CN101322705B - Applications of koumine in preparing medicament for treating chronic ache - Google Patents
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Abstract
The invention discloses the application of koumine to the preparation of medicines for treating chronic pains and belongs to the application of gelsemium alkaloid monomer. The analgesic experiments of the koumine on chronic pains of animals prove that the koumine has potent dose-dependent analgesic effect, the analgesic potency is superior to that of the classical antipyretic-analgesic and anti-inflammatory drugs which are aspirin and indomethacin, the therapeutic index of the koumine is much higher than that of the total alkaloids of gelsemium, the koumine possibly has no tolerance, no addiction and little side effect, which indicates that the koumine has potent and low-toxicity analgesic effect, the mechanism of action of the koumine is possibly different from those of clinically common opium analgesics or aspirin analgesics. The koumine and the pharmaceutically acceptable salt thereof have the application of preparing of the medicines for treating chronic pains, have no serious disadvantages of the clinically common analgesics, and can be developed into a novel analgesic which has potent analgesic effect on treating chronic pains such as inflammatory pain, neuropathic pain, cancer pain, and the like, has no tolerance and addiction and little side effect, thus the koumine has bright industrialization prospect.
Description
Technical field
The present invention relates to the application of Herba Gelsemii Elegantis alkaloid monomer, especially relate to the application of koumine (Koumine) in preparation treatment chronic pain medicine.
Background technology
Much more serious acute and chronic pain is perplexing the patient who counts in necessarily, wherein to see the most serious with chronic pain.Chronic pain mainly contains two types: inflammatory pain and neurogenic (nerve) pain.China has chronic pain medical history person to account for 20%～30%, and the U.S. accounts for 35%, and Canada accounts for 29%, and patient's average course of disease is about 10.7 years.Chronic pain is not only multiple, delay, and has a strong impact on patient's work and life.Medicine analgesia is one of the main means of patient's pain for the treatment of clinically at present, and wherein antipyretic-antalgic anti-inflammatory agents such as opium kind analgesics such as morphine and aspirin are the most commonly used.At present, surplus global antipyretic analgesic annual production has reached 20 ten thousand tons, wherein acetaminophen, aspirin, ibuprofen, naproxen, diclofenac are 5 big pillar products, and annual sales amount can reach more than 50 hundred million dollars.The analgesic morphine over nearly 20 years output increase by 10 times, existing global annual production is above 20000 kilograms.Therefore, the medicine of treatment pain is the focus of each big drugmaker competition of the current whole world.But opium kind analgesics easily produces toleration, addiction, and side effect such as respiration inhibition, minimizing gastrointestinal peristalsis; A little less than the antipyretic-antalgic anti-inflammatory agent analgesia was renderd a service, untoward reaction such as gastrointestinal reaction, gastric ulcer, gastrorrhagia were serious, and its clinical practice is limited.Therefore, effectively pain management and the new type analgesic thing that reduces toxic and side effects are one of current new drug development focuses in searching.At present, external many scientists just are being devoted to draw materials from animals and plants, the development of new analgesic.
Herba Gelsemii Elegantis (Gelsemium elegans Benth.) is the loganiaceae plant herb of climing rattan recklessly, is divided into two kinds of Chinese Herba Gelsemii Elegantis and North America Herba Gelsemii Elegantis.H Gerrad in 1887 etc. are made into Galenicals, by some national Martindale-The Extra Pharmacopoeias are recorded; The record of Herba Gelsemii Elegantis is all arranged in ADI and the Japan " medicine among the people in the world ".China is more long to the research history of Herba Gelsemii Elegantis, " legendary god of farming's book on Chinese herbal medicine ", Compendium of Material Medica are on the books, China's Herba Gelsemii Elegantis, abound with in Fujian, ground such as Zhejiang, Guangdong, has multiple physiological and pharmacological activity, as suppressing effects such as respiratory center, antitumor, antiinflammatory, relaxing smooth muscle, mydriasis, anticoagulant.
External Herba Gelsemii Elegantis among the people is treated all kinds of pain, especially chronic neuropathic pain and cancerous pain.Discover that the main effective ingredient of homemade Herba Gelsemii Elegantis is an indoles alkaloid, at present known have 40 surplus kind of monomer.The sixties in 20th century, 422 hospitals of naval and 416 hospitals are mixed with " ethoxybenzamide " injection institute innerlich anwenden with gelsemium alkaloids, and finding all has good efficacy to multiple pain.Clinical and basic research shows, gelsemium alkaloids has significant analgesic activity, usefulness is only second to morphine, and be higher than other biological alkali, and its no addiction, toleration, non-evident effect (Tan Jianquan, Qiu becomes it, Zheng Linzhong. the analgesic activity of kounidine and no dependence. Pharmacology and Clinics of Chinese Materia Medica, 1988,4 (1): 24-28); It is worth noting that its mechanism of action may be different from opiates or aspirin class analgesic, prompting Herba Gelsemii Elegantis alkaloid has the potential value that is developed as new type analgesic.
Research aspect the Herba Gelsemii Elegantis analgesic effect, existing academic documents and 1 piece of relevant patent application document (a kind of important gelsemium alkaloids of anticancer analgesic and contain its pharmaceutical composition and preparation method thereof, publication number: CN1528767A, open day: 2007.9.15), only relate to gelsemium alkaloids, do not relate to the research of Herba Gelsemii Elegantis alkaloid monomer.
Although gelsemium alkaloids does not have cumulative toxicity, its therapeutic dose is but more approaching with toxic dose, and therapeutic index is about 3～5, and the safe treatment window is narrower, has limited the application of gelsemium alkaloids as analgesic, and clinical practice is restricted.Present known Herba Gelsemii Elegantis alkaloid comprises multiple monomer, as koumine, first, oneself etc. and humantenmine, second, third, etc., kind surplus in the of totally 40.Various monomeric toxicity are not of uniform size, as mouse peritoneal injection koumine, first, oneself LD
50Be respectively 100mg/kg, 56.2mg/kg and 0.185mg/kg.Thereby in recent years under the temptation of the significant clinical efficacy of Herba Gelsemii Elegantis, active day by day again to its research and development, but R﹠D direction turns to the Herba Gelsemii Elegantis alkaloid monomer from gelsemium alkaloids.
Koumine (Koumine) is a kind of monomer in the Herba Gelsemii Elegantis alkaloid, is the highest monomer of content in the Chinese Herba Gelsemii Elegantis alkaloid, and molecular formula is C
20H
22N
2O, structural formula is:
The source of koumine is mainly extraction separation from the Herba Gelsemii Elegantis plant at present, as use column chromatography, or " high-speed countercurrent chromatography separates the method for preparing the Herba Gelsemii Elegantis alkaloid monomer from Herba Gelsemii Elegantis " (separate case is applied for a patent) of using inventor's invention, this invention provides efficient, quick-acting separation and purification koumines monomeric approach, for the commercial application of koumine lays the foundation.
In recent years comparatively deep to koumine research, find that it has multiple physiological and pharmacological activity, as antitumor action (Wu Darong, Qin Rui, Cai Jing, Chi Debiao. the research of koumine antitumor action, Pharmacology and Clinics of Chinese Materia Medica, 2006,22 (5): 6-8), regulate immunity function (Sun Lisha, Lei Linsheng, Fang Fangzhi, Yang Shuqin, Wang Jian. koumine is to the inhibitory action of mouse boosting cell breeder reaction and humoral immune reaction, Pharmacology and Clinics of Chinese Materia Medica, 1999,15 (6): 10-12), treatment psoriasis (Zhang Lanlan, Huang Changquan, Zhang Zhongyi, Deng. the observation of curative effect of koumine treatment psoriasiform animal model. No.1 Military Medical Univ.'s journal, 2005,25 (5): 547-549) and antiplatelet aggregative activity (Fang Fangzhi, Dan Chunwen, Chen Pingyan. koumine is to the accumulative influence of rabbit platelet, Pharmacology and Clinics of Chinese Materia Medica, 1998,14 (1): 21-24) etc.But existing koumine activity research does not relate to it in the ease pain Study on Effect, does not more relate to its research to the chronic pain analgesic activity.Anti-chronic pain effect of relevant koumine and possible purposes thereof are not seen document and patent report.The invention discloses anti-chronic pain effect of koumine and the application in preparation treatment chronic pain medicine thereof.
Summary of the invention
In order to overcome the deficiencies in the prior art, the purpose of this invention is to provide a kind of Herba Gelsemii Elegantis alkaloid monomer koumine chronic pain is had the new purposes of potent low toxicity analgesic activity, relate to the application in preparation treatment chronic pain medicine of koumine and pharmaceutically acceptable salt thereof.
The technical solution adopted for the present invention to solve the technical problems is: the application of koumine in preparation treatment chronic pain medicine.
Described koumine is one of Herba Gelsemii Elegantis alkaloid monomer, and molecular formula is C
20H
22N
2O, structural formula is:
The acceptable salt of koumine and pharmacy thereof has the application of preparation treatment chronic pain medicine.
Described chronic pain comprises inflammatory pain, neuropathic pain, cancerous pain.
Animal chronic pain analgesic experiment proof koumine has the potent analgesic activity of dose dependent, analgesia is tired and is better than classical antipyretic-antalgic anti-inflammatory agent aspirin and indomethacin, therapeutic index is higher than gelsemium alkaloids far away, it is little not have toleration, addiction and side effect, show that the koumine analgesic activity has the characteristics of potent low toxicity, its mechanism of action may be different from clinical opiates commonly used or aspirin class analgesic.
The invention has the beneficial effects as follows:
1. overcome the security flaw of gelsemium alkaloids at ease pain, increase substantially therapeutic index: koumine is estimated the therapeutic index of mice chronic pain and is reached 54, see embodiment 1 for details, significantly expand the safe treatment window, it is little not have toleration, addiction and side effect, and its mechanism of action may be different from clinical opiates commonly used or aspirin class analgesic.Than gelsemium alkaloids, be more suitable for preparing the medicine for the treatment of chronic pain.
2. potential great economy effect.Present global analgesic market is huge: morphine over nearly 20 years output increase by 10 times, existing global annual production is above 20000 kilograms; Surplus the annual production of the antipyretic analgesic whole world has reached 20 ten thousand tons, wherein acetaminophen, aspirin, ibuprofen, naproxen, diclofenac are 5 big pillar products, and annual sales amount can reach more than 50 hundred million dollars.As previously mentioned, this two class medicine commonly used each has its defective, is not desirable analgesic.Koumine, a kind of Herba Gelsemii Elegantis alkaloid monomer, the analgesic activity that has potent low toxicity than gelsemium alkaloids, the acceptable salt of koumine and pharmacy thereof has the application of preparation treatment chronic pain medicine, the shortcoming of not having the clinical analgesic commonly used of above-mentioned two classes, examining way according to national original new drug develops, being expected to become analgesia effect comprises by force inflammatory pain, chronic pain such as neurogenic and cancerous pain is effective, no toleration and addiction and side effect are little, have country's 1 class new type analgesic of the independent intellectual property of China, industrialization prospect is clear and definite.
3. koumine of the present invention can derive from the purification of natural plants Herba Gelsemii Elegantis, and the Herba Gelsemii Elegantis plant is abounded with in China, thereby can promote the development of relevant medical material industry.
Description of drawings
Below in conjunction with drawings and Examples the present invention is further detailed.
Fig. 1 gives the inhibitory action of koumine to the mice chronic pain for nape portion subcutaneous injection.
Abscissa express time min among the figure, vertical coordinate represent that the accumulation of per 5 minutes mices licks sufficient number of times; 1 is the normal saline group, 2 for morphine 10mg/kg group, 3 for aspisol 100mg/kg group, 4 is koumine 10mg/kg group, 5 is that koumine 5mg/kg organizes, 6 is that koumine 2.5mg/kg organizes, 7 are koumine 1.875mg/kg group, and 8 are koumine 1.25mg/kg group.
Fig. 2 is the subcutaneous inhibitory action of koumine to the mice chronic pain that give at the bottom of the formalin injection parapodum.
Abscissa express time min among the figure, vertical coordinate represent that the accumulation of per 5 minutes mices licks sufficient number of times; 1 is the normal saline group, and 2 are morphine 3.76mg/kg group, and 3 are indomethacin 7.16mg/kg group, and 4 are koumine 6.12mg/kg group, and 5 are koumine 3.06mg/kg group, and 6 are koumine 1.53mg/kg group.
Fig. 3 is the subcutaneous inhibitory action of koumine to the mice chronic pain that give in formalin injection offside vola.
Abscissa express time min among the figure, vertical coordinate represent that the accumulation of per 5 minutes mices licks sufficient number of times; 1 is the normal saline group, and 2 are koumine 6.12mg/kg group.
The specific embodiment
The present invention illustrates the purposes of koumine in preparation treatment chronic pain medicine by different modes of administration (nape portion subcutaneous injection gives, subcutaneously at the bottom of the formalin injection parapodum give, subcutaneous the giving in formalin injection offside vola) on the animal chronic pain model.
Embodiment 1
Nape portion subcutaneous injection gives koumine causes the mice chronic pain to formalin analgesic activity.
1.1 medicine and reagent:
Koumine is obtained from natural plants Herba Gelsemii Elegantis extraction separation purification by the present patent application people, (precision takes by weighing koumine to purity＞98.5%, with 1mol/l HCl dissolving, adds the normal saline dilution, transfer pH (4＜pH＜7) with 1mol/l NaOH, be diluted to the required solution of each dosage group with normal saline.)。Morphine hydrochloride injection (10mg/ml), Shenyang No. 1 Pharmaceutical Factory product, lot number 102090936065021.Aspirin-Al-lysine for injection freeze-dried powder (9g/ props up, and effective ingredient is an aspirin), Shanghai Xinya Pharmaceutical Industry Co. Ltd., lot number H31020058.Formalin, the upright chemical reagent work of the Tianjin North Star, lot number 20070828.
1.2 animal:
Kunming mouse, male, 18-22g, Medical University Of Fujian's Experimental Animal Center provides.Raise down in 25 ℃ of room temperature light dark period 12/12h, free diet adapts to laboratory and is used for formal experiment after 3 days.
1.3 method:
80 of mices, (1.25,1.875,2.5,5,10mg/kg), experiment is divided into 8 groups, 10 every group to be divided into normal saline group, morphine positive controls, aspisol positive controls, koumine various dose processed group at random by body weight.Each organizes mice by the corresponding intervention of following enforcement:
1) morphine positive controls mouse subcutaneous injection morphine 10mg/kg;
2) aspisol positive controls mouse subcutaneous injection 100mg/kg (in the aspirin composition);
3) koumine various dose processed group mice difference subcutaneous injection koumine 1.25,1.875,2.5,5,10mg/kg;
4) normal saline group mouse subcutaneous injection equal-volume normal saline.
Behind the 30min, the whole end subcutaneous injection 5% formalin solution 20 μ l in a mice left side, the active situation of mice in the 60min after the observed and recorded formalin injection.With 5min is a unit, and foot (formalin injection foot) time is licked in each unit accumulation of statistics mice, and preceding two unit (1-10min) are licked the foot time and added up to and be called 1 and lick the sufficient time mutually, reflection maincenter acute pain situation; Remaining element (10-60min) is licked the foot time and is added up to and to be called 2 and to lick the sufficient time mutually, the chronic pain situation that the reflection inflammation causes.Licking the foot time mutually with 2 is index, estimates koumine causes chronic pain to formalin influence.Calculate koumine pain suppression ratio as follows.Pain suppression ratio=(normal saline group second is licked sufficient time-administration group second mutually and licked the sufficient time mutually) ÷ normal saline group second is licked sufficient time * 100% mutually.Calculate the ED of medicine with probit method
50: suppression ratio surpassed 50% animal and be designated as effective analgesia animal, with effective analgesia number of animals, every treated animal example number and dosage, Bliss method calculating ED
50
1.4 result
Each is organized mice foot of licking in the 60min after formalin injection and reacts as shown in Figure 1, and 2 influences of licking foot time and pain suppression ratio are mutually seen Table 1.
Table 1 nape portion subcutaneous injection give koumine to formalin cause chronic pain analgesic activity (x ± SD, n=10)
*P＜0.05,
*Compare with the normal saline group P＜0.01
The result shows that each dosage group koumine energy dose dependent reduction formalin causes mice 2 and licks sufficient reaction mutually, has statistical significance; Analgesia is tired and is much better than bad empirin (effective ingredient is classical antipyretic-antalgic anti-inflammatory agent aspirin).Show that the chronic pain that koumine causes inflammation has remarkable analgesic activity.
2 phase pain suppression ratio are surpassed 50% animal and be designated as effective analgesia animal, calculate koumine analgesic median effective dose (ED through probit method
50) be 1.85mg/kg, 95% credibility interval is 1.35～2.54mg/kg.Through reading up the literature the half lethal dose (LD of koumine mouse peritoneal injection
50) be 100mg/kg, according to therapeutic index (TI) computing formula: TI=LD
50/ ED
50, the TI that tentatively calculates koumine is 54.1, the safety of visible monomer koumine is higher than gelsemium alkaloids far away, has the potential using value that is developed to drug for relieving chronic pain.
The subcutaneous analgesic activity of koumine that give at the bottom of the formalin injection parapodum to the mice chronic pain.
2.1 medicine and reagent:
Koumine is obtained from natural plants Herba Gelsemii Elegantis extraction separation purification by the present patent application people, (precision takes by weighing koumine to purity＞98.5%, with 1mol/l HCl dissolving, adds the normal saline dilution, transfer pH (4＜pH＜7) with 1mol/l NaOH, be diluted to the required solution of each dosage group with normal saline.)。Morphine hydrochloride injection (10mg/ml), Shenyang No. 1 Pharmaceutical Factory product, lot number 102090936065021.The indomethacin freeze-dried powder, SIGMA company, lot number 115K0689.Formalin, the upright chemical reagent work of the Tianjin North Star, lot number 20070828.
2.2 animal:
Kunming mouse, male, 18-22g, Medical University Of Fujian's Experimental Animal Center provides.Raise down in 25 ℃ of room temperature light dark period 12/12h, free diet adapts to laboratory and is used for formal experiment after 3 days.
2.3 method:
60 of mices, (1.53,3.06,6.12mg/kg), experiment is divided into 6 groups, 10 every group to be divided into normal saline group, morphine positive controls, indomethacin positive controls, koumine various dose processed group at random by body weight.Each organizes mice by the corresponding intervention of following enforcement (vola subcutaneous injection volume is 10 μ l):
1) morphine positive controls right side of mice vola subcutaneous injection morphine 3.76mg/kg;
2) indomethacin positive controls right side of mice vola subcutaneous injection 7.16mg/kg (in the indomethacin composition);
3) koumine various dose processed group mice difference vola, right side subcutaneous injection koumine 1.53,3.06,6.12mg/kg;
4) normal saline group right side of mice vola subcutaneous injection equal-volume normal saline.
Behind the 30min, right side of mice vola subcutaneous injection 5% formalin solution 10 μ l respectively organize the active situation of mice in the 60min after the observed and recorded formalin injection, and statistics 2 is licked the sufficient time mutually, and calculate the pain suppression ratio.Pain suppression ratio=(normal saline group second is licked sufficient time-administration group second mutually and licked the sufficient time mutually) ÷ normal saline group second is licked sufficient time * 100% mutually.
3.4 result
Each is organized mice foot of licking in the 60min after formalin injection and reacts as shown in Figure 2, and 2 influences of licking foot time and pain suppression ratio are mutually seen Table 2.
At the bottom of the table 2 formalin injection parapodum subcutaneous give the analgesic activity of koumine to the mice chronic pain (x ± SD, n=10)
*P＜0.05,
*Compare with the normal saline group P＜0.01
The result shows that subcutaneous each dosage group koumine that gives all can weaken formalin and causes mice 2 and lick sufficient reaction mutually at the bottom of the formalin injection parapodum, has statistical significance.Show that the chronic pain that koumine causes inflammation has remarkable analgesic activity.
Embodiment 3
The subcutaneous analgesic activity of koumine that give in formalin injection offside vola to the mice chronic pain.
3.1 medicine and reagent:
Koumine is obtained from natural plants Herba Gelsemii Elegantis extraction separation purification by the present patent application people, (precision takes by weighing koumine to purity＞98.5%, dissolve with 1mol/l HCl, add the normal saline dilution, transfer pH (4＜pH＜7) with 1mol/l NaOH, be diluted to the required solution of each dosage group with normal saline.) formalin, the upright chemical reagent work of the Tianjin North Star, lot number 20070828.
3.2 animal:
Kunming mouse, male, 18-22g, Medical University Of Fujian's Experimental Animal Center provides.Raise down in 25 ℃ of room temperature light dark period 12/12h, free diet adapts to laboratory and is used for formal experiment after 3 days.
3.3 method:
20 of mices are divided into normal saline group, koumine offside administration group (6.12mg/kg) at random by body weight, and experiment is divided into 2 groups, 10 every group.Each organizes mice by the corresponding intervention of following enforcement (vola subcutaneous injection volume is 10 μ l):
1) koumine processed group right side of mice vola subcutaneous injection koumine 6.12mg/kg;
2) normal saline group right side of mice vola subcutaneous injection equal-volume normal saline.
Behind the 30min, the whole end subcutaneous injection 5% formalin solution 10 μ l in a mice left side, the active situation of mice in the 60min after the observed and recorded formalin injection, statistics 2 is licked the foot time mutually and is calculated koumine pain suppression ratio.Pain suppression ratio=(normal saline group second is licked sufficient time-administration group second mutually and licked the sufficient time mutually) ÷ normal saline group second is licked sufficient time * 100% mutually.
3.4 result
Each is organized mice foot of licking in the 60min after formalin injection and reacts as shown in Figure 3, and 2 influences of licking foot time and pain suppression ratio are mutually seen Table 3.
Table 3 formalin injection offside vola is subcutaneous give the analgesic activity of koumine to the mice chronic pain (x ± SD, n=10)
*P＜0.05,
*Compare with the normal saline group P＜0.01
The result shows that subcutaneous each the dosage group koumine that gives in formalin injection offside vola can weaken formalin and causes mice 2 and lick sufficient reaction mutually, has statistical significance.Show that the chronic pain that koumine causes inflammation has remarkable analgesic activity.
Claims (4)
1. as a kind of structural formula of unique active component following Herba Gelsemii Elegantis alkaloid monomer koumine or the application of its pharmaceutically acceptable salt in preparation treatment chronic pain medicine
2. application according to claim 1 is characterized in that described chronic pain is an inflammatory pain.
3. application according to claim 1 is characterized in that described chronic pain is a neuropathic pain.
4. application according to claim 1 is characterized in that described chronic pain is a cancerous pain.
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| CN102293768B (en) * | 2011-06-25 | 2012-08-29 | 福建医科大学 | Use of koumine in preparation of drug for treating rheumatoid arthritis |
| CN102321094B (en) * | 2011-07-24 | 2013-10-02 | 福建医科大学 | New Gelsmium elegans Benth. alkaloid compound as well as preparation method and application thereof |
| CN103099776B (en) * | 2013-02-20 | 2014-11-05 | 福建医科大学 | Koumine sustained-release preparation and preparation method thereof |
| CN109953991B (en) * | 2017-12-14 | 2022-05-10 | 福建医科大学 | Use of gelsmin for treating diseases or disorders associated with amyloid deposition and/or tauopathy |
| CN112402420A (en) | 2019-08-23 | 2021-02-26 | 福建医科大学 | Application of koumine in preparation of medicines for treating inflammatory bowel diseases |
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