CN112569238A - Application of imatinib and derivative thereof and analgesic combined medicine or compound preparation in treating pain - Google Patents
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Abstract
The invention discloses an application of imatinib and derivatives thereof and analgesic drug combined medicine or compound preparation in treating pain, belonging to the technical field of medicines. The drug is a composition containing imatinib and derivatives thereof and an analgesic drug in a dose ratio of greater than or equal to 2:1, and can be used for preparing a drug for treating pain and a drug for preventing analgesic tolerance and addiction side effects; when the composition is used for preparing the medicament, the dosage of the imatinib and the derivative thereof is 100-400 mg/day, and the imatinib and the derivative thereof and the analgesic medicament can be simultaneously, separately or sequentially administered. The invention combines or compounds imatinib and derivatives thereof with analgesics in a dosage ratio of more than or equal to 2:1, can effectively exert analgesic effect of the analgesics, can effectively prevent serious side effect of opioids from generating, does not influence analgesic effect of the opioids, and further expands clinical indications of the addictive analgesic drugs.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to application of imatinib and derivatives thereof in combination with opioid medication or preparation of compound preparations in pain treatment.
Background
At present, the analgesic drugs commonly used in clinic mainly include three major drugs, i.e., opioid analgesics represented by morphine, non-steroidal anti-inflammatory analgesics represented by aspirin, and other analgesics, and these drugs selectively relieve and eliminate various pains by acting on the central or peripheral nervous system and peripheral tissue inflammation, thereby achieving the analgesic effect.
The opioid analgesic drug mainly plays an analgesic role by exciting opioid receptors, the opioid receptors have higher distribution density at the inner sides of thalamus, spinal glia areas, ventricles of brain and the like, are related to pain stimulation afferent and pain sense signal integration and perception, comprise three receptors of mu, delta and kappa, and all belong to G protein coupled receptors, the analgesic effect parts of mu receptors are brain, spinal cord and periphery, the analgesic effect parts of delta receptors are spinal cord, and the analgesic effect parts of kappa receptors are spinal cord and periphery. Therefore, the analgesic effect of opioid analgesics such as morphine is shown to be multi-site characteristic, and peripheral pain sense conduction and central pain sense are blocked, so that a strong analgesic effect is generated. Thus, opioid analgesia may be suitable for pain of various causes, but is currently used only for short-term applications where cancer is severe and other analgesics are ineffective, primarily because the use of such drugs is limited by the susceptibility to addiction and tolerance resulting from multiple consecutive applications. Classic opium drug addiction and tolerance are serious, and the opioid drug addiction and tolerance are usually only used as analgesic drugs for treating severe cancer pain and acute pain, are severe pain treatment drugs for three-step cancer treatment, and have good analgesic effect; the novel opium drugs such as hydrocodone hydrochloride and the like have addiction of different degrees in the process of being applied to medium and severe cancer pain and chronic non-cancer pain to cause substance abuse, and the clinical application is greatly limited due to the addiction of serious side effects, for example, the abuse caused by the Oxycontin (OxyContin) brings disasters to the society and personal health, so that the public can warn the attention points of the application of the opium drugs.
Non-steroidal anti-inflammatory analgesics represented by aspirin have a site of analgesic action mainly on the periphery, have a weak central analgesic action, and mainly aim at pain caused by tissue injury or inflammation, and inhibit Cyclooxygenase (COX) in a peripheral lesion site to reduce PGS synthesis to relieve pain, have a moderate analgesic action, have a good analgesic effect, but have a poor effect on severe pain such as acute sharp pain, sharp pain caused by severe trauma, and smooth muscle colic.
Other analgesics mainly have other receptors acting on opioid receptors, such as NMDA receptor, NK1 receptor, purine and pyrimidine receptor, hemp receptor and other drugs, and have weak analgesic effect, such as rotundine has good effect on chronic persistent dull pain, and the analgesic effect is weaker than pethidine but stronger than antipyretic analgesic and anti-inflammatory drugs; lappaconitine can be used as a candidate drug for mild and moderate pain, but cannot meet the treatment requirement of severe pain at present.
However, intense pain such as cancer pain, burn, incised wound, etc. is pain induced by various factors, the pain-causing mechanism is complicated, the generation of severe pain cannot be prevented by using only peripheral analgesics, and central analgesics must be used. Opioid analgesics such as morphine have strong analgesic effects, are effective for various pains, and are clinically irreplaceable, but the side effects such as addiction, tolerance and the like greatly limit the application thereof. At present, a single compound is improved to achieve the effects of strong analgesia, and meanwhile, serious side effects such as addiction and tolerance can be prevented, so that a good drug or compound is not found, and a method for eliminating opiate addiction and tolerance better and a treatment means for relieving or delaying the occurrence of drug addiction and tolerance are not available clinically, so that great difficulty is brought to the treatment of serious pain. On the other hand, although opioid drugs have strong analgesic effect, their addiction and tolerance and other serious side effects also severely limit the application range of opioid drugs with strong analgesic effect. Therefore, finding a drug or a treatment mode with good analgesic effect and small side effect becomes a major problem to be solved urgently in clinical pain treatment and pharmaceutical research at present.
Imatinib or the derivative imatinib mesylate, also known as Gleevec (or STI571), is a derivative of anilinopyrimidine. The preclinical studies could be traced back to the last century until the end of 1999, after the application of Chronic Myelogenous Leukemia (CML) was reported in the 41 st society of hematology in the United states, it really received attention, and thus large-scale studies were initiated, successfully developed by Nowa, Switzerland, and approved by the U.S. FDA in 2001 for marketing. Because it can be called as the first molecular targeted tumor generation mechanism of human anti-cancer new drug, so it is reviewed as milestone discovery by "Science" journal, and listed as one of the 10 technological breakthroughs in the world in 2001 together with human genetic engineering, etc. In order to solve the problem of tolerance and addiction of clinical opioid analgesic, the present application proposes a substantially improved new technology based on the previously applied patents (CN 105974131A and CN 106074555A) "the use of c-kit as a target for drug addiction treatment" and "the new use of imatinib and its derivatives in treating addiction" and the report of imatinib derivatives of Yan Wang and Howard B.Gutstein et al, imatinib mesylate, which is useful for preventing morphine tolerance (Nat Med.; 18(3): 385-387. doi:10.1038/nm.2633.) and imatinib fluid administration for opioid dependence treatment (PCT/US2008/079198), i.e., a way of using a new dose range (i.e., the lowest clinically used dose of 100 mg/day, the highest dose of not more than 400 mg/day) in combination with an addictive compound analgesic or preparing various new formulations (without being limited to fluid), provides a drug combination mode or a preparation with various specifications which has strong analgesic effect, can prevent addiction and tolerance side effect in opioid pain treatment and has effective proportion for various pains. Moreover, the imatinib mesylate dosage (100mg-400 mg/day/70 kg) used in the invention has few side effects in the clinical use process, is within the clinical use safe dosage range, has good clinical effectiveness and safety, can be widely applied to the treatment of various clinical acute and chronic pains, and solves the bottleneck problem of clinical analgesia at present.
The invention discovers that the low dose of imatinib mesylate, namely 5mg/kg, can be used for tolerance treatment and prevention but cannot prevent and treat addiction and relapse after withdrawal, the dose higher than 10mg/kg can prevent and treat opioid tolerance and addiction, and can also successfully prevent addiction of opium and other substances and relapse after withdrawal without influencing the analgesic effect of morphine. And in the clinical dose range of 100mg-400 mg/day/70 kg, when the dose ratio of the imatinib mesylate to the morphine is less than 2:1, the addiction and tolerance of opium cannot be prevented, and when the dose ratio of the imatinib mesylate to the morphine is more than or equal to 2:1, the addiction and tolerance of opium can be successfully prevented without influencing the analgesic effect of the morphine. The typical dose effect has similar examples in the clinical application of the second type of analgesic aspirin, such as the drug action effects of small dose aspirin for resisting thrombus, medium dose aspirin for relieving fever and pain, high dose anti-inflammation and anti-rheumatism, three types of clinical indications of antithrombotic, relieving fever and pain and anti-inflammation and anti-rheumatism are completely different and have substantial differences. Therefore, the dose proportioning effect (the dose proportioning range of the imatinib mesylate and the opioid in the rat is more than 2:1, the clinical dose is more than 100 mg/day for other species, and the dose is equivalent to that of the imatinib mesylate) is a substantial new discovery of the imatinib mesylate in analgesia and addiction side effect prevention, the imatinib mesylate and the opioid are jointly used in the dose proportioning range or prepared into various compound preparations to prevent and treat the addiction side effect in opioid analgesia application, the drug is applied to different indications in different dose ranges, and the invention is substantially different from the application and progress of the prior invention.
Compared with the existing drugs for treating addiction, the imatinib mesylate drug has obvious difference in action mechanism, and the imatinib mesylate inhibits various signal transduction pathways such as PKC, PI3K-AKT, ERK and the like by blocking c-kit receptors to regulate kinase activity, protein expression and gene expression and regulate and start morphine reward, memory and neural plasticity processes, and blocks various effects generated by morphine, thereby achieving the effect of preventing and treating addiction of addictive analgesics.
The invention provides various compound preparations or combined preparations prepared from imatinib and derivatives thereof and opioid for preventing and treating addiction side effects of opioid analgesic drugs from the aspects of dose proportion and a new action mechanism process for the first time, is better suitable for clinical requirements, avoids unnecessary disasters caused by abuse, and promotes the prevention and treatment of the application safety of analgesic drugs to a great extent on the basis. From the view of molecular structure, imatinib and morphine have no interactive group, therefore, the imatinib and the derivative thereof are provided to be combined with morphine or to be prepared into compound preparations for carrying out analgesic treatment and preventing opioid addiction and tolerance side effects, which is effective, does not influence the analgesic effect of opioid, and simultaneously can expand the analgesic indications of opioid.
Disclosure of Invention
Aiming at the problems of addiction and tolerance side effects in analgesia of analgesic drugs in the background, the invention aims to provide a new application of imatinib and derivatives thereof in the field of analgesic drugs, and the imatinib and the derivatives thereof and the analgesic drugs are combined or used as a compound preparation according to the proportion of 2:1 to prevent or reduce the addiction and tolerance of the analgesic drugs, have no influence on the analgesic effect of the drugs, and expand the analgesic adaptation disease range of the analgesic drugs.
The invention mainly carries out the following researches:
(1) the imatinib and the derivative thereof and morphine are combined or compound preparations for preventing or treating opioid addiction mechanism and dose proportioning effect.
In order to prove that the imatinib and the derivative thereof and morphine combined drug or compound preparation can prevent or treat addiction in the single morphine medication process and have the effect of dose proportioning dependence, the invention is completed by the following experiments: by using a pain model, after morphine analgesia, a mouse is immediately placed in a Conditional Place Preference (CPP) training experimental device, whether the conditional place preference can be formed after morphine analgesia is firstly observed, so that addiction can be caused in the morphine analgesia process, and simultaneously, the dose proportioning effect of imatinib mesylate on prevention of the formation of CPP after morphine analgesia is observed. In the experiment of dose proportioning effect of imatinib mesylate and morphine, 1, 5, 10, 20 and 30mg/kg of imatinib mesylate is intraperitoneally administered to experimental rats in advance, then 5 and 10mg/kg of morphine is subcutaneously injected, or mixed injections prepared by respectively adopting 1, 5, 10, 20 and 30mg/kg of imatinib mesylate and 5 and 10mg/kg of morphine are administered, and a classical rat condition position preference model for evaluating addiction is adopted to determine the dose proportioning effect of imatinib mesylate on rat morphine condition position preference to form prevention and treatment effects; further adopting acute morphine for 60 minutes after the administration to observe the change of c-kit activity of midbrain limbic dopamine systems including VTA, nucleus accumbens, amygdala, hippocampus and prefrontal cortex, observing the change of c-kit phosphorylation level by immunohistochemistry combined with western-blot, observing activated cell distribution by immunofluorescence co-labeling, determining downstream activation target molecules by multicolor immunofluorescence co-labeling, determining a new mechanism of morphine addiction molecules and an action mechanism of imatinib mesylate for preventing and treating addiction.
The results show that the mice can form CPP after morphine analgesia by adopting a pain model, and different dose ratios (greater than or equal to 2:1) of imatinib mesylate and morphine have different degrees of inhibition effects on the formation of the CPP of the morphine. Whether co-administered or mixed, rats not administered imatinib mesylate had a conditioned place preference for formation, 10, 20, 30mg/kg, but not 1, 5mg/kg, prevented a conditioned place preference for formation of 5mg/kg morphine following administration of imatinib mesylate; 20. 30mg/kg, instead of 1, 5, 10mg/kg, of imatinib mesylate prevented the conditional local preference for 10mg/kg morphine, indicating that a dose ratio of imatinib mesylate to morphine of greater than or equal to 2:1 prevents morphine addiction. After the acute morphine is administrated, the immunohistochemistry, western-blot and multicolor immunofluorescence co-labeling results show that the nucleus accumbens is specifically activated, but not other brain area neuron c-kit receptors and a plurality of signal transduction pathways such as PKC, PI3K-AKT, ERK and the like regulate kinase activity, protein expression, gene expression and regulation to start the processes of morphine rewarding, memory and neural plasticity; the imatinib mesylate can inhibit various signal transduction pathways such as PKC, PI3K-AKT, ERK and the like by blocking c-kit receptors to regulate kinase activity, protein expression, gene expression and regulation and start morphine reward, memory and neural plasticity processes, thereby achieving the effect of preventing morphine addiction.
(2) The imatinib and the derivative thereof and morphine are combined or compound preparations for preventing or treating opioid addiction mechanism and dose proportioning effect.
In order to prove that the imatinib and the derivative thereof and morphine combined drug or compound preparation can prevent or treat tolerance of morphine in the single drug administration process and has the effect of dose ratio dependence, the invention is completed by the following experiments: the method comprises the steps of using a hot plate pain model, carrying out intraperitoneal administration on experimental rats with 1, 5, 10, 20 and 30mg/kg of imatinib mesylate in advance, then carrying out subcutaneous injection with 5 and 10mg/kg of morphine, or respectively adopting 1, 5, 10, 20 and 30mg/kg of imatinib mesylate and 5 and 10mg/kg of morphine to prepare mixed injection for administration, and determining the dose proportioning effect of the imatinib mesylate on the rat morphine tolerance to form the prevention and treatment effect according to the thermal pain threshold.
The results show that different dose ratios (greater than or equal to 2:1) of imatinib mesylate and morphine in the hot plate pain model have different degrees of inhibition of morphine tolerance expression. Either in combination or in a mixed formulation, morphine tolerance develops in rats not administered imatinib mesylate, 10, 20, 30mg/kg, but not 1, 5mg/kg prevents morphine tolerance expression of 5mg/kg following administration of imatinib mesylate; 20. 30mg/kg, instead of 1, 5, 10mg/kg, of imatinib mesylate prevented the conditional local preference for 10mg/kg morphine, indicating that a dose ratio of imatinib mesylate to morphine of greater than or equal to 2:1 prevents morphine addiction.
(3) The imatinib and the derivative thereof and morphine are combined or compound preparation in a dosage ratio to prevent central analgesic side effects of morphine without influencing the exertion of analgesic effect.
In order to prove that the combined medicine or compound preparation of the imatinib and the derivative thereof and the morphine in the dosage ratio has no influence on the exertion of the analgesic effect of the morphine, the invention is completed by the following experiments: in the combined drug experiment, 1, 5, 10, 20 and 30mg/kg of imatinib mesylate is intraperitoneally administered 30 minutes in advance, and then 10mg/kg of morphine is subcutaneously injected. In the administration experiment of the compound preparation, 1, 5, 10, 20 and 30mg/kg of imatinib mesylate is mixed with 10mg/kg of morphine respectively and then is immediately injected subcutaneously. And respectively observing the influence of the imatinib mesylate and morphine dose proportioning effect combined medicine or compound preparation on each detection index by adopting a classical pain model (a hot plate pain-causing experiment, an acetic acid writhing experiment, a formalin pain-causing experiment and a plantar CTA chronic pain-causing experiment model).
The results show that the combination of imatinib mesylate and morphine or the compound preparation has no significant influence on various detection indexes no matter what dosage ratio.
(4) In clinical application, the dosage ratio of the imatinib or the derivative thereof to the morphine is 100-400 mg/day.
Adopting a morphine tolerance model, wherein the dosage ratio of imatinib mesylate to morphine is greater than or equal to 2:1 can prevent morphine tolerance expression and improve the thermal pain threshold of rats by adopting a morphine tolerance model, and the dosage ratio of imatinib mesylate to morphine is less than 2:1 and has no effect, wherein the lowest dosage of imatinib mesylate is 10 mg/kg; using pain model, after morphine analgesia, CPP can be formed, different dose ratios (greater than or equal to 2:1) of imatinib mesylate and morphine have different degrees of inhibition on morphine tolerance expression, and dose ratios lower than 2:1 have no effect, wherein the lowest dose of imatinib mesylate is 10 mg/kg. Indicating that the imatinib mesylate and morphine composition in a dose ratio of greater than or equal to 2:1 can prevent the onset of morphine addiction and also prevent the onset of tolerance side effects, wherein the minimum dose of imatinib mesylate is 10 mg/kg. In clinical application, the equivalent dose conversion between human and animal according to the conversion of body surface area can be referred to pharmacological experimental methodology compiled by professor of xu Tertiary cloud:
for example: the dosage of the rat is Xmg/kg, and the converted clinical dosage of the adult is as follows:
since the clinical dose of human is Xmg/kg × 0.2kg/0.018 is 11.1 Xmg/day, the rat imatinib mesylate dose (1, 5, 10, 20, 30mg/kg) is converted into the clinical dose of adult 11, 55, 110, 220, 330 mg/day, respectively.
According to the marketed drug, glivectiminib
The published clinical test data shows that 400 mg/day/70 kg has few side effects in the clinical use process, so 100-400 mg/day/70 kg is selected as imatinib mesylate which is used as the clinical dose to be matched with the opioid analgesic.
Based on the research content, the invention provides the following technical scheme:
use of imatinib or a derivative thereof with an analgesic for the manufacture of a medicament, said use comprising: (1) use of a composition comprising imatinib or a derivative thereof and an analgesic drug for the manufacture of a medicament for the treatment of pain; (2) use of a composition comprising imatinib or a derivative thereof and an analgesic drug for the manufacture of a medicament for the prevention of analgesic tolerance and addictive side effects.
In the application, the ratio of the imatinib or the derivative thereof to the analgesic drug is more than or equal to 2:1 according to the effective component, and the clinical dosage of the imatinib or the derivative thereof is 100-400 mg/day.
The analgesic drug comprises addictive opium such as morphine, codeine, pethidine, fentanyl, methadone, oxycodone, hydromorphone, nalbuphine and cannabis components which act on a central analgesic system to generate analgesic effect, and non-opium various addictive compounds or salts thereof.
The pain is applicable to the indications of the analgesic drug for single-use treatment and other different types of acute and chronic pain.
The composition comprising imatinib or a derivative thereof and an analgesic drug, wherein imatinib or a derivative thereof and the analgesic drug are administered simultaneously, separately or sequentially.
The medicine is suitable for being prepared into the following dosage forms or one of different specifications: injection, infusion solution, subcutaneous implant, pill, tablet, powder, granule, capsule, powder, oral liquid, sustained release agent, tincture, suppository, patch, etc.
The invention has the following beneficial effects: compared with the traditional single medicine, the combination or compound medicine of imatinib and derivatives thereof with the dosage ratio of more than or equal to 2:1 and analgesic can effectively exert the analgesic effect of the analgesic, and simultaneously can effectively prevent the serious side effect of opioid from generating without influencing the analgesic effect of the opioid, effectively solve the problem of clinical pain treatment, effectively prevent side effect and further expand the clinical indications of the addictive analgesic.
Drawings
FIG. 1 is a graph showing the effect of dose-matching of imatinib mesylate and morphine on morphine addiction in rats; a is the effect of imatinib mesylate in combination with 5mg/kg morphine on morphine addiction formation in rats; b is the effect of imatinib mesylate in combination with 10mg/kg morphine on morphine addiction formation in rats; c is the influence of the compound administration of the imatinib mesylate and 5mg/kg morphine on the addiction formation of the morphine in rats; d is the influence of the compound administration of imatinib mesylate and 10mg/kg morphine on the addiction formation of morphine in rats.
Figure 2 is a new molecular mechanism for the prevention of morphine addiction by imatinib mesylate; a is a c-kit immunohistochemical detection assay; b is c-kit immunoblot detection analysis; c is C-kit and ERK immunofluorescence double-label detection analysis; d is c-kit and Akt immunofluorescence double-label detection analysis; e is c-kit and PKCzeta immunofluorescence double-label detection analysis; f is Opal/TSA multi-marker staining detection analysis.
Figure 3 is a graph showing the effect of dosing imatinib mesylate to morphine on addiction formation during analgesia; a is the influence of the compound administration of imatinib mesylate and 10mg/kg morphine on the addiction formation of mouse morphine; and B is the influence of the compound administration of the imatinib mesylate and 15mg/kg morphine on the addiction formation of the morphine in the mice.
Figure 4 is a graph of the effect of imatinib mesylate to morphine dose ratios on morphine tolerance in rats; a is the effect of imatinib mesylate in combination with 5mg/kg morphine on morphine tolerance in rats; b is the effect of combination administration of imatinib mesylate and 10mg/kg morphine on morphine tolerance in rats; c is the influence of the compound administration of imatinib mesylate and 5mg/kg morphine on the tolerance of rats to morphine; d is the effect of the compound administration of imatinib mesylate and 10mg/kg morphine on the tolerance of rats to morphine.
FIG. 5 is a graph showing the effect of dose-matching of imatinib mesylate and morphine on central analgesic effect of morphine in rats; a is the influence of the combined administration of imatinib mesylate and morphine on the central analgesic effect; b is the influence of the compound administration of imatinib mesylate and morphine on the central analgesic effect;
FIG. 6 shows the effect of dose-matching effect of imatinib mesylate and morphine on acute visceral analgesic effect of mouse morphine; a is the influence of the combined administration of imatinib mesylate and morphine on the acute visceral analgesic effect; b is the influence of the compound administration of imatinib mesylate and morphine on the acute visceral analgesic effect;
FIG. 7 shows the effect of dose-matching effect of imatinib mesylate and morphine on acute inflammation analgesia in rat morphine; a is the influence of the combined administration of imatinib mesylate and morphine on the analgesic effect of acute inflammation; b is the influence of the compound administration of imatinib mesylate and morphine on the central analgesic effect;
FIG. 8 shows the effect of dose-matching effect of imatinib mesylate and morphine on chronic inflammatory analgesic effect of morphine in rats; a is the influence of the combined administration of imatinib mesylate and morphine on the analgesic effect of chronic inflammation; b is the influence of the compound administration of imatinib mesylate and morphine on the analgesic effect of chronic inflammation;
FIG. 9 is a conversion of the dose of imatinib mesylate used with the clinical dose.
Detailed Description
The present invention will be described in further detail with reference to examples, but the embodiments of the present invention are not limited thereto. The analgesic used in the examples below is morphine, which is widely representative, and one skilled in the art can reproduce similar findings with other opioids having similar mechanisms of action to morphine. Materials, reagents and the like used in the following examples are commercially available unless otherwise specified.
Example 1: the influence of dose proportioning effect of imatinib mesylate and morphine on rat morphine addiction formation and molecular mechanism experiment 1: effect of dose proportioning effect of imatinib mesylate and morphine on morphine addiction formation in rats
Materials (I) and (II)
Medicine preparation: morphine (Morphine, Qinghai pharmaceutical works), imatinib mesylate (Selleck Chemicals).
Experimental animals: SPF grade SD male rats weighing 180-220 g. Provided by lakan slykh scenda experimental animals experiment limited, the animal certification number is No.43004700040706, and the production license number is: SCXK (Xiang) 2016-. Rat feed purchased from the laboratory animal center of Wuhan university.
An experimental instrument: conditional position preference apparatus (developed by the institute of medicine make internal disorder or usurp of Chinese academy of medical sciences): the experiment is automatically controlled by a computer. The device consists of a conditioned place preference box consisting of three boxes: two side chambers and a middle chamber. The three chambers are separated by a movable partition plate, and the inside and the outside are black. The box A and the box B are positioned on two sides of the middle box and have the same size, 9 squares capable of emitting yellow light diodes are arranged on the side wall of the box A, a bottom plate is made of stainless steel bars, and a bottom plate of the box B is made of stainless steel grids. The residence time and the number of times of entrance and exit of the rats in each box can be transmitted to a computer through data, and behavioural data are automatically collected and recorded.
Second, Experimental methods
And (3) testing a basic value: on day 1, the partition was removed, the three chambers were opened, the CPP program on the computer was started, the rat was placed in the middle chamber and allowed to move freely for 15 minutes in the three chambers, and the computer synchronously recorded the residence time in each chamber. Elimination was performed according to the test results, and the animals were divided into 6 groups (morphine + physiological saline group, morphine + imatinib mesylate group (1mg/kg), morphine + imatinib mesylate group (5mg/kg), morphine + imatinib mesylate group (10mg/kg), morphine + imatinib mesylate group (20mg/kg), morphine + imatinib mesylate group (30mg/kg)), 10 animals per group, and the concomitant drug side and non-concomitant drug side of each rat were distinguished.
Conditional location preference training: and (3) closing the three interchamber channels on days 2 to 9, wherein the imatinib mesylate and the morphine are administered in a combined mode or a compound preparation mode. On days 2, 4, 6 and 8, different doses of imatinib mesylate (1, 5, 10, 20, 30mg/kg, i.p.) or physiological saline (1mL/kg, i.p.) were intraperitoneally injected into each group, morphine (5, 10mg/kg, s.c.) was subcutaneously injected after 30 minutes, or rats in each group were simultaneously subcutaneously injected with different dose ratios of imatinib mesylate (1, 5, 10, 20, 30mg/kg, s.c.) or physiological saline (1mL/kg, s.c.) and morphine (5, 10mg/kg, s.c.) mixed reagent and placed on the concomitant drug side for 45 minutes; on days 3, 5, 7, and 9, rats in morphine group were injected with saline intraperitoneally (1mL/kg, i.p.), subcutaneously (1mL/kg, s.c.) after 30 minutes, or subcutaneously (1mL/kg, s.c.) and placed on the non-concomitant side for 45 minutes. The concomitant side of each rat was fixed. After the experiment, each group of rats was returned to the rearing cage.
Morphine CPP test: on day 10, CPP testing, similar to the baseline testing phase. The channel between the three chambers was opened, without any injection, the CPP program on the computer was started, the rat was placed from the middle chamber and allowed to move freely in the chamber for 15 minutes, and the computer synchronously recorded the residence time in each chamber. CPP score (CPP score) is the difference between time on the concomitant side and time on the non-concomitant side. Comparing the measured value of the rat after the rat has the conditional position preference in the medicine accompanying box with the previously measured value to determine whether the rat has the conditional position preference.
Third, experimental results
The results are shown in figure 1A, the condition site preference score of the imatinib mesylate and morphine combination administration group is significant and dose ratio dependent compared with the normal saline and morphine group, the intraperitoneal injection of 10, 20 and 30mg/kg of imatinib mesylate can inhibit the formation of condition site preference of rats of 5mg/kg of morphine, and the intraperitoneal injection of 1 and 5mg/kg of imatinib mesylate has no inhibition; conditioned place preference still exists for rats not administered imatinib mesylate. FIG. 1B shows that intraperitoneal injection of 20 mg/kg/g imatinib mesylate inhibits conditioned place preference for 10mg/kg morphine in rats, whereas 1mg/kg, 5mg/kg, 10mg/kg imatinib mesylate is not inhibitory, indicating that imatinib mesylate and morphine in a dose ratio of greater than or equal to 2:1 inhibits morphine addiction in rats. Similarly, similar results were obtained with the imatinib mesylate and morphine combination in figures 1C and 1D.
Experiment 2: novel mechanism for preventing morphine addiction by using imatinib mesylate
From the results of experiment 1, imatinib mesylate (10-30mg/kg) had varying degrees of inhibitory effect on morphine CPP formation, whether administered in combination or in a mixed formulation. The experiment adopts immunohistochemistry, western-blot and multicolor immunofluorescence molecular experiments to detect the change of c-kit phosphorylation level of a drug reward brain area and downstream activation target molecules thereof, and determines a new molecular mechanism of morphine addiction and an action mechanism of imatinib mesylate for preventing and treating addiction.
Materials (I) and (II)
Medicine preparation: morphine (Morphine, Qinghai pharmaceutical works), imatinib mesylate (Selleck Chemicals).
Experimental animals: SPF grade SD male rats weighing 180-220 g. The animal qualification number is No.42010200001637, and the production license number: SCXK (jaw) 2016-. Rat feed purchased from the laboratory animal center of Wuhan university.
Second, Experimental methods
The animals were then divided into saline + saline group, saline + imatinib mesylate group, morphine + saline, morphine + imatinib mesylate group, 10 rats per group, each rat was administered either saline (1ml/kg, i.p.) or imatinib mesylate (30mg/kg, i.p.) intraperitoneally, morphine (10mg/kg, s.c.) was injected subcutaneously after 30 minutes, the mesolimbic dopamine system was observed after 60 minutes including VTA, the change of c-kit activity of nucleus accumbens, amygdala, hippocampus and prefrontal cortex, the observation of the change of c-kit phosphorylation level by immunohistochemistry combined with western-blot, the observation of activated cell distribution by immunofluorescence co-labeling, the determination of downstream activation target molecules by multicolor immunofluorescence co-labeling, the determination of a new morphine addiction molecule mechanism and an action mechanism of imatinib mesylate for preventing and treating addiction.
Third, experimental results
The results are shown in figure 2, after the acute morphine is administrated, the co-labeling results of immunohistochemistry, western-blot and multicolor immunofluorescence show that the nucleus accumbens is specifically activated but not other brain area neuron c-kit receptors and a plurality of signal transduction pathways such as PKC, PI3K-AKT, ERK and the like after the receptors regulate kinase activity, protein expression, gene expression and regulation to start morphine reward, memory and neural plasticity processes, and the nucleus accumbens c-kit receptors are the specific brain areas activated by the acute morphine administration; the imatinib mesylate can inhibit various signal transduction pathways such as PKC, PI3K-AKT, ERK and the like by blocking c-kit receptors to regulate kinase activity, protein expression, gene expression and regulation and start morphine reward, memory and neural plasticity processes, thereby achieving the effect of preventing morphine addiction.
Example 2: influence of dose proportioning effect of imatinib mesylate and morphine on addiction formation of morphine during analgesia process
From example 1, imatinib and its derivative imatinib mesylate inhibit morphine addiction formation in rats by inhibiting c-kit phosphorylation activity in nucleus accumbens region, opioid drugs such as morphine are clinically common analgesic drugs, and the dose ratio of morphine and other opioid drugs is greater than or equal to 2:1, and the opioid drugs can prevent and treat morphine addiction side effects.
Materials (I) and (II)
Medicine preparation: morphine (Morphine, Qinghai pharmaceutical works), imatinib mesylate (Selleck Chemicals).
Experimental animals: male mice of the SPF-grade Kunming strain weigh 18-22 g. The animal qualification number is No.42010200001574, and the production license number: SCXK (Hubei) 2017-. Rat feed purchased from the laboratory animal center of Wuhan university.
An experimental instrument: conditional position preference apparatus (developed by the institute of medicine make internal disorder or usurp of Chinese academy of medical sciences): the experiment is automatically controlled by a computer. The device consists of a conditioned place preference box consisting of three boxes: two side chambers and a middle chamber. The three chambers are separated by a movable partition plate, and the inside and the outside are black. The box A and the box B are positioned on two sides of the middle box and have the same size, 9 squares capable of emitting yellow light diodes are arranged on the side wall of the box A, a bottom plate is made of stainless steel bars, and a bottom plate of the box B is made of stainless steel grids. The residence time and the number of times of the mice in each box can be transmitted to a computer through data, and behavioural data can be automatically collected and recorded.
Second, Experimental methods
And (3) testing a basic value: the same as in example 1.
Conditional location preference training: and (3) closing the three interchamber channels on days 2 to 9, wherein the imatinib mesylate and the morphine are administered in a compound preparation mode. On days 2, 4, 6, and 8, mice in each group were injected intraperitoneally with 0.6% acetic acid solution (0.2mL, i.p.) and then subcutaneously with different dose ratios of imatinib mesylate (1.5, 7.5, 15, 30, 45mg/kg, 1, 5, 10, 20, 30mg/kg, s.c, respectively, equivalent to rats) or a mixture of physiological saline (1mL/kg, s.c.) and morphine (10, 15mg/kg, s.c.) and placed on the concomitant drug side for 45 minutes; on days 3, 5, 7, and 9, rats in each group were injected intraperitoneally with 0.6% acetic acid solution (0.2mL, i.p.), followed by subcutaneous injection of physiological saline (1mL/kg, s.c.), and placed on the non-concomitant side for 45 minutes. The concomitant side of each mouse was fixed. Each group of mice was returned to the cage after the experiment.
Morphine CPP test: the same as in example 1.
Third, experimental results
The results are shown in fig. 3A, in the analgesic process of morphine, the difference of the morphine + imatinib mesylate compound administration group is still significant and dose ratio dependent compared with the morphine + normal saline group, after 30mg/kg and 45mg/kg of imatinib mesylate is subcutaneously injected, the mouse 10mg/kg of morphine conditional position preference cannot be formed, while 1.5 mg/kg, 7.5 mg/kg and 15mg/kg of imatinib mesylate have no inhibition, and the mouse without the imatinib mesylate administration has the conditional position preference still existed; figure 3B shows that after subcutaneous injection of 30, 45mg/kg imatinib mesylate, mice 15mg/kg morphine had conditioned place preference for failure to form, whereas 1.5, 7.5, 15mg/kg imatinib mesylate had no inhibitory effect, indicating that imatinib mesylate and morphine in a dose ratio dependent manner inhibited morphine addiction in mice at the time of analgesia, and that the dose ratio of the two required was greater than or equal to 2: 1.
Example 3: effect of imatinib mesylate on rat morphine tolerance
According to the results of the examples 1 and 2, the composition of imatinib mesylate and morphine in the dosage ratio of 2:1 or more can obviously prevent the formation of morphine addiction in rats or mice, in the example, imatinib mesylate and morphine are selected as analgesic drugs for central pain of rats, and the influence of combined administration and compound administration of imatinib mesylate and morphine on morphine tolerance is studied by establishing rat morphine tolerance and hot plate pain models.
Materials (I) and (II)
Medicine preparation: morphine (Qinghai pharmaceutical factory); imatinib mesylate (Selleck Chemicals).
Experimental animals: SPF grade SD female rats weighing 180-220 g. The animal qualification number is No.42010200001863, and the production license number: SOCK 2017-.
Second, Experimental methods
Basic pain area determination: measuring the basal pain threshold of the rat by using a hot plate method at 50 +/-0.5 ℃ and the time of the first occurrence of licking of the rat, and taking an average value twice for avoiding scalding the rat, wherein the measuring time is less than 60 seconds, and the removing time is more than 30 seconds and less than 5 seconds. Rats were divided into 6 groups (morphine + saline group, morphine + imatinib mesylate group (1mg/kg), morphine + imatinib mesylate group (5mg/kg), morphine + imatinib mesylate group (10mg/kg), morphine + imatinib mesylate group (20mg/kg), morphine + imatinib mesylate group (30mg/kg)) according to the basal pain threshold, 10 per group.
Each group of rats was injected intraperitoneally with different doses of imatinib mesylate (1, 5, 10, 20, 30mg/kg, i.p.) or physiological saline (1mL/kg, i.p.) daily, 30 minutes later with subcutaneous morphine (10mg/kg, s.c.); or injecting different dose proportions of imatinib mesylate (1, 5, 10, 20, 30mg/kg, s.c.) or physiological saline (1mL/kg, s.c.) and morphine (10mg/kg, s.c.) mixed reagent into rats subcutaneously. The pain threshold of the rats was determined after 30 minutes. The administration was continued for four days and the pain threshold was determined after daily administration. On the fifth day, rats of each group were administered morphine subcutaneously (10mg/kg, s.c.) and the thermal pain threshold was determined.
Third, experimental results
The results are shown in fig. 4A, the thermal pain threshold of the rats in the combination administration group of imatinib mesylate and morphine is significant compared with that in the group of normal saline and morphine, the dose ratio of the thermal pain threshold and the dose ratio of the normal saline and morphine in the rats is dependent, 20mg/kg and 30mg/kg of imatinib mesylate by intraperitoneal injection can significantly reduce the morphine-induced rat tolerance expression, 1mg/kg, 5mg/kg and 10mg/kg of imatinib mesylate are not inhibitory, and the rat morphine tolerance still exists in rats not administered with imatinib mesylate, which indicates that the dose ratio of imatinib mesylate and morphine in the rats inhibits the formation of morphine tolerance, and the dose ratio of the two needs to be greater than or equal to 2: 1. Similarly, similar results were obtained with the imatinib mesylate and morphine combination in figure 4B.
Example 4: influence of dose proportioning effect of imatinib mesylate and morphine on central analgesic effect of morphine in rats
The results of examples 1, 2 and 3 show that imatinib or its derivative imatinib mesylate can prevent morphine addiction formation and tolerance expression, opioid drugs such as morphine are clinically common analgesic drugs, and the dosage ratio of the two drugs is greater than or equal to 2:1, and side effects can be prevented and treated after the opioid drugs are used.
Materials (I) and (II)
Medicine preparation: morphine (Qinghai pharmaceutical factory); imatinib mesylate (Selleck Chemicals).
Experimental animals: SPF grade SD female rats, 180-220 g. The animal qualification number is NO.42000600025195 provided by the experimental animal research center of Hubei province, and the production license number is: SOCK (jaw) 2015-0018. Rat feed purchased from the laboratory animal center of Wuhan university.
Second, Experimental methods
Basic pain threshold determination: the same as in example 3. Rats were randomly divided into 4 groups (imatinib mesylate + morphine, imatinib mesylate + physiological saline, physiological saline + morphine, physiological saline + physiological saline) by threshold time, 10 per group.
Each group was injected intraperitoneally with different doses of imatinib mesylate (1, 5, 10, 20, 30mg/kg, i.p.) or physiological saline (1mL/kg, i.p.), with 30 minutes later injection of morphine subcutaneously (10mg/kg, s.c.) or physiological saline (1mL/kg, s.c.); or four groups of rats are injected with mixed reagents of imatinib mesylate (1, 5, 10, 20, 30mg/kg, s.c.) or physiological saline (1mL/kg, s.c.) and morphine (10mg/kg, s.c.) or physiological saline (1mL/kg, s.c.) in different dose ratios. After 30 minutes, the rats were gently placed on a 50 ± 0.5 ℃ hot plate, the time for the rats to lick the foot after the first time was recorded, and if the rats did not lick the foot after 60 seconds, the rats were taken out, and the pain threshold time was calculated as 60 seconds. The performance of rats before and after administration was observed and the observation was carefully recorded.
Third, experimental results
The results are shown in fig. 5A, and compared with the morphine + physiological saline group, the thermal pain threshold of the rats is not obviously changed in the imatinib mesylate + morphine combination administration group; the rat HPPT of the imatinib mesylate and normal saline group has no obvious change compared with the normal saline and normal saline group. The hot plate pain-causing experiment shows that the central analgesic effect of morphine cannot be weakened by combined administration of imatinib mesylate and morphine in any dosage ratio. Similarly, similar results were obtained with the imatinib mesylate and morphine combination in figure 5B.
Example 5: influence of dose proportioning effect of imatinib mesylate and morphine on acute visceral analgesic effect of mouse morphine
The results of example 4 show that imatinib mesylate has no obvious influence on central analgesic effect of rat morphine, in this example, imatinib mesylate and morphine are selected as analgesic drugs for acute visceral pain of mice, and the influence of combined administration and compound administration of imatinib mesylate and morphine on analgesic effect of morphine for visceral pain of mice caused by writhing acetate is discussed by establishing an experimental model for pain-induced by writhing acetate of mice.
Materials (I) and (II)
Medicine preparation: morphine (Qinghai pharmaceutical factory); imatinib mesylate (Selleck Chemicals).
Experimental animals: male mice of Kunming species of SPF grade, 18-22 g. The animal qualification number is No.42010200001139, and the license number is: SOCK (jaw) 2015-0012.
Second, Experimental methods
The test solution is randomly divided into four groups, namely a normal saline + normal saline, a normal saline + morphine, imatinib mesylate + normal saline, and imatinib mesylate + morphine, wherein each group comprises 10 animals. Each group of mice was intraperitoneally injected with different doses of imatinib mesylate ((1.5, 7.5, 15, 30, 45mg/kg, corresponding to rat equivalent doses of 1, 5, 10, 20, 30mg/kg, i.p.) or physiological saline (1mL/kg, i.p.), subcutaneously injected with morphine (10mg/kg, s.c.) or physiological saline (1mL/kg, s.c.) after 30 minutes, or intraperitoneally injected with different doses of imatinib mesylate (1.5, 7.5, 15, 30, 45mg/kg, corresponding to rat equivalent doses of 1, 5, 10, 20, 30mg/kg, i.p.) or physiological saline (1mL/kg, i.p.), orally administered to mice after 30 minutes with 0.2mL of 0.6% acetic acid solution, observing the latency and number of writhing reactions of mice within 0-20 minutes Stretching of the body and hind limbs, tilting of the buttocks and creeping.
Third, experimental results
The results are shown in fig. 6A, and compared with the morphine + physiological saline group, the writhing frequency of the mice is not obviously changed in the imatinib mesylate + morphine group; compared with the normal saline and normal saline group, the imatinib mesylate and normal saline group has no obvious change in the times of writhing of the mice. The results show that in the acetic acid writhing experiment, the acute visceral analgesic effect of morphine on mice is not obviously influenced by combined administration of imatinib mesylate and morphine in any dosage ratio. Similarly, similar results were obtained with the imatinib mesylate and morphine combination in figure 6B.
Example 6: influence of dose proportioning effect of imatinib mesylate and morphine on analgesic effect of acute chemical inflammation of rat morphine
The results of examples 4 and 5 show that imatinib mesylate has no obvious influence on central analgesic effect of rat morphine and acute visceral analgesic effect of mouse morphine, in the example, imatinib mesylate and morphine are selected as analgesic drugs for rat acute inflammatory pain, and the influence of combined administration and compound administration of imatinib mesylate and morphine on the analgesic effect of 5% formalin-induced rat acute inflammatory pain morphine is discussed by establishing a rat 5% formalin-induced pain experimental model.
Materials (I) and (II)
Drugs and reagents: morphine (Qinghai pharmaceutical factory); imatinib mesylate (Selleck Chemicals).
Experimental animals: SPF grade SD male rats weighing 180-220 g. Provided by slyke scenda laboratory animals ltd, Hunan province, the animal certification number is No.43004700041685, the production license number: SOCK (Xiang) 2016-.
Second, Experimental methods
The test solution is randomly divided into four groups, namely a normal saline + normal saline, a normal saline + morphine, imatinib mesylate + normal saline, and imatinib mesylate + morphine, wherein each group comprises 10 animals. Each group of rats was injected intraperitoneally with different doses of imatinib mesylate (1, 5, 10, 20, 30mg/kg, i.p.) or physiological saline (1mL/kg, i.p.), with 30 minutes later injection of morphine subcutaneously (10mg/kg, s.c.) or physiological saline (1mL/kg, s.c.); or injecting different dose proportions of imatinib mesylate (1, 5, 10, 20, 30mg/kg, s.c.) or physiological saline (1mL/kg, s.c.) and morphine (10mg/kg, s.c.) or physiological saline (1mL/kg, s.c.) into rats subcutaneously to obtain mixed reagents. After 30 minutes, the surface of the left hind paw of the rat was given 50 μ L of 5% formalin solution and the total time the rat licked the red swollen left hind paw was recorded every five minutes for one hour. The formalin pain test is divided into two phases, wherein the first phase is 0-10 min, which is acute pain and can be inhibited by central analgesic drugs such as morphine; the inflammation reaction mediated by prostaglandin part is 10-60 minutes, and belongs to acute pathological pain.
Third, experimental results
The results are shown in fig. 7A, and the time for which rats lick the hind paw is not significantly changed in the imatinib mesylate + morphine group compared to the morphine + saline group; the time of the rats after licking the feet is not obviously changed in the imatinib mesylate and normal saline group compared with the normal saline and normal saline group. The result shows that in formalin pain-inducing experiments, the analgesic effect of morphine is not influenced by the combined medication of imatinib mesylate and morphine no matter what dosage ratio. Similarly, similar results were obtained with the imatinib mesylate and morphine combination in figure 7B.
Example 7: influence of dose proportioning effect of imatinib mesylate and morphine on analgesic effect of chronic inflammation of rat morphine
The results of examples 4, 5 and 6 show that imatinib mesylate has no obvious influence on the analgesic effect of acute pain of morphine in rats and mice, and in the example, imatinib mesylate and morphine are selected as analgesic drugs for chronic inflammatory pain in rats, and the influence of combined administration of imatinib mesylate and morphine and compound administration on the chronic inflammatory pain in rats caused by CFA is studied by establishing a rat Freund's complete adjuvant (CFA) chronic plantar pain test model.
Materials (I) and (II)
Medicine preparation: morphine (Qinghai pharmaceutical factory); imatinib mesylate (Selleck Chemicals).
Experimental animals: SPF grade SD female rats weighing 180-220 g. The animal qualification number is No.42010200001281, and the production license number: SOCK 2017-.
Second, Experimental methods
Basic pain area determination: the same as in example 3.
Preparation of chronic inflammatory pain model: after determination of the basal injury threshold, rats with normal threshold were selected and randomized into CFA (40) and NS (40, saline). Modeling of CFA chronic plantar inflammation: the CFA group rats use 1mL injector to extract 125 μ L CFA, inject to the left hind limb plantar subcutaneous of rat, press and hold the pinhole and massage for several minutes after injection to promote the drug diffusion; the NS group was injected with physiological saline in the same solvent in the same manner to prepare a control model. After modeling, the rats were weighed daily for weight change and observed for changes in the left foot (e.g., redness, transudation or infection at the site of injection on the sole of the foot), and the circumference of the highest part of the left foot was measured (and the same part of the right foot was measured for comparison).
On the third day after successful molding, rats were tested for pain threshold using a hotplate apparatus prior to dosing. The CFA group of rats was then randomly divided into four groups according to the circumference of the highest left foot: normal saline + normal saline, normal saline + morphine, imatinib mesylate + normal saline, imatinib mesylate + morphine, 10 in each group; the NS groups were also randomly divided into four groups: normal saline + normal saline, normal saline + morphine, imatinib mesylate + normal saline, imatinib mesylate + morphine, 10 individuals per group. Each group of rats was injected intraperitoneally with different doses of imatinib mesylate (1, 5, 10, 20, 30mg/kg, i.p.) or physiological saline (1mL/kg, i.p.), with 30 minutes later injection of morphine subcutaneously (10mg/kg, s.c.) or physiological saline (1mL/kg, s.c.); or injecting different dose proportions of imatinib mesylate (1, 5, 10, 20, 30mg/kg, s.c.) or physiological saline (1mL/kg, s.c.) and morphine (10mg/kg, s.c.) or physiological saline (1mL/kg, s.c.) into rats subcutaneously to obtain mixed reagents. The pain threshold of the rats was determined after 30 minutes. The administration was continued for three days, and the thermal pain threshold was determined before and after daily administration for a whole week.
Third, experimental results
The results are shown in FIG. 8A, after the model is made, compared with the morphine + normal saline group, the rat thermal pain threshold value is not obviously changed in the combined administration group of the imatinib mesylate and the morphine at the fourth day and the fifth day, the rat is tolerant to the morphine at the sixth day after the model is made, the morphine tolerance can be obviously prevented by 20mg/kg and 30mg/kg of the imatinib mesylate, the thermal pain threshold value is improved, 1mg/kg, 5mg/kg and 10mg/kg of the imatinib mesylate have no effect, which indicates that in the Freund complete adjuvant pelagic inflammation chronic pain experiment, the imatinib mesylate can not influence the morphine in the analgesic effect, and can prevent the expression of the morphine tolerance in the dosage ratio of more than or equal to 2:1 after the tolerance. Similarly, similar results were obtained with the imatinib mesylate and morphine combination in figure 8B.
Conclusion of the above examples: the imatinib and the derivative imatinib mesylate and morphine can prevent the formation and the expression of addiction in a dosage ratio of greater than or equal to 2:1, wherein the dosage is within the safe range of the currently clinically used dosage, as shown in fig. 9. In addition, the dose ratio of imatinib mesylate and opioid analgesics such as morphine is used, so that the pharmaceutical composition is applied to acute and chronic pains caused by hot plates, acetic acid, formalin, Freund's complete adjuvant and the like, and the analgesic effect of morphine is not influenced. Therefore, the imatinib or the derivative thereof can be used in proportion to the dosage of opioid analgesics such as morphine and the like to prevent the generation of addiction and tolerance side effects in opioid pain therapy; meanwhile, the formula for preventing and treating the side effect is provided, and the two are used according to the dosage proportion of more than or equal to 2:1 and are suitable for treating various types of pain, so that the range of opioid analgesic indications is widened.
The above embodiments are preferred embodiments of the present invention, but the present invention is not limited to the above embodiments, and any other changes, modifications, substitutions, combinations, and simplifications which do not depart from the spirit and principle of the present invention should be construed as equivalents thereof, and all such changes, modifications, substitutions, combinations, and simplifications are intended to be included in the scope of the present invention.
Claims (6)
1. Use of imatinib or a derivative thereof with an analgesic for the manufacture of a medicament, comprising:
(1) use of a composition comprising imatinib or a derivative thereof and an analgesic drug for the manufacture of a medicament for the treatment of pain;
(2) use of a composition comprising imatinib or a derivative thereof and an analgesic drug for the manufacture of a medicament for the prevention of analgesic tolerance and addictive side effects.
2. Use according to claim 1, characterized in that: the proportion of the imatinib or the derivative thereof and the analgesic drug is more than or equal to 2:1 according to the effective component, and the clinical dosage of the imatinib or the derivative thereof is 100-400 mg/day.
3. Use according to claim 1, characterized in that: the analgesic drug comprises addictive opium such as morphine, codeine, pethidine, fentanyl, methadone, oxycodone, hydromorphone, nalbuphine and cannabis components which act on a central analgesic system to generate analgesic effect, and non-opium various addictive compounds or salts thereof.
4. Use according to claim 1, characterized in that: the pain is applicable to the indications of the analgesic drug for single-use treatment and other different types of acute and chronic pain.
5. Use according to claim 1, characterized in that: the composition comprising imatinib or a derivative thereof and an analgesic drug, wherein imatinib or a derivative thereof and the analgesic drug are administered simultaneously, separately or sequentially.
6. Use according to claim 1, characterized in that: the medicine is suitable for being prepared into the following dosage forms or one of different specifications: injection, infusion solution, subcutaneous implant, pill, tablet, powder, granule, capsule, powder, oral liquid, sustained release agent, tincture, suppository, and patch.
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| PCT/CN2020/119253 WO2021063387A1 (en) | 2019-09-30 | 2020-09-30 | Use of composition of imatinib and derivative thereof in preparation of drug for preventing, treating and controlling addiction relapse |
| US17/709,358 US20220218707A1 (en) | 2019-09-30 | 2022-03-30 | Use of composition of imatinib or derivative thereof in preparation of drug for preventing, treating, and controlling addiction relapse |
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