CN113181248B - Traditional Chinese medicine composition for preventing and treating peripheral neurotoxicity caused by antitumor drugs and preparation method and application thereof - Google Patents

Traditional Chinese medicine composition for preventing and treating peripheral neurotoxicity caused by antitumor drugs and preparation method and application thereof Download PDF

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CN113181248B
CN113181248B CN202110476845.8A CN202110476845A CN113181248B CN 113181248 B CN113181248 B CN 113181248B CN 202110476845 A CN202110476845 A CN 202110476845A CN 113181248 B CN113181248 B CN 113181248B
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林丽珠
孙玲玲
冯靖宇
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First Affiliated Hospital of Guangzhou University of Chinese Medicine
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Abstract

The invention relates to a traditional Chinese medicine composition for preventing and treating peripheral neurotoxicity caused by antitumor drugs, and a preparation method and application thereof. The traditional Chinese medicine composition disclosed by the invention is characterized in that common monkshood mother root, asarum, clematis stem, cassia twig and angelica dahurica are used together, the effects of activating blood circulation and removing blood stasis and warming yang and dredging collaterals are achieved, the five traditional Chinese medicine components are matched with each other and are mutually synergistic, an unexpected significant effect is achieved in the aspect of preventing and treating peripheral neurotoxicity caused by antitumor drugs, the survival quality of patients can be obviously improved, and the traditional Chinese medicine composition further has the advantages of low toxic and side effects, low treatment cost and the like.

Description

Traditional Chinese medicine composition for preventing and treating peripheral neurotoxicity caused by antitumor drugs and preparation method and application thereof
Technical Field
The invention belongs to the technical field of traditional Chinese medicines, and particularly relates to a traditional Chinese medicine composition, a preparation method and application thereof, in particular to a traditional Chinese medicine composition for preventing and treating peripheral neurotoxicity caused by antitumor drugs, and a preparation method and application thereof.
Background
Due to advances in cancer diagnosis and treatment, there are now about 2800 million cancer survivors worldwide. Thus, long-term quality of life is an increasingly important issue, and it is important to address long-term toxicity resulting from cancer treatment. Of particular importance are chemotherapy-induced peripheral neuropathy (CIPN), which can cause permanent symptoms and even inability to walk in up to 40% of cancer survivors. CIPN can appear after treatment of various cancers including breast cancer, intestinal cancer, lung cancer, testicular cancer and hematological malignancies, taxus, platinum compounds, vinca alkaloids, thalidomide, bortezomib and other therapeutic drugs, including the latest immunotherapy and the like, different drugs affect different component nervous systems, including dorsal root ganglia to distal axons, mainly manifested as peripheral nerve paresthesia or defect, symmetric numbness of upper and lower limbs, peripheral accompanied by pinprick-like and burning-like paresthesia, even sensory ataxia and dysfunction and the like, and severe patients can cause muscular atrophy, limb disuse, tendon reflex disappearance and serious influence on life quality. Among these, patients who have been associated with other neuropathies or are predisposed to peripheral neuropathies (e.g., diabetes) are often at higher risk.
Some medicines are clinically verified to be used for preventing and treating peripheral neurotoxicity, and western medicine mainly uses some antioxidants or cell membrane protective agents and the like for treating and preventing at present, such as growth factors, reduced glutathione, calcium, magnesium agents, amifostine, vitamin E, lithium salts and the like, but the curative effect is general, so that a plurality of chemotherapy patients have to bear pain and inconvenience caused by neurotoxicity. The external treatment method of traditional Chinese medicine has the characteristics of simplicity, convenience, cheapness, inspection and the like, has a long history in China, is agglutinated with the essence of traditional Chinese medicine, and is a treasure in traditional Chinese medicine. The traditional Chinese medicine soaking treatment utilizes the synergistic effect of heat and drug efficacy to generate treatment efficacy on organisms, and is a comprehensive body of drug treatment and physical treatment. Through external fumigation and washing, peripheral blood circulation is improved, and blocked channels are dredged, namely the effect of warming and reaching the channels can promote the striae and the qi and blood to be smooth, so that the effects of dredging the channels and collaterals, regulating qi and blood, dispelling wind and removing dampness, warming the channels and expelling cold, relaxing muscles and tendons, activating blood circulation, reducing swelling, relieving pain and the like are achieved. Especially for patients with advanced cancer, the traditional Chinese medicine has more advantages of weak healthy energy, intolerance to attack, poor curative effect by only taking internal medicine and external treatment method.
Disclosure of Invention
Aiming at the defects of the prior art, the invention aims to provide a traditional Chinese medicine composition and a preparation method and application thereof, in particular to a traditional Chinese medicine composition for preventing and treating peripheral neurotoxicity caused by antitumor drugs and a preparation method and application thereof.
In order to achieve the purpose, the invention adopts the following technical scheme:
in a first aspect, the invention provides a traditional Chinese medicine composition for preventing and treating peripheral neurotoxicity caused by antitumor drugs, and the traditional Chinese medicine composition is prepared from raw materials including radix aconiti, asarum, caulis clematidis armandii, cassia twig and radix angelicae.
The monarch drug of the traditional Chinese medicine composition has the effects of pungent and bitter in flavor, expelling wind and removing dampness by heat, warming channels and relieving pain, and is used for treating diseases such as anemofrigid-damp arthralgia and arthralgia.
The ministerial drug cassia twig, pungent in flavor and sweet in flavor, has the functions of warming and dredging channels and collaterals, dispelling cold and relieving pain, and can guide the drug to directly reach the focus. The meridians are usually normal, and the middle energizer is usually used for the syndrome of yang deficiency, cold stagnation, or blood deficiency, congealing cold, manifested as paralysis of hands and feet, blood arthralgia with wind arthralgia, etc., and the herbs are often used for the syndrome of blood circulation, meridians dredging, pungent-warm and cold-dispelling. Record of Changsha Yao Jie (Changsha Yao Jie): gui Zhi enters liver to move blood, runs through meridians to achieve Rong and Depression, excels in relieving wind pathogen, regulates wood qi to the greatest extent, ascends clear yang to collapse, descends turbid yin to reverse, relaxes spasm of muscles and tendons, promotes obstruction of joints, enters liver and gallbladder to disperse and restrain, relieves pain extremely, and clears meridians to remove stagnation and stagnation, and even removes damp-cold.
The asarum has pungent and warm properties, and has effects of invigorating heart, lung and kidney channels, relieving exterior syndrome, dispelling cold, dispelling pathogenic wind, relieving pain, and inducing resuscitation, and can be used for treating rheumatalgia; the angelica dahurica is warm in nature, pungent in flavor, fragrant in smell, slightly bitter, capable of dispelling wind-damp, promoting blood circulation, expelling pus, promoting granulation and relieving pain; chuan mu is bland, bitter and cold in nature, good at clearing heat and dredging meridians, and indicated for arthralgia of joints. The three medicines are all adjuvant medicines.
The medicines are combined to play the roles of promoting blood circulation, removing blood stasis, warming yang and dredging collaterals. The five traditional Chinese medicine components are specifically selected and matched, and are mutually synergistic, so that the traditional Chinese medicine composition has an unexpected obvious effect on the aspect of preventing and treating peripheral nerve toxicity caused by antitumor drugs, can obviously improve the life quality of patients, and has the advantages of low toxic and side effects, low treatment cost and the like.
Wherein the radix Aconiti is dried mother root of Aconitum carmichaeli Debx of Aconitum of Ranunculaceae. Has effects of dispelling pathogenic wind, removing dampness, warming channels, dispelling cold and relieving pain. Can be used for treating arthralgia due to wind-cold-dampness, arthralgia, numbness of limbs, hemiplegia, headache due to wind-cold evil, psychroalgia of heart and abdomen, cold hernia pain, traumatic injury, blood stasis, and carbuncle of yin nature. And can be used for anesthesia and relieving pain.
Wherein the herba asari is root and rhizome of Asarum heterotropoides Fr.Schmidt var.mandshurium (Maxim.) Kitag., Asarum sieboldii Miq.var.seoulense Nakai or Asarum sieboldii Miq.. The first two are called "Liaoxi". Has effects of relieving exterior syndrome, dispelling cold, dispelling pathogenic wind, relieving pain, dredging orifice, warming lung, and eliminating fluid retention. It can be used for treating wind-cold type common cold, headache, toothache, rheumatalgia, nasosinusitis, and cough due to lung cold.
Wherein caulis Clematidis Armandii is caulis Clematidis Armandii Franch or caulis Sparganii Clematis montana Buch-ham. Has effects of clearing heat, promoting urination, dredging channels and promoting lactation. It can be used for treating retention of urine due to damp-heat, edema, stranguria, aphtha of the mouth and tongue due to up-flaming of heart-fire, damp-heat arthralgia, joint disorder, amenorrhea of women, and galactostasis.
Wherein the ramulus Cinnamomi is twig of Cinnamomum cassia Presl of Piper of Lauraceae. Has the effects of inducing sweat, expelling pathogenic factors from muscles, warming and activating meridians, supporting yang, and regulating qi. It can be used for treating common cold due to wind-cold, pain due to cold accumulation and blood stagnation, phlegm retention, water retention syndrome, and palpitation.
Wherein the radix Angelicae Dahuricae is root of Angelica dahurica (Fisch ex Hoffm) Benth.et Hook.f. and Angelica dahurica (Fisch ex Hoffm.) Benth.et Hook.f. of Angelica dahurica of Angelica of Umbelliferae. Has the effects of relieving exterior syndrome, dispelling cold, dispelling pathogenic wind, relieving pain, dredging nasal orifice, eliminating dampness, relieving leukorrhagia, relieving swelling, expelling pus, dispelling pathogenic wind and relieving itching. It can be used for treating wind-cold type common cold, headache, toothache, arthralgia, nasosinusitis, leukorrhagia, skin sore, carbuncle, skin pruritus, etc.
All the traditional Chinese medicines related to the invention can be purchased from a common traditional Chinese medicine store, and the specification of the traditional Chinese medicines accords with the standard of Chinese pharmacopoeia.
Preferably, the preparation raw materials of the traditional Chinese medicine composition comprise, by weight, 3-36 parts of radix aconiti, 3-30 parts of asarum, 3-30 parts of caulis clematidis armandii, 3-30 parts of cassia twig and 3-30 parts of radix angelicae.
When the components in the traditional Chinese medicine composition are combined according to the specific mass ratio, the traditional Chinese medicine composition has more remarkable effect on preventing and treating peripheral nerve toxicity caused by the antitumor drugs.
The weight parts of the radix aconiti can be 3 parts, 5 parts, 10 parts, 11 parts, 11.5 parts, 12 parts, 12.5 parts, 13 parts, 15 parts, 17 parts, 20 parts, 22 parts, 25 parts, 30 parts or 36 parts and the like.
The asarum herb may be 3, 5, 9, 9.5, 10, 10.5, 11, 12, 15, 17, 20, 22, 25 or 30 parts by weight.
The parts by weight of the caulis clematidis armandii can be 3 parts, 5 parts, 9 parts, 9.5 parts, 10 parts, 10.5 parts, 11 parts, 12 parts, 15 parts, 17 parts, 20 parts, 22 parts, 25 parts or 30 parts and the like.
The cassia twig can be 3 parts, 5 parts, 9 parts, 9.5 parts, 10 parts, 10.5 parts, 11 parts, 12 parts, 15 parts, 17 parts, 20 parts, 22 parts, 25 parts or 30 parts by weight and the like.
The angelica dahurica can be 3 parts, 5 parts, 9 parts, 9.5 parts, 10 parts, 10.5 parts, 11 parts, 12 parts, 15 parts, 17 parts, 20 parts, 22 parts, 25 parts or 30 parts by weight and the like.
Other specific point values within the above numerical ranges can be selected, and are not described in detail herein.
Further preferably, the preparation raw materials of the traditional Chinese medicine composition comprise, by weight, 11-13 parts of radix aconiti, 9-11 parts of asarum, 9-11 parts of caulis clematidis armandii, 9-11 parts of cassia twig and 9-11 parts of radix angelicae.
Preferably, the anti-tumor drug comprises oxaliplatin or paclitaxel.
After receiving treatment of antineoplastic drugs such as oxaliplatin or paclitaxel, patients can suffer from peripheral nerve sensory paralysis or defects, symmetric numbness of upper and lower limbs, abnormal sensations accompanied by acupuncture and burning at the periphery, arthralgia, even sensory ataxia, dysfunction and the like, and severe patients can suffer from muscular atrophy, do not use limbs, disappear tendon reflex and seriously affect the quality of life. When the traditional Chinese medicine composition is used for intervention, symptoms can be delayed to appear or even not appear, and patients with the symptoms can be relieved.
In a second aspect, the present invention provides a preparation method of the traditional Chinese medicine composition for preventing and treating peripheral neurotoxicity caused by an antitumor drug according to the first aspect, wherein the preparation method comprises: mixing radix Aconiti and water, boiling with strong fire, decocting with slow fire, adding herba asari, caulis Clematidis Armandii, ramulus Cinnamomi and radix Angelicae Dahuricae, decocting, and concentrating to obtain the Chinese medicinal composition.
Preferably, the mass of the water is 5-15 times of the total mass of the raw materials, for example, 5 times, 6 times, 7 times, 9 times, 10 times, 11 times, 12 times, 13 times or 15 times, and other specific points in the numerical range can be selected, and are not described in detail herein.
Preferably, the time for decocting with slow fire is 1-2h, for example, 1h, 1.2h, 1.4h, 1.5h, 1.7h, 1.8h, 1.9h or 2h, and other specific values in the numerical range can be selected, and are not described herein again.
Preferably, the time for continuing decocting is 30-60min, such as 30min, 35min, 40min, 45min, 50min, 55min or 60min, and other specific values in the numerical range can be selected, and are not repeated herein.
As a preferred technical scheme of the invention, the preparation method of the traditional Chinese medicine composition for preventing and treating peripheral neurotoxicity caused by the antitumor drugs comprises the following steps: mixing radix Aconiti and 5-15 times of water, boiling with strong fire, decocting with slow fire for 1-2 hr, adding herba asari, caulis Clematidis Armandii, ramulus Cinnamomi and radix Angelicae Dahuricae, decocting for 30-60min, and concentrating to obtain the Chinese medicinal composition.
In a third aspect, the present invention provides a method for using the traditional Chinese medicine composition for preventing and treating peripheral neurotoxicity caused by the antitumor drugs according to the first aspect, wherein the method for using comprises: fumigating, washing, soaking or wet-applying the Chinese medicinal composition on affected parts including joints of limbs and/or extremities.
In a fourth aspect, the present invention provides an application of the traditional Chinese medicine composition for preventing and treating peripheral neurotoxicity caused by an antitumor drug in preparation of a drug for preventing and treating peripheral neurotoxicity caused by an antitumor drug.
In a fifth aspect, the present invention provides an application of the traditional Chinese medicine composition for preventing and treating peripheral neurotoxicity caused by an antitumor drug in preparation of a drug for treating peripheral neurotoxicity caused by an antitumor drug.
Compared with the prior art, the invention has the following beneficial effects:
the traditional Chinese medicine composition disclosed by the invention is characterized in that common monkshood mother root, asarum, clematis stem, cassia twig and angelica dahurica are used together, the effects of activating blood circulation and removing blood stasis and warming yang and dredging collaterals are achieved, the five traditional Chinese medicine components are matched with each other and are mutually synergistic, an unexpected significant effect is achieved in the aspect of preventing and treating peripheral neurotoxicity caused by antitumor drugs, the survival quality of patients can be obviously improved, and the traditional Chinese medicine composition further has the advantages of low toxic and side effects, low treatment cost and the like.
Drawings
FIG. 1 is a statistical plot of the mechanical stimulus depopulation reflex thresholds for various groups;
FIG. 2 is a statistical plot of the number of cold stimulus induced withdrawal reflexes for each group;
FIG. 3 is an under-mirror contrast plot of rat L4-6 dorsal root ganglion tissues and cells from each group (where a. control-10.0 x represents under 10 times the mirror of the control group; b. model-10.0 x represents under 10 times the mirror of the model group; c. model-20.0 x represents under 20 times the mirror of the model group; d. HXTB-10.0 x represents under 10 times the mirror of the treatment group);
FIG. 4 is a WB map of the expression levels of rat L4-6 dorsal root ganglion Bcl-2, Bax proteins for each group;
FIG. 5 is a statistical graph of the expression levels of the Bcl-2, Bax proteins of dorsal root ganglia of rats of groups L4-6.
Detailed Description
The technical solution of the present invention is further described below by way of specific embodiments. It should be understood by those skilled in the art that the examples are only for the understanding of the present invention and should not be construed as the specific limitations of the present invention.
The test animals referred to in the examples below were SPF grade SD male rats aged about 7-8 weeks and weighing about 200. + -.20 g, purchased from the centre of the test animals in Guangdong province.
Preparation example 1
The embodiment provides a traditional Chinese medicine composition for preventing and treating peripheral neurotoxicity caused by antitumor drugs, and the preparation method comprises the following steps:
mixing 12g of radix aconiti and 520g of water, boiling with strong fire, decocting with slow fire for 1.5h, adding 10g of asarum, 10g of caulis clematidis armandii, 10g of cassia twig and 10g of radix angelicae, continuing to decoct for 50min, and concentrating the water decoction to 200mL to obtain the traditional Chinese medicine composition.
Preparation example 2
The embodiment provides a traditional Chinese medicine composition for preventing and treating peripheral neurotoxicity caused by antitumor drugs, and the preparation method comprises the following steps:
mixing 11g of radix aconiti and 520g of water, boiling with strong fire, decocting with slow fire for 1h, adding 9g of asarum, 11g of caulis clematidis armandii, 9g of cassia twig and 11g of radix angelicae, continuing to decoct for 60min, and concentrating the water decoction to 200mL to obtain the traditional Chinese medicine composition.
Preparation example 3
The embodiment provides a traditional Chinese medicine composition for preventing and treating peripheral neurotoxicity caused by antitumor drugs, and a preparation method thereof, wherein the traditional Chinese medicine composition comprises the following steps:
mixing 13g of radix aconiti and 520g of water, boiling with strong fire, decocting with slow fire for 2h, adding 11g of asarum, 9g of caulis clematidis armandii, 11g of cassia twig and 9g of radix angelicae, continuing to decoct for 40min, and concentrating the water decoction to 200mL to obtain the traditional Chinese medicine composition.
Example 1
The traditional Chinese medicine composition prepared in preparation example 1 is used for preventing neurotoxicity caused by oxaliplatin, and specifically comprises the following components:
1. the treatment scheme comprises the following steps:
(1) the characteristics of the treated population are as follows: 100 patients with advanced malignant tumors who received oxaliplatin chemotherapy for the first time were planned. Age 35-72 years, with 69 men and 31 women. 15 cases of liver cancer, 56 cases of intestinal cancer, 8 cases of pancreatic cancer and 21 cases of gastric cancer. The groups were randomly divided into 2 groups of 50 cases.
(2) The using method comprises the following steps: treatment groups: oxaliplatin per treatment course (85 mg/m) 2 Adding into 500mL 5% glucose solution, dripping, 1 time every 2 weeks), intervening for 7 days, 1 time every day, diluting water decoction into 500mL each time for the most common part (extremity joint and extremity end) with neurotoxicity of oxaliplatin, soaking with clean towel, and wet-compressing with warm towel at 40 deg.C for 2 h. Control group: after oxaliplatin treatment in each treatment course, the intervention is carried out for 7 days, and the towel is soaked in 500mL warm water and then is subjected to wet compress for 2 hours at 40 ℃.
2. Evaluation indexes are as follows:
evaluation of neurotoxicity peripheral neurotoxicity was assessed by reference to the universal toxicity criteria of the national cancer institute (NCI-CTC version 3.0) and evaluated after the end of the 6 th course of treatment. The difference in incidence of peripheral neurotoxicity between the two groups was analyzed.
3. The research results are as follows:
the statistical results are shown in table 1, and it can be seen from the data in table 1 that: the incidence of peripheral neurotoxicity in the treated group was 20%, the incidence of peripheral neurotoxicity in the control group was 62%, and the peripheral neurotoxicity after treatment could be reduced by 42% (there was a clear difference between the two groups, p < 0.05). The peripheral neurotoxicity of the treatment group is mainly mild, while the peripheral neurotoxicity of the control group is mainly moderate, so that the traditional Chinese medicine composition can effectively prevent the peripheral neurotoxicity caused by the antitumor drugs.
TABLE 1
Figure BDA0003047698650000091
Example 2
The traditional Chinese medicine composition prepared in preparation example 1 is used for treating neurotoxicity caused by oxaliplatin, and the specific formula is as follows:
1. the treatment scheme comprises the following steps:
(1) the characteristics of the treated population are as follows: 50 patients who underwent oxaliplatin 6-course chemotherapy and developed peripheral neurotoxicity. The mean age was 58.60 ± 14.00 years, 32 years for the youngest and 75 years for the largest, with 31 men and 19 women.
(2) The using method comprises the following steps: continuously intervening for 30 days, 1 time per day, diluting the water decoction into 500mL for each affected part (extremity joint or extremity end), soaking in clean towel, and wet-compressing with 40 deg.C hot towel for 2 h.
2. Evaluation indexes are as follows:
the peripheral neurotoxicity grading is judged by adopting a self-treatment pre-treatment and post-treatment contrast method and the neurotoxicity evaluation by referring to the universal toxicity standard of the national cancer institute (NCI-CTC version 3.0). The judgment standard of the curative effect of peripheral neurotoxicity symptoms is as follows: and (3) curing: reducing to 0 grade; the effect is shown: the reduction after treatment is 2 grades compared with the reduction before treatment; the method has the following advantages: the reduction after treatment is 1 grade than before treatment; and (4) invalidation: there was no improvement in symptoms and signs or there was a slight improvement in symptoms but no improvement in original signs. Total effective rate is (number of cure cases + number of significant cases + number of effective cases)/total number of cases × 100%.
3. The research results are as follows:
the statistical results are shown in table 2, and it can be seen from the data in table 2 that: among 50 patients, 33 patients are cured, 2 patients are obviously effective, 14 patients are effective, 1 patient is ineffective, and the cure rate is as follows: 66 percent and the total effective rate of 98 percent, which shows that the traditional Chinese medicine composition can effectively treat peripheral nerve toxicity caused by antitumor drugs.
TABLE 2
Figure BDA0003047698650000101
Example 3
The Chinese medicinal composition prepared in preparation example 2 is used for preventing neurotoxicity caused by albumin-bound paclitaxel, and specifically comprises the following components:
1. treatment regimens
(1) The characteristics of the treated population are as follows: 120 patients with advanced malignancies who received primary chemotherapy with albumin-bound paclitaxel were treated. Age 42-70 years, with 69 males and 51 females. 12 cases of breast cancer, 10 cases of ovarian cancer, 13 cases of pancreatic cancer, 11 cases of esophageal cancer, 16 cases of gastric cancer and 58 cases of lung cancer; the groups were randomly divided into 2 groups of 60 cases.
(2) The using method comprises the following steps: treatment groups: albumin-bound paclitaxel (260 mg/m) per treatment course 2 Adding into 100mL of 0.9% sodium chloride injection, dripping, and administering for 1 time every 3 weeks) for 7 days, 1 time per day, diluting the water decoction into 500mL for each affected part (extremity joint or extremity end), soaking in clean towel, and wet-compressing with 40 deg.C hot towel for 2 h. Control group: the intervention is carried out for 7 days after each course of treatment of paclitaxel, and the towel is soaked in 500mL warm water and then is subjected to wet compress for 2 hours at 40 ℃.
2. Evaluation indexes are as follows:
evaluation of neurotoxicity peripheral neurotoxicity was assessed by reference to the universal toxicity criteria of the national cancer institute (NCI-CTC version 3.0) and evaluated at the end of the 4 th course of treatment. The difference in incidence of peripheral neurotoxicity between the two groups was analyzed.
3. The research results are as follows:
the statistical results are shown in Table 3, the incidence of peripheral neurotoxicity in the treated group was 30.00%, the incidence of peripheral neurotoxicity in the control group was 53.33%, and the peripheral neurotoxicity after treatment was reduced by 23.33% (there was a clear difference between the two groups, p < 0.05). The peripheral neurotoxicity of the treatment group is mainly mild, while the peripheral neurotoxicity of the control group is mainly moderate, which shows that the traditional Chinese medicine composition can effectively prevent the peripheral neurotoxicity caused by the antitumor drugs.
TABLE 3
Figure BDA0003047698650000111
Example 4
The traditional Chinese medicine composition prepared in preparation example 3 is used for animal experiments to verify the treatment effect on the peripheral neurotoxicity caused by oxaliplatin, and specifically comprises the following steps:
1. study protocol
(1) A standard oxaliplatin peripheral neurotoxicity model is established by adopting an oxaliplatin intraperitoneal injection administration mode, and the establishment method of the model specifically comprises the following steps:
21 SPF SD male rats with the weight of 200 +/-20 g are divided into 3 groups by a random number table method, wherein each group comprises 7 rats: control group (group C), model group (group M) and blood circulation dredging arthralgia formula medicated bath group (group H). Group C and group H rats were intraperitoneally injected with 2mL of 5% glucose solution, group M and group H rats were intraperitoneally injected with 2mL of prepared oxaliplatin solution (0.2mg/mL), 2 times per week for 4 weeks (respectively injected on days 1, 2, 8, 9, 15, 16, 22 and 23), and a rat model of oxaliplatin peripheral neuropathy was established, and a mechanical stimulation paw withdrawal reflex threshold test and a cold stimulation induced persistent pain test were performed before and during molding every week. After the molding was successful, the group H was administered with the Chinese medicinal composition of preparation example 3, and the rats in group H were placed in a plastic box covered with a cover, and the rats were soaked in 2L of the liquid medicine with a concentration of 30g/L with the water temperature controlled between 38-42 deg.C, 1 time per day for 30min each time. The medicated bath is used for 1 day with 1 course of 7 days and 3 courses of continuous treatment. The C group and the M group are soaked in the same volume of fresh water every day, and the conditions are equal to those in the H group. During the administration period, all groups were monitored for general condition and toxicity responses, and weekly mechanical stimulation paw withdrawal reflex threshold test, cold stimulation induced persistent pain test. After 3 weeks, the rats were anesthetized with 2% pentobarbital sodium, and the abdominal aorta was then bled and the dorsal root ganglion of segment L4-6 was removed for subsequent experiments.
2. Evaluation index and results:
(1) effect on mechanical stimulation paw withdrawal reflex threshold
The evaluation method comprises the following steps: using the Von Frey pain tester, the probe stimulates the rat sole, and the stimulation intensity is recorded in g. Before modeling (day 0), before administration, and in the period of administration, 7, 14, 21 days of detection, the rat is placed in a transparent acrylic cage with a metal grid on the chassis, before the detection, the rat is allowed to adapt to the environment for 5 minutes, the detection is started after the activities of exploration, combing and the like of the rat basically disappear, each bilateral hind paw is alternately and repeatedly measured for 5 times, the interval of each time is more than 6 seconds, the reflection times of the hind paw such as paw withdrawal, twitch and paw licking which immediately appear when the paw is stimulated and when the probe is just removed are recorded, the normal activity of the rat raises the paw without counting the paw withdrawal range, and the positive reaction probability (the times of positive reaction/10 multiplied by 100%) is calculated.
The results are shown in figure 1 (each bar represents the average of 10 MWT measurements for each group of 7 rats): wherein Control represents a Control group; model represents a Model set; HXTB represents the treatment group. Compared with the control group, the model group and the medicated bath group have the phenomena of tactile sensation and hyperalgesia gradually during the molding period (0-28 days), the threshold difference with the control group is gradually increased along with the accumulation of the application time of the oxaliplatin, and the mechanical stimulation foot contraction reflex threshold (MWT) is obviously reduced (P is less than 0.05). However, the mechanical stimulation transpodal reflex threshold (MWT) of the medicated bath group began to gradually increase from 1 week (day 35) after the administration, and at the end of the final experiment, the mechanical stimulation transpodal reflex threshold (MWT) was substantially identical to that of the control group (P > 0.05). The model group recovered slowly after the oxaliplatin was discontinued, and by the end of the experiment, the mechanical stimulation foot contraction reflex threshold (MWT) was significantly different (P < 0.05) from the other two groups. The traditional Chinese medicine composition has good effect of recovering peripheral neurotoxicity.
(2) Effect on Cold stimulation induced foot contraction reflex times
The evaluation method comprises the following steps: reference is made to the method of Jasmin et al (Jasmin L, Kohan L, Franssen M, et al. the cold plate as a test of negative organisms: description and application to the study of respiratory and inflammatory Pain molds. [ J ]. Pain,1998,75(2-3):367.), detected 0 days before molding, and 7, 14, 21 days during dosing. The rat is placed on a cold plate with the surface temperature of (4 +/-1) DEG C, a transparent acrylic cage is covered on the periphery of the cold plate, the rat is allowed to adapt to the environment for 5 minutes before testing, the cumulative foot contraction, twitching and licking times of the rat within 5 minutes are manually recorded after activities such as exploration, combing and the like basically disappear, and the foot lifting caused by normal activities of the rat is not counted in the foot contraction range.
The results are shown in figure 2 (each bar represents the number of cold stimulus withdrawal reflex for 7 rats per group): wherein Control represents a Control group; model represents a Model set; HXTB represents the treatment group. Compared with the control group, the cold stimulation podiatric reflex times of the model group and the medicated bath group are gradually increased during the molding period (0-28 days), the difference between the model group and the medicated bath group is gradually increased along with the accumulation of the medication time of the oxaliplatin, and the oxaliplatin molding at the end of the 28 th day is obviously different from the control group (P is less than 0.05). However, after the administration, the cold stimulation and foot contraction reflex times of the medicated bath group start to gradually decrease, and at the end of the experiment, the medicated bath group is basically consistent with the control group (P is more than 0.05). The model group is still difficult to recover after the oxaliplatin is stopped, the number of times of foot contraction is not obviously reduced until the experiment is finished, and the result is obviously different from the other two groups (P < 0.05).
(3) Effect on rat L4-6 dorsal root ganglion tissues and cells
The evaluation method comprises the following steps: after the experiments (1) and (2) are finished, taking the L4-6 dorsal root ganglia, fixing, dehydrating, embedding in paraffin, and then continuously cutting 5 mu m thick sections along the longitudinal axis. After conventional HE staining, morphological changes of the tissue were observed under a microscope. Typical pathological changes in the section, such as inflammation, necrosis, degeneration, hyperplasia and fibrosis, are described.
The results are shown in FIG. 3: wherein a.control _10.0x represents under 10 times of the control group; model — 10.0x represents the model set under 10 times of the mirror; model — 20.0x represents model set at 20 times mirror; hxtb — 10.0x represents treatment group under 10-fold scope. The control group and medicated bath group have abundant and regular neuron number, clear nucleus and cytoplasm boundary, obvious nucleolus, and no obvious inflammation. And the model group has swelling of more neuron cell bodies, under a 20-fold microscope, the increase of the clearance around the cells is visible (arrow (I)), the disappearance of nucleus of more neuron cell bodies and the cytoplasmic lysis (arrow (II)), and the reduction of satellite cells around the neuron cell bodies (arrow (III)) and the demyelination of more nerve fibers (arrow (IV)).
(4) Effect on rat L4-6 dorsal root ganglion Pi3k, Akt1, Bcl-2, Bax protein expression level
The evaluation method comprises the following steps: taking 2L 4-6 segments of dorsal root ganglion tissues from each rat, mixing the tissues in the same group, adding RIPA lysate, crushing the tissues by using a high-speed mechanical homogenizer at the speed of 12,000rpm, centrifuging for 10 minutes, taking the supernatant, and detecting the protein concentration by using a BCA protein kit; mu.L of the protein solution was added to 50. mu.L of 5 Xloading Buffer, denatured at 95 ℃ for 10min, and electrophoresed on SDS-PAGE gel of appropriate concentration. After electrophoresis, cutting gel and transferring the membrane, sealing with 5% skimmed milk for 1h, then respectively putting the PVDF membrane into small self-sealing bags filled with 3mL of anti-PDX 1(1:1000Bax, 1:1000Bcl-2, 1:1000Pi3k, 1:1000Akt1, 1:10000GAPDH) antibody diluent, incubating overnight at 4 ℃, incubating for 1h at room temperature with secondary antibody, washing the membrane for 3 times with TBST, then carrying out ECL reaction, and developing in an automatic developing instrument. The grey values were scanned with a professional image analysis system and analyzed using ImageJ.
The results are shown in FIGS. 4 and 5: wherein Control or C represents a Control group; model or M represents a Model set; HXTB or H represents the treatment group. The Pi3k, Akt1, Bcl-2 and Bax protein expression levels of the medicated bath group are obviously up-regulated (P is less than 0.05), the Bcl-2/Bax ratio is also obviously up-regulated (P is less than 0.05), and the up-regulation degree of the protein expression levels of the medicated bath group has statistical significance compared with the normal group and the model group (P is less than 0.05). The traditional Chinese medicine composition can improve peripheral neuropathy caused by oxaliplatin by inhibiting apoptosis of L4-6 dorsal root neuron cells.
The applicant declares that the present invention illustrates a traditional Chinese medicine composition for preventing and treating peripheral neurotoxicity caused by an anti-tumor drug, a preparation method and applications thereof through the above embodiments, but the present invention is not limited to the above embodiments, that is, the present invention is not meant to be implemented only by relying on the above embodiments. It should be understood by those skilled in the art that any modification of the present invention, equivalent substitutions of the raw materials of the product of the present invention, addition of auxiliary components, selection of specific modes, etc., are within the scope and disclosure of the present invention.
The preferred embodiments of the present invention have been described in detail, however, the present invention is not limited to the specific details of the above embodiments, and various simple modifications may be made to the technical solution of the present invention within the technical idea of the present invention, and these simple modifications are within the protective scope of the present invention.
It should be noted that, in the above embodiments, the various features described in the above embodiments may be combined in any suitable manner, and in order to avoid unnecessary repetition, the present invention does not separately describe various possible combinations.

Claims (7)

1. An external traditional Chinese medicine composition for preventing and treating peripheral neurotoxicity caused by antitumor drugs is characterized in that the traditional Chinese medicine composition is prepared from 11-13 parts by weight of radix aconiti, 9-11 parts by weight of asarum, 9-11 parts by weight of caulis clematidis armandii, 9-11 parts by weight of cassia twig and 9-11 parts by weight of radix angelicae dahuricae; the anti-tumor drug is oxaliplatin or paclitaxel.
2. The preparation method of the external traditional Chinese medicine composition for preventing and treating peripheral neurotoxicity caused by the antitumor drug as claimed in claim 1, wherein the preparation method comprises the following steps: mixing radix Aconiti and water, boiling with strong fire, decocting with slow fire, adding herba asari, caulis Clematidis Armandii, ramulus Cinnamomi and radix Angelicae Dahuricae, decocting, and concentrating to obtain the Chinese medicinal composition.
3. The method for preparing a topical Chinese medicinal composition for preventing and treating peripheral neurotoxicity caused by antineoplastic drugs as claimed in claim 2, wherein the time of decocting with slow fire is 1-2 h.
4. The method for preparing a topical Chinese medicinal composition for preventing and treating peripheral neurotoxicity caused by antineoplastic agents as claimed in claim 2, wherein the time for decocting is 30-60 min.
5. The preparation method of the external traditional Chinese medicine composition for preventing and treating peripheral neurotoxicity caused by the antitumor drug as claimed in claim 2, wherein the preparation method comprises the following steps: mixing radix Aconiti and 5-15 times of water, boiling with strong fire, decocting with slow fire for 1-2 hr, adding herba asari, caulis Clematidis Armandii, ramulus Cinnamomi and radix Angelicae Dahuricae, decocting for 30-60min, and concentrating to obtain the Chinese medicinal composition.
6. The use of the topical Chinese medicinal composition for preventing and treating peripheral neurotoxicity caused by antineoplastic agent as defined in claim 1 in the preparation of medicament for preventing peripheral neurotoxicity caused by antineoplastic agent.
7. The use of the topical Chinese medicinal composition for preventing and treating peripheral neurotoxicity caused by antineoplastic agent as defined in claim 1 in the preparation of medicament for treating peripheral neurotoxicity caused by antineoplastic agent.
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