricted experiment flow figure that disappears.
Fig. 6 is that Romidepsin promotes the restricted result that disappears of CPP.
Fig. 7 rebuilds experiment flow figure after disappearing.
Fig. 8 rebuilds after Romidepsin minimizing is disappeared.Wherein A figure represents the restricted program that disappears repeating through 4 times, and mice CPP disappears completely; B figure shows reconstruction Test 3 results, and Romidepsin used and obviously reduced preference reconstruction paracmasis.
Detailed description of the invention
Further describe by the following examples the present invention, it should be understood that these embodiment, only for the object of illustration, do not limit the scope of the invention.
The methamphetamine using in the embodiment of the present invention is standard substance, purchased from Chinese drug inspection office; Romidepsin is purchased from bio tech ltd of Novi, Chengdu.
The condition Place Preference black and white case experimental system that the CPP experimental system using in the present embodiment is infrared video tracking-computer automatic analysis, (Shanghai Yishu Information Technology Co., Ltd.'s model: RD1111-CPP-M-4).
Measurement data represents with mean ± standard deviation, applies SPSS16.0 software and carries out variance analysis, and p<0.05 is for there being significant difference.
embodiment 1: the condition Place Preference (CPP) of methamphetamine induction forms
Mice stratified random is divided into 4 groups, normal saline group, MA-paired group, MA independent environment group, Romidepsin-paired group (R-paired), every group of 8 mices.Just, in the time that CPP sets up training, process difference for three groups, all the other processing are identical.Methamphetamine condition Place Preference (CPP) experiment flow is shown in Fig. 1.
1) natural preference test: test first three day (d1, d2, d3), 8:30 every day left and right, first laboratory animal (4 same cages of every subgroup mice) is transported to CPP device to test chamber, open CPP device, open the CPP box center-aisle type dividing plate that shuttles back and forth, mice (head is towards white box) is softly placed to two box intersections, be allowed to condition at two boxes interior freely movable 15 minutes, and shoot with video-corder active situation in d3 test, note down the time of staying of each mice in each box by computer-aided system, i.e. record preference basic value t black(second), t white(second) analyze its natural preference situation.Determine the natural preference case of mice according to natural preference test result.Record the CPP basic value of each mice, m-natural preference box time when T0=non-natural is had a preference for box.
2) CPP sets up:
MA-paired group
Training: according to natural preference result and pertinent literature, natural preference box is difficult for setting up CPP, therefore select non-preference box to accompany medicine box as methamphetamine, carries out conditioning training.Training period adopts enclosed type dividing plate, and the box that will shuttle back and forth is separated into two independently boxes, and methamphetamine processing (MA-paired) mice, at d4, d6, is placed non-preference box training 30 minutes after the Methamphetaminium Chloride of d8 lumbar injection 1mg/kg; D5, d7, place nature preference box training 30 minutes after d9 lumbar injection 0.2ml/10g normal saline.
Normal saline group mice all gave normal saline in 6 days, and other processes the same experimental mice of training.MA independent environment group mice, d4-9 all disposes in set independent environment, does not put into CPP device, and administration is with MA-paired group.Romidepsin-paired group (R-paired), Romidepsin dosage is 1 mg/kg, it processes training with MA-paired experimental group.
Preference test: experiment d10, open CPP device, open the CPP box center-aisle type dividing plate that shuttles back and forth, mice (head is towards white box) is softly placed to two box intersections, be allowed to condition in two boxes freely movable 15 min, note down the time of staying of each mice in each box by computer-aided system, record CPP test value t black(second), t white(second), get its value for T1, (m-natural preference box time when non-natural preference box) poor.
CPP result is calculated:
In order to reduce systematic error, the each factor of balance test, CPP value is defined as: test value-basic value, that is: T(n) m-natural preference box time when (non-natural preference box time [accompanying medicine side]-natural preference box time)-T0(non-natural preference box).
3) MA-paired is set up the vertical preference to companion's medicine-chest.See accompanying drawing 2.
Compare with independent environment group with normal saline matched group, MA-paired is set up the vertical preference to companion's medicine-chest, and difference has significant.And Romidepsin itself does not cause conditioned place preference, do not produce opportunistic detest effect yet, do not there is addiction.
In embodiment 1, determine that mice forms the experimental program of CPP.Embodiment 2-4 first sets up CPP with the experiment flow of MA-paired group, disappears and rebuild experimentation on this basis.
embodiment 2: the non-limiting experiment of disappearing
Mice is divided 2 groups, Romidepsin group and normal saline group, 8 every group.
1) D1-10 is with embodiment 1 1) ~ 2) in MA-paired group, carry out natural preference (Test 0), CPP training and preference test (Test 1).
2) D10-17: accept 15 min preference tests (test 1-test 8) every day, and after testing with each preference, give immediately 1. Romidepsin lumbar injection (1 mg/kg) by grouping, or 2. distilled water lumbar injection (0.2 ml/10g), after injection, put into home cage.
The present embodiment has test result Test 0,1,2,3,4,5,6,7,8 10 times.
4) result show use non-limiting paracmasis Romidepsin promote CPP disappear.See Fig. 4.
embodiment 3: the restricted experiment of disappearing
Mice is divided 2 groups, Romidepsin group and normal saline group.Every group 8.The restricted experiment flow that disappears is shown in Fig. 5.
1) D1-9 is with embodiment 1 1) ~ 2) in MA-paired group, carry out natural preference (Test 0), CPP training and preference test (Test 1).
2) D11-12 is restricted paracmasis.
D11, animal is limited in MA-paired side 3 min, and then immediately, Romidepsin group gives 1 mg/kg Romidepsin, and normal saline group is to normal saline;
D12, animal is limited in MA-unpaired side 3 min, and then immediately, 2 groups all to normal saline.
3) D13, has a preference for test (Test 2).
The present embodiment has test result Test 0,1,23 times.
4) result show use restricted paracmasis Romidepsin promote CPP disappear.See Fig. 6.
embodiment 4: rebuild experiment after disappearing
Mice is divided 2 groups, Romidepsin group and normal saline group.1. Romidepsin injection (1 mg/kg) ip, 2. distilled water injection (0.2 ml/10g).Every group 8.After disappearing, rebuild experiment flow and see Fig. 7.
1) D1-9 is with embodiment 1 1) ~ 2) in MA-paired group, carry out natural preference (Test 0), CPP training and preference test (Test 1).
2) D11-18 is restricted paracmasis.
D11, animal is limited in MA-paired side 3 min, and then Romidepsin group gives Romidepsin 1 mg/kg, and normal saline group is to normal saline; D12, animal is limited in MA unpaired side 3 min, and then 2 subgroups are all to normal saline;
D13-18: repeat again D11-12,3 times;
3) D19: have a preference for test (Test 2).
4) latter 24 hours of D20:Test 2, carries out reinstatement test (Test 3).Give MA(0.2 mg/kg) have a preference for immediately test.
The present embodiment has test result Test 0,1,2,34 times.
5) result shows that Romidepsin group reduces the reconstruction after disappearing.See Fig. 8, wherein A figure represents the restricted program that disappears repeating through 4 times, and mice CPP disappears completely.B figure shows reconstruction Test 3 results, and Romidepsin used and obviously reduced preference reconstruction paracmasis.
Claims (3)
- The application of 1.Romidepsin in treatment amphetamines psychotropic drugs addiction.
- 2. the application of Romidepsin claimed in claim 1 in treatment amphetamines psychotropic drugs addiction, is characterized in that Romidepsin promotes amphetamine psychotropic drugs addiction to disappear.
- 3. the application of Romidepsin claimed in claim 1 in treatment amphetamines psychotropic drugs addiction, is characterized in that rebuilding after Romidepsin minimizing amphetamine psychotropic drugs addictive behavior disappears.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007030697A2 (en) * | 2005-09-07 | 2007-03-15 | Braincells, Inc. | Modulation of neurogenesis by hdac inhibition |
| WO2012061779A1 (en) * | 2010-11-04 | 2012-05-10 | Abbott Gmbh & Co. Kg | Drug formulations |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007030697A2 (en) * | 2005-09-07 | 2007-03-15 | Braincells, Inc. | Modulation of neurogenesis by hdac inhibition |
| WO2012061779A1 (en) * | 2010-11-04 | 2012-05-10 | Abbott Gmbh & Co. Kg | Drug formulations |
Non-Patent Citations (4)
| Title |
|---|
| ANTONIO CONTESTABILE，ET AL: "Histone Deacetylase (HDAC) Inhibitors as Potential Drugs to Target Memory and Adult Hippocampal Neurogenesis", 《CURRENT PSYCHOPHARMACOLOGY》, vol. 1, 31 December 2012 (2012-12-31), pages 14 - 28 * |
| MELISSA MALVAEZ, ET AL: "Modulation of chromatin modification facilitates extinction of cocaine–induced conditioned place preference", 《BIOL PSYCHIATRY》, vol. 67, no. 1, 1 January 2010 (2010-01-01), pages 36 - 43 * |
| WILLIAM RENTHAL,ET AL: "ΔFosB mediates epigenetic desensitization of the c-fos gene after chronic amphetamine exposure", 《J NEUROSCI》, vol. 28, no. 29, 16 July 2008 (2008-07-16), pages 7344 - 7349 * |
| 王雷: "伏隔核组蛋白乙酰化及其介导的基因转录对大鼠可卡因成瘾觅药动机作用的研究", 《中国博士学位论文全文数据库，医药卫生科技辑》, 15 November 2010 (2010-11-15), pages 071 - 10 * |
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Application publication date: 20140618 |