CN104784627A - Traditional Chinese medicine externally used film agent used for treatment surgical open or closed injury and preparation method thereof - Google Patents

Traditional Chinese medicine externally used film agent used for treatment surgical open or closed injury and preparation method thereof Download PDF

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CN104784627A
CN104784627A CN201510065218.XA CN201510065218A CN104784627A CN 104784627 A CN104784627 A CN 104784627A CN 201510065218 A CN201510065218 A CN 201510065218A CN 104784627 A CN104784627 A CN 104784627A
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chinese medicine
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pain
external membrane
medicine external
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CN104784627B (en
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肖琼
马德林
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Abstract

The invention relates to a traditional Chinese medicine externally used film agent used for treatment surgical open or closed injury and a preparation method thereof, the effective ingredients are extracted from the following raw material medicines by weight shown in the specification, the traditional Chinese medicine externally used film agent has analgesic, anti-inflammatory and detumescence effects, can promote wound healing, can be used for treatment surgical open or closed injury, and can also be used to treat burns, arthritis, muscle strain, boils, such as inflammation, sore, furuncle carbuncle and other inflammation.

Description

A kind ofly be used for the treatment of Chinese medicine external membrane of the open or closed injury of surgery and preparation method thereof
Technical field
The present invention relates to a kind of Chinese medicine external membrane being used for the treatment of surgery open wound or closed injury and preparation method thereof.
Background technology
Occur in teleneuron and the pathologic abnormality of conducting system of exciting nerve, be reacted to brain and the sensation that causes, be called pain.Pain comprises two aspects: one is that the pain that noxious stimulation acts on caused by human body is felt; Two is pain reactions, namely human body to a series of reaction of noxious stimulation as dysphoria, perspiration, cardiopalmus, anxiety and fear etc.
The classification of pain clinically: twinge, also known as the first pain, fast pain, nervus centripetalis is A δ fine fibre, and be characterized in that pain is clear, sharp-pointed, location is clear and definite, occur rapidly or disappear, emotion changes is little; Causalgia, also known as the second pain, slow pain, nervus centripetalis is C class crude fibre, and be characterized in that pain is felt and formed slowly, the persistent period is long, locates poor, has certain emotional response; Ache, distending pain, the nervus centripetalis belonging to internal organs or deep tissue is that vegetative nerve fiber and C class crude fibre import into more, is characterized in that pain not easily describes, locates very poor, can cause obvious emotion changes and internal organs Tenseness.
The reason that pain occurs is a lot, pain stimulation source sends stimulation, as physical stimulation (fall, beat, turn round, lancinate, press and pound) etc. and chemical stimulation (acid, alkali, scald, burn or other chemical stimulation) import spinal cord posterior cord on brain stem to brain postcentral gyrus through peripheral sensory nerve.Produce at stimulus and to cause when pain stimulation is transmitted to spinal cord that the nervus motorius on this horizontal position and orthosympathetic excitement cause muscular tone enhancings, vasoconstriction, sore place regional flow reduce, confession hypoxgia, ischemia, anoxia produce algogenic substance.These algogenic substances are on the one hand to central medullary (brain stem, brain conduct); Stimulate peripheral nerve sensor, pain focus of excitation further on the other hand, then form strong, lasting pain perception through afferent nerve conduction to spinal cord, brain stem and brain.If peripheral stimulation source long action time, pain focus of excitation both can be transmitted to brain soon by A δ fine fibre and produce pain, can be transmitted to brain generation emotion changes and internal organs Tenseness again along crude fibre and internal organs vegetative nerve.
Wound causes the mechanism of pain: after wound (open wound or closed trauma), the histiocytes such as wound site skin, muscle, nerve, blood vessel break and discharge chemical algogenic substance as K +(potassium ion), H +(hydrion), 5-hydroxy tryptamine, Kallidin I, histamine, prostaglandin etc.Make wound site secondary inflammatory reaction, algogenic substance and inflammatory mediator is filled with intercellular substance in cell, cause local swelling, formation rationality and chemical irritation, stimulate local nerve tip and neural sensor to produce nocuity focus of excitation (pain focus of excitation); Nocuity focus of excitation is along nervus centripetalis A δ fiber and C class nerve fiber and vegetalitas visceral nerve fiber to maincenter transmission, stimulation gray nucleus dorsal horn makes it discharge algogenic substance SP material and calcitonin generelated peptide (CGRP) increases, pain focus of excitation is easily changed, and transmit to high-order maincenter, again arrive brain through brain stem to thalamus along spinothalamic tract specificity conducting system (fast pain) and the non-specific conducting system of network structure (slow pain) and produce pain location and pain reaction.
If in the market for the drug main of pain relieving: one is the analgesic acting on central nervous system.Opioid analgesic and derivant thereof, as morphine, dolantin, fentanyl, anadol, analgesia sheet, methadone etc. and their derivant; Nonopioid analgesic and analgesia adjuvant, comprise salicylic acid, phenyl amines, non-steroidal anti-inflammatory class medicine, the analgesic etc. of central analgesics and other type; Two is the Local Block narcotic analgesics acting on nerve root, neuroganglion, nerve trunk, nerve fiber and teleneuron.As procaine, mepivacaine, prilocaine, chloroprocaine, lignocaine, tetracaine, bupivacaine, Etidocaine, prilocaine, cinchocaine, benzene assistant cocaine etc.These adverse effectes are many, such as toxic reaction, anaphylaxis, methemoglobinemia, nerve injury etc.
The weight proportion that the present inventor discloses each crude drug of wherein pharmaceutical composition in Chinese patent " a kind of Chinese traditional medicine membranous plaster preventing and treating angina pectoris and preparation method thereof " is:
Preferably:
Most preferably:
Above-mentioned formula energy dilating coronary blood vessel, increase coronary flow, improve the myocardial ischemia-anoxemia equilibrium of supply and demand, reduce myocardial oxygen consumption, strengthen cardiac function, reduce blood viscosity, aforementioned pharmaceutical compositions is made Chinese traditional medicine membranous plaster, for preventing and treating coronary heart diseases and angina pectoris for this reason.
The traditional Chinese medical science thinks that the maintenance of normal human's physiological function depends on meridians, QI and blood is unobstructed.The normal defeated cloth of gas, blood, body fluid moves to body tissue and internal organs, and body surface is respectively organized between internal organs, and the function between each internal organs and internal organs maintains balance mutually.When human body suffer various damage factor as: cut, cut, break, sting, fall, beat, turn round, press, pound etc. and after the wound such as chemical substance, meridians, the QI and blood of local organization are cut off, form stagnation of QI-blood, stagnation of QI and blood may bring about pain, therefore otch or site of injury have and obviously have an intense pain.Because wound destroys between body surface organization and internal organs, the meridian qi and blood between internal organs and internal organs and function balance, often show a series of untoward reaction of internal organs, as: flatulence, the general health status such as poor appetite, lassitude declines.If wound area is large, tissue injury is serious, and often because of Massive Bleeding, cause asthenia of qi and blood, asthenia of qi and blood causes again qi depression to blood stasis " stagnation of QI and blood may bring about pain ".Chinese traditional treatment principle: blood circulation promoting and blood stasis dispelling, dredging the meridian, circulation of qi promoting of enriching blood.
The present inventor finds in an experiment, and its pharmaceutical composition disclosed in Chinese patent " a kind of Chinese traditional medicine membranous plaster preventing and treating angina pectoris and preparation method thereof " also has the effects such as treatment surgery opening and closed injury antiinflammatory, detumescence, pain relieving.By the research of animal pharmacodynamics, animal analgesia mechanism, clinical observation on the therapeutic effect and clinical analgesia mechanism, and the explanation such as Drug Percutaneous Absorption experiment, toxicological experiment: can reduce the algogenic substance in (or neutralization) local wound face and inflammatory mediator as etc. K +ion, PGE 2deng; Can excite central analgesia matter, such as enkephalin, β-Nei calf peptide, the release of nerve sheath sugar ester increase; Reduce algogenic substance SP, calcitonin gene-related peptide (such as CGRP) release; Suppress Inflammatory substances such as tumor necrosis factor, interleukin, nitric oxide production effect.There is pain relieving, antiinflammatory, detumescence effect, can wound healing be promoted, be used for the treatment of the open and closed injury of surgery and there is significant effect.For adapting to therapeutic use, this pharmaceutical composition being made Chinese medicine external membrane, obtains good therapeutic effect.
Summary of the invention
The invention provides a kind of Chinese medicine external membrane, its effective ingredient is made up of the Chinese medicine of following weight proportion:
Preferred:
The invention provides prescription of this Chinese medicine external membrane and preparation method thereof.
The prescription of Chinese medicine external membrane: the weight ratio of active ingredients of traditional Chinese medicine, film former, plasticizer is:
Active ingredients of traditional Chinese medicine 60%-75%
Film former 20-32%
Plasticizer 5-10%
Optimizing prescriptions is:
Active ingredients of traditional Chinese medicine 71%
Film former 23%
Plasticizer 6%
Wherein film former is a kind of or two kinds or the multiple combinations such as polyvinyl alcohol (PVA), Pioloform, polyvinyl acetal, polyvinylpyrrolidone (PVP), preferred PVA.Plasticizer be glycerol, triacetyl glycerine, ethylene glycol, sorbitol phthalic acid ester etc. one or more, preferably glycerine.
Preferred prescription is:
Active ingredients of traditional Chinese medicine 71%
PVA 23％
Glycerol 6%
Chinese medicine external Membranous preparation method comprises the following steps:
Step one, by the medical material containing volatile oil in prescription, the 15 taste medical materials such as Rhizoma Chuanxiong, Lignum Santali Albi, Radix Curcumae, Lignum Aquilariae Resinatum, Rhizoma Cyperi, Lignum Dalbergiae Odoriferae, Olibanum, Myrrha, Flos Chrysanthemi, Flos Caryophylli, the Radix Aucklandiae, Radix Angelicae Sinensis, the Radix Angelicae Dahuricae, Bulbus Allii Macrostemonis, Rhizoma Acori Graminei add 2.5-4 times of water, with extraction by steam distillation volatile oil a;
Step 2, filtered by the water cooking liquid after above-mentioned extraction by steam distillation volatile oil, medicinal residues b is for subsequent use; Filtrate is condensed into thick paste at 60 DEG C, relative density is 1.12-1.15, add 1.7 times of 95% ethanol, make ethanol content be 60%, be stirred well to completely evenly, leave standstill 24 hours, Aspirate supernatant, sediment fraction filters, and decompression filtrate recycling ethanol is condensed into thick paste c (relative density 1.15-1.17,60 DEG C);
Step 3, Radix Salviae Miltiorrhizae, Radix Puerariae, Benzoinum, the Radix Astragali, Radix Paeoniae Rubra, Rhizoma Corydalis 6 taste medicine are added in the medicinal residues b in above-mentioned steps two, with 9 times amount alcohol reflux twice, 90% ethanol for the first time, second time 80% ethanol, each 1-1.5h, filters, twice filtrate is merged distilling under reduced pressure, is condensed into the thick paste d that relative density is 1.15-1.17 (temperature is 45 DEG C-60 DEG C);
Step 4, depend on pine torch, Caulis Polygoni Multiflori is ground into coarse powder (crossing 20 mesh sieves), according to the percolation under Chinese Pharmacopoeia fluid extract and extractum item, use 90% ethanol, about 10-12 times amount dipping 24h, carries out percolation, collect percolate, reclaim ethanol, be condensed into thick paste e (relative density 1.15-1.17,60 DEG C);
Step 5, by the thick paste e in the magma c in step 2, the thick paste d in step 3, step 4, i.e. c, d, e three thick paste mixing and stirring.Add the volatile oil a in step one, then add Radix Notoginseng powder, Borneolum Syntheticum powder and Storax oil and be mixed together, stir and make the total compound of active drug, be positioned in blender and stir, mixing homogenizing, makes medicinal liquid make ultrafine particle molecule.Leave standstill after 10-20 minute, remove minute bubbles after colloid mill, disappear completely to bubble, obtain active ingredients of traditional Chinese medicine f;
Step 6, mixs homogeneously the active ingredients of traditional Chinese medicine f manufactured in step 5 with film former and plasticizer, inserts masking in moulding machine medicine groove, dry rear demoulding;
Step 7, cuts into the specification that clinical wound area varies in size, to obtain final product.
Select multiple drugs of causing resuscitation by administering aromatic drugs in prescription, they have eliminating turbid pathogen with aromatics, activating QI to alleviate the depression, and understand things pain-stopping has synergism each other; Select multiple drug for invigorating blood circulation and eliminating stasis simultaneously, there is blood circulation promoting and blood stasis dispelling, pain relieving, and drugs of causing resuscitation by administering aromatic drugs can be strengthened open blood key, promoting blood circulation, pain relieving, strengthen drug effect synergism each other between various medicine; Also have selected promoting the circulation of QI to relieve pain medicine, the capable then blood of gas, gas is capable, and expectorant disappears, thus alleviates qi depression to blood stasis, phlegm stagnating in meridian and the pain that causes; Have selected purging liver-fire, QI invigorating medicine for promoting pneuma, they can make irritability adjust to reach, catharsis appropriateness, and can suppressing again aromatic drug, unlikely to cross what pungent warm-dryness syndrome strong, simultaneously can QI invigorating, promote the production of body fluid, row is stagnant, dredging blood vessel, to remedy the fraud of aromatic drug consumption gas.This prescription is made up of 26 taste medicines.In prescription, drugs of causing resuscitation by administering aromatic drugs group and drug for invigorating blood circulation and eliminating stasis group and crude drug etc. are the principal agent of disease therapy, are again the promoter that externally applied transdermal absorbs.
Chinese medicine external membrane of the present invention is by the suppression to algogenic substance, inflammatory mediator, the increase of anti-pain material and reach postoperative antiinflammatory, analgesic activity.Antiinflammatory, the clinical immediate union of hindering face of favourable promotion of subsiding a swelling.
Chinese medicine external membrane of the present invention, by In vitro Bactericidal Experiments, proves there is certain antibacterial action to various bacteria, obvious with G+ coccus and G+ bacillus, also has antibacterial action to bacillus pyocyaneus, escherichia coli, anaerobe, bacteroides fragilis, peptostreptococcus.
By animal pharmacodynamics test, mice agar granuloma, Rat Carrageenan colloidality pedal swelling, mice caused by dimethylbenzene xylene auricle edema swollen to rat granuloma have obvious inhibitory action, illustrate that Chinese medicine external membrane of the present invention has obvious antiinflammatory action.
By to analgesic experiments such as hot plate method in mice, rat Tail-flick latency, mice laser stimulation method, the electricity irritation of rat local wound, prove that Chinese medicine external membrane of the present invention has good analgesic activity.
By the research to its analgesic mechanism, the algogenic substance in (or neutralization) the local wound face that proves that Chinese medicine external membrane of the present invention can reduce and inflammatory mediator as etc. K +ion, PGE 2deng, central analgesia matter can be excited, such as enkephalin, β-Nei calf peptide, the release of nerve sheath sugar ester increase, and reduce algogenic substance SP, calcitonin gene-related peptide (such as CGRP) release, suppress Inflammatory substances such as tumor necrosis factor, interleukin, Effect of Nitric Oxide.Thus there is easing pain and diminishing inflammation effect.
The invention provides one and there is pain relieving, antiinflammatory, detumescence effect, can wound healing be promoted, be used for the treatment of the Chinese medicine external membrane of surgery opening or closed injury.This Chinese medicine external membrane also can be used for treating swelling and ache of the inflammation such as burn, arthritis, muscular strain, skin ulcer, furuncle, carbuncle.
Concrete embodiment
Embodiment 1: the preparation of Chinese medicine external membrane
(1) the raw material weight proportioning of the active ingredients of traditional Chinese medicine of Chinese medicine external membrane is prepared:
(2) preparation process:
Step one, in proportion the 15 taste medical materials such as Rhizoma Chuanxiong, Lignum Santali Albi, Radix Curcumae, Lignum Aquilariae Resinatum, Rhizoma Cyperi, Lignum Dalbergiae Odoriferae, Olibanum, Myrrha, Flos Chrysanthemi, Flos Caryophylli, the Radix Aucklandiae, Radix Angelicae Sinensis, the Radix Angelicae Dahuricae, Bulbus Allii Macrostemonis, Rhizoma Acori Graminei in prescription are added 2.5-4 times of water, with extraction by steam distillation volatile oil a;
Step 2, filtered by the water cooking liquid after above-mentioned extraction by steam distillation volatile oil, medicinal residues b is for subsequent use; Filtrate being condensed at 60 DEG C thick relative density is 1.12-1.15, add 1.7 times of 95% ethanol, make ethanol content be 60%, be stirred well to completely evenly, leave standstill 24 hours, draw supernatant, sediment fraction filters, and is reduced pressure by filtrate, reclaims ethanol, be condensed into magma c (relative density 1.15-1.17, temperature 60 C);
Step 3, Radix Salviae Miltiorrhizae, Radix Puerariae, Benzoinum, the Radix Astragali, Radix Paeoniae Rubra, Rhizoma Corydalis 6 taste medicine are added in the medicinal residues b in above-mentioned steps two, with 9 times amount alcohol reflux twice, 90% ethanol for the first time, second time 80% ethanol, filters, and twice filtrate is merged distilling under reduced pressure, be condensed into the thick paste d that relative density is 1.15-1.17, temperature 45-60 DEG C;
Step 4, depend on pine torch, Caulis Polygoni Multiflori is ground into coarse powder (crossing 20 mesh sieves), according to the percolation under fluid extract and extractum item, use 90% ethanol, about 10-12 times amount dipping 24h carries out percolation, collects percolate, reclaims ethanol, be condensed into thick paste e (relative density 1.15-1.17,60 DEG C);
Step 5, by the thick paste e in the magma c in step 2, the thick paste d in step 3, step 4, i.e. c, d, e three thick paste mixing and stirring, add the volatile oil a in step one, then add Radix Notoginseng powder, Borneolum Syntheticum powder and Storax oil, whole mixing and stirring, make the total compound of active drug, be positioned in blender and stir, mixing homogenizing, makes medicine make the molecule of ultrafine particle.Leave standstill about 10-20 minute, remove minute bubbles after colloid mill, disappear completely to bubble, obtain active ingredients of traditional Chinese medicine f;
Step 6, by the active ingredients of traditional Chinese medicine f that manufactures in step 5 and film former PVA and plasticizer glycerol, according to the ratio mix homogeneously of 71%:23%:6%, inserts masking in moulding machine medicine groove, dry rear demoulding;
Step 7, cuts into the specification that clinical wound area varies in size, to obtain final product.
Embodiment 2: Chinese medicine external membrane In vitro Bactericidal Experiments of the present invention
First group:
1. materials and methods:
1.1. reagent material is supplied: Chinese medicine external membrane of the present invention (Hefei moral woods health care Science and Technology Ltd. provides).
1.2. for examination strain: staphylococcus aureus (12 strains, containing ATCC25923), group B streptococcus (14 strain), alpha streptococcus (12 strain), block its coccus (6 strain), staphylococcus epidermidis (10 strain), bacillus pseudodiphthericus (10 strain), diphtheroid (10 strain), bacillus pyocyaneus (14 strain), escherichia coli (10 strains, containing ATCC25922), bacteroides fragilis (16 strain), peptostreptococcus (16 strain), Candida albicans (12 strain).Above 12 kind of 142 strain bacterium, wherein reference culture is from DSMZ of Beijing Biological Product Inst..From Anhui Province, each large hospital attached to a medical college and provinces and cities' various big hospital 7 hospitals obtain clinical strain.Strain identification foundation " national Clinical Laboratory rule of operation " (second edition), " practical medical test " (first edition).
1.3. for examination culture medium: anaerobe anaerobic culture medium, fungus Sabouraud culture medium, streptococcus, false diphtheria, diphtheroid 5% sheep blood medium, other coccuses select MH culture medium.
1.4.MIC/MBC test:
1.4.1. for the preparation of examination bacterium liquid: each strains tested is inoculated in respectively in above-mentioned corresponding culture medium, 37 DEG C of cultivations, Candida albicans, anaerobe (putting anaerobism bag) cultivates 48 hours, other antibacterial culturing 24 hours, select Standard Plate, subcultivation is in fluid medium, anaerobe, Candida albicans, streptococcus cultivate 24 hours, and other antibacterial culturing adjust bacterial concentration after 6 hours be 10 8cFu/ml is for subsequent use.
1.4.2. the preparation of pastille culture medium: add test medicine respectively for examination culture medium, what make culture medium contains concentration, investigational agent Chinese medicine external membrane of the present invention respectively containing 128,64,32,16,8,4,2,1,0.5mg crude drug/ml, positive control drug Mupirocin Ointment (lot number: 98090229 manufacturers: Sino-U.S. Tianjin SmithKline drugmaker) respectively containing 128,64,32,16,8,4,2,1,0.5mg crude drug/ml, then pour plate solidifying after for subsequent use.Separately establish the negative control culture medium one group of not pastille.
1.4.3. (bacteria containing amount is about 10 to get test liquid one ring respectively for examination strain inoculating loop 4cFu) be inoculated in the culture medium of different pharmaceutical species concentrations, 37 DEG C of incubators cultivate (anaerobe puts anaerobism bag) Candida albicans, anaerobic culture 48 hours, after other bacterium cultivate 24 hours, and observed result.
1.4.4. result judges: on two flat boards of former and later two different gradient drug concentration, and bacterial growth quantity has that 80--90%'s be reduced to MIC suddenly; In the culture medium of the most high dilution of medicine, without for examination bacteria growing, in this place draws materials and is again inoculated into without fungus content culture medium, still not giving birth to elder is MBC.Finally by after total data statistical procedures, record MIC 50, MIC 90X± SD, MBC average.
2. result, in table 1:
Table 1. Chinese medicine external membrane of the present invention In vitro Bactericidal Experiments result (MIC, MBC)
3. conclusion:
Chinese medicine external membrane of the present invention, certain antibacterial action is had to above-mentioned tested 12 kinds of bacterium, be obvious with G+ coccus and G+ bacillus, also antibacterial action is had to bacillus pyocyaneus, escherichia coli, anaerobe, bacteroides fragilis, peptostreptococcus, but required dosage is greater than G+ bacterium, there is bacteriostasis for Candida albicans, without bactericidal action, positive controls Mupirocin Ointment is better than to the antibacterial action of anaerobe.
Second group:
1. materials and methods:
1.1. reagent material is supplied: Chinese medicine external membrane of the present invention (Hefei moral woods health care Science and Technology Ltd. provides).
1.2. for examination strain: staphylococcus aureus (21 strains, containing ATCC25923), group B streptococcus (10 strain), alpha streptococcus (18 strain), block its coccus (10 strain), bacillus pseudodiphthericus (15 strain), diphtheroid (4 strain), bacillus pyocyaneus (10 strain), escherichia coli (14 strains, containing ATCC25922), bacteroides fragilis (15 strain), peptostreptococcus (17 strain), Candida albicans (8 strain).Above 11 kind of 142 strain bacterium, wherein reference culture is from DSMZ of Beijing Biological Product Inst..From Anhui Province, each large hospital attached to a medical college and provinces and cities' various big hospital 7 hospitals obtain clinical strain.Strain identification foundation " national Clinical Laboratory rule of operation " (second edition), " practical medical test " (first edition).
1.3. for examination culture medium: aerobicly select MH culture medium, anaerobe anaerobic culture medium, fungus Sabouraud culture medium, streptococcus, false diphtheria, diphtheroid 5% sheep blood medium.
1.4.MIC/MBC test:
1.4.1. for the preparation of examination bacterium liquid: each strains tested is inoculated in respectively in above-mentioned corresponding culture medium, 37 DEG C of cultivations, Candida albicans, anaerobic culture 48 hours, other antibacterial culturing 24 hours, select Standard Plate subcultivation in fluid medium, anaerobe, Candida albicans, streptococcus cultivate 24 hours, other antibacterial culturing are after 6 hours, and adjustment bacterial concentration is 10 8cFu/ml is for subsequent use.
1.4.2. the preparation of pastille culture medium: add test medicine respectively for examination culture medium, what make culture medium contains concentration, investigational agent Chinese medicine external membrane of the present invention respectively containing 128,64,32,16,8,4,2,1,0.5mg crude drug/ml, positive control drug Mupirocin Ointment (lot number: 98090229 manufacturers: Sino-U.S. Tianjin SmithKline drugmaker) respectively containing 128,64,32,16,8,4,2,1,0.5mg crude drug/ml, then pour plate solidifying after for subsequent use.Separately establish the negative control culture medium one group of not pastille.
1.4.3. for the inoculation of examination bacterium: test liquid one ring got respectively by inoculating loop, and (bacteria containing amount is about 10 4cFu) be inoculated in the culture medium of different pharmaceutical species concentrations, 37 DEG C of incubators cultivate (anaerobe puts anaerobism bag).Candida albicans, anaerobic culture 48 hours, after other bacterium cultivate 24 hours, observed result.
1.4.4. result judges: on two flat boards of former and later two different gradient drug concentration, and bacterial growth quantity has that 80--90%'s be reduced to MIC suddenly; In the culture medium of the most high dilution of medicine, without for examination bacteria growing, in this place draws materials and is again inoculated into without fungus content culture medium, still not giving birth to elder is MBC.Finally by after total data statistical procedures, record MIC 50, MIC 90X± SD, MBC average.
2. result, in table 2:
Table 2. Chinese medicine external membrane of the present invention In vitro Bactericidal Experiments result (MIC, MBC)
3. conclusion:
Chinese medicine external membrane of the present invention, certain antibacterial action is had to above-mentioned tested 11 kinds of bacterium, be obvious with G+ coccus and G+ bacillus, also antibacterial action is had to bacillus pyocyaneus, escherichia coli, anaerobe, bacteroides fragilis, peptostreptococcus, but required dosage is greater than G+ bacterium, there is bacteriostasis for Candida albicans, without bactericidal action, positive control drug Mupirocin Ointment is better than to the antibacterial action of anaerobe.
Embodiment 3: Chinese medicine external membrane animal pharmacodynamics test
1. antiinflammatory experiment:
1.1. on the impact that rat granuloma is swollen
Experiment selects healthy wister rat, male and female half and half, female unpregnancy, body weight 130--140g.Be divided into model control group (local not administration) at random; Excipient control group; Positive controls (local is coated with Corium elephatis SHENGFU GAO 10g crude drug/kg, hereinafter referred to as " SHENGFU GAO ", and lot number: 961206 manufacturers: Tianjin Darentang Pharmaceutical Factory); The Chinese medicine external membrane group of embodiment 1, local is coated with Chinese medicine external membrane 20g crude drug/kg of the present invention (dosage of human body or animal per kg body weight is 20g).Zoopery proxima luce (prox. luc), loses hair or feathers in each Mus hypogastric region (comprising both sides groin).During experiment, rat faces upward position and fixes under pentobarbital sodium intraperitoneal injection of anesthesia, the subcutaneous each implantation of both sides groin one piece of 20mg sterilizing cotton balls, and after before implanting, each cotton balls all adds penicillin mixed liquor 0.1ml, skin suture also presses the dosage local wound drug of topical application in table 1.For preventing medicine from coming off, fixed again after the drug of topical application.And timing is observed, if the person of coming off, fixes at any time.Routine is raised with condition.Drug of topical application every day once (all removes previous medicine before each administration), and successive administration put to death animal after 7 days.Complete stripping both sides granuloma induced by implantation of cotton pellets, after claiming weight in wet base, 60 DEG C of baking ovens claimed dry weight after 12 hours, deducted the weight of cotton balls own, were granuloma weight.Respectively organize the difference of granuloma induced by implantation of cotton pellets weight.Result carries out statistical analysis, lists in table 3:
The impact (X ± SD) that table 3. Chinese medicine external membrane of the present invention swells on rat granuloma
Animal group Number of animals (only) Dosage (g/kg) Granuloma weight in wet base (mg) Granuloma dry weight (mg) Remarks
Model control group 14 － 94.3±11.48 36.7±2.93
Excipient control group 14 － 96.7±13.69 37.1±4.17
Positive controls (SHENGFU GAO) 14 10 89.4±6.36 32.3±3.31*
Chinese medicine external membrane group 14 20 82.6±10.51* 27.4±4.34**
[0099]compare with model control group: * P<0.05, * * P<0.01
This experimental result shows: Chinese medicine external membrane has obvious inhibitory action to rat granuloma is swollen.
1.2. on the granulomatous impact of mice agar:
Experiment selects healthy kunming mice, body weight 24-26g, male and female half and half, female unpregnancy.Be divided into model control group at random, excipient control group, the Chinese medicine external membrane matched group of positive controls (Corium elephatis SHENGFU GAO, lot number: 961206 manufacturers: Tianjin Darentang Pharmaceutical Factory) and embodiment 1, administration is the same.Experiment proxima luce (prox. luc), depilation 4 × 4 ㎝ in the middle of each Mus back 2.During experiment, in each mouse back depilation district (in median line below), 0.2ml is rounded for subcutaneous injection 2% sterilizing agar.After 1 hour, by dosage in table 2 in injection place skin application, every day applies once, continuous 14 days, and for preventing medicine from coming off, after the drug of topical application, local is fixed again.And timing is observed, if the person of coming off, fixes at random.Raise with condition.After last administration 24 hours, put to death animal, peel off complete granuloma and weigh.Respectively organize the difference of granulation weight.Result through statistical procedures rank rear in table 4:
Table 4. Chinese medicine external of the present invention membrane is on the granulomatous impact of mice agar (X ± SD)
Animal group Number of animals (only) Dosage (g/kg) Agar granuloma weight (mg) Remarks
Model control group 20 － 24.94±3.07
Excipient control group 20 － 23.43±2.27
Positive controls (SHENGFU GAO) 20 10 19.82±2.45
Chinese medicine external membrane group 20 20 16.94±2.20*
Compare with model control group: * P<0.05.
This experimental result shows: Chinese medicine external membrane has obvious inhibitory action to mice agar granuloma.
1.3. on the impact of Rat Carrageenan colloidality pedal swelling
Male Wistar Rats is selected in experiment, body weight 140-160g, is divided into model control group at random, excipient control group, the Chinese medicine external membrane group of positive controls (Corium elephatis SHENGFU GAO, lot number: 961206 manufacturers: Tianjin Darentang Pharmaceutical Factory) and embodiment 1.After rat paw topical, animal activity medicine easily comes off, and when historical facts or anecdotes is tested, sobering animal is faced upward position and fixes, right lower limb unfixing (in case causing sufficient sole of the foot edema after the binding of local).First measure toes place, left and right thickness with micrometer vernier caliper, and mark.By table 3 dosage, in right back toes place skin coating after 2 hours, in the right back toes subcutaneous injection 1% carrageenin 0.1ml of coating, and 1,2,4 and 6 hour after injection surveys toes thickness (wiping medicine before measurement) at mark same method, before deducting administration, thickness is swelling, result through statistical procedures rank rear in table 5:
Table 5. Chinese medicine external membrane of the present invention is on the impact (X ± SD) of rat paw edema
Compare with model control group: * P<0.05, * * P<0.01.
This experimental result shows: Chinese medicine external membrane can suppress chondrus ocellatus Holmes colloidality rat paw edema preferably.
1.4. xylol causes the impact of mice auricle swelling:
Experiment selects healthy kunming mice, body weight 22--24g, male and female half and half, female unpregnancy.Be divided into model control group at random, excipient control group, the Chinese medicine external membrane group of positive controls (Corium elephatis SHENGFU GAO, lot number: 961206 manufacturers: Tianjin Darentang Pharmaceutical Factory) and embodiment 1.After the two-sided depilation of the experiment left ear of proxima luce (prox. luc) mice, by dosage local application twice in table 4, experiment coating on the same day washes away medicinal liquid with 75% ethanol in 2 hours, and model group, vehicle group and Xiangpishengji paste group are all undertaken by same method.After 30 minutes, drip painting dimethylbenzene 0.05ml in the two-sided auricle of left ear and cause inflammation, animal is put to death after 4 hours, two ear same area auricles are got with 8mm card punch, put ten thousand/balance to weigh, left ear heavily deducts auris dextra weight, is auricle swelling degree, respectively organize auricle swelling degree difference, result lists in table 6 through statistical procedures:
Table 6. Chinese medicine external membrane of the present invention is on the impact (X ± SD) of mice auricle swelling
Animal group Number of animals (only) Dosage (g/kg) Agar granuloma weight (mg)
Model control group 20 － 21.44±3.52
Excipient control group 20 － 19.82±3.17
Positive controls 20 10 17.24±2.29
Chinese medicine external membrane group 20 20 16.35±2.68*
Compare with model control group: * P<0.05.
This experimental result shows: Chinese medicine external membrane has the good dimethylbenzene that suppresses to mice auricle swelling effect.
2. analgesic experiment:
2.1. to hot plate method in mice analgesic activity:
Healthy kunming mice is selected in experiment, female, body weight 20-23g.Be divided into model control group, excipient control group, red medicine plaster group (lot number: 970106 manufacturers: Shenyang Traditional Chinese Medicine Factory) at random, and the Chinese medicine external membrane group of embodiment 1.The constant temperature water bath of the threshold of pain (55 ± 0.5 DEG C) is all first surveyed before each mouse experiment) reject the threshold of pain and be less than 5 seconds and be greater than the animal of 30 seconds.After 4 hours, foot medicine (model control group and excipient control group are cleaned equally) is washed away with ethanol by the toes place coating after two of dosage in table 5.After treating ethanol volatilization, put by mice on 55 ± 0.5 DEG C of constant temperature water bath aluminium sheets, cover with bell glass, record drops into after mice and starts the time of adding oneself metapedes to mice, respectively organize the difference of the threshold of pain before and after administration as the threshold of pain after administration, result through statistical procedures rank rear in table 7:
Table 7. Chinese medicine external membrane of the present invention is to the analgesic activity (X ± SD) of hot plate method in mice
Animal group Number of animals (only) Dosage (g/kg) The front threshold of pain (s) of administration The threshold of pain (s) after administration Analgesia rate (%)
Model control group 20 － 17.45±3.35 18.8±3.19 8.1±3.52
Excipient control group 20 － 18.3±2.20 19.0±2.47 8.4±4.27
Red medicine plaster group 20 10 17.9±2.77 26.6±3.65 48.6±7.78*
Chinese medicine external membrane group 20 20 18.6±2.93 29.1±4.86 56.5±9.32*
Compare with model control group: * P<0.05.
This experimental result shows: Chinese medicine external membrane topical application, has certain analgesic activity to hot plate method in mice induced pain.
2.2. to the analgesic activity of rat Tail-flick latency:
Experiment selects healthy wister rat, male and female half and half, female unpregnancy, body weight 160-180g.Be divided into model control group at random, excipient matched group; Red medicine plaster group (lot number: 970106 manufacturers: Shenyang Traditional Chinese Medicine Factory), and the Chinese medicine external membrane group of embodiment 1.Because rat tails skin is thicker, consider that drug absorption is more difficult, then in conjunction with clinical administrated method, so each rat experiment afterbody lose hair or feathers by we before experiment, and in lower 1/3 place, extremely subcutaneous with sharp blade longitudinal incision, long 2cm, cuts 3 road otch along tail surrounding is parallel.Ensure incision site, length is consistent with the degree of depth as far as possible.Within postoperative 30 minutes, start to survey the front threshold of pain of administration (surveying threshold of pain instrument 22V, 250W, 16mm cinema lamp to be brewed to), between spot alignment two longitudinal incisions, skin makes marks, record causes the incubation period of threshold of pain whipping, measures three times, averages as the front threshold of pain of administration.
Reject the animal being less than 3 seconds its incubation period He being greater than 10 seconds.Then on the stimulation point made marks, lower each 0.5cm place, is affixed on afterbody by the Chinese medicine external membrane of embodiment 1 and red medicine plaster and excipient annular, outward with immobilization with adhesive tape (doing the place's not administration of photostimulation point, unsuitable tension during immobilization with adhesive tape).And after administration 0.5,1,2,4,6,8 and 12 hour, (each time period all surveys three times to survey each Pain Regulation In The Rat with same method, every minor tick 2 minutes, averages) compare the change of the different time threshold of pain and the front threshold of pain of administration after administration, result after statistical procedures list in 8:
Table 8. Chinese medicine external membrane of the present invention is to Rat Tall Flick method analgesic effect (X ± SD)
Compare with model control group: * P<0.05, * * P<0.01.
This experimental result shows: Chinese medicine external membrane, to rat tails (injured skin) external, has good analgesic activity to Tail-flick latency.
2.3. to the analgesic activity of mice laser stimulation method:
Experiment selects healthy kunming mice, body weight 18--20g, male and female half and half, female unpregnancy.Be divided into model control group at random, excipient control group, the Chinese medicine external membrane group of morphine hydrochloride group (lot number: 950812 manufacturers: Shenyang No. 1 Pharmaceutical Factory) and embodiment 1.Each animal one day on pretreatment, centered by back median line and two hip joint line cross points, depilation 2 × 4cm 2.Longitudinal cut is made, long 1cm in depilation district, conventional stitching during experiment.And make marks in the other 0.2cm of otch, flicking animal J2-CO 2after laser therapeutic apparatus (Anbui Optical Machinery Inst., Chinese Academy of Sciences's production) exposure label(l)ing place skin (labelling surveys the not administration of sore spot skin) surveys the front threshold of pain of administration, by different group, centered by otch, apply medicine, coating scope is skin in the 0.5cm of otch both sides.And after awarding administration 1,2,4,8 and 12 hour, survey the threshold of pain (occur shouting to start power supply to animal, reaction of struggling for latent time) with same method in mark, the change of more each treated animal threshold of pain in different time.It is 8 seconds that laser irradiates deadline.Result through statistical procedures rank rear in table 9:
Table 9. Chinese medicine external membrane of the present invention is to the analgesic activity (X ± SD) of mice laser stimulation method
Compare with model control group: * P<0.05, * * P<0.01.(note: morphine intramuscular injection)
Table 9 result represents: " Chinese medicine external membrane single administration 1 of the present invention is little of 8 hours, and its dosage has certain antagonism electricity irritation to cause shouting of mice.P<0.05 is compared with blank group.1-2 hour after the administration of morphine hydrochloride group, has very strong analgesic activity, but the persistent period does not have Chinese medicine external membrane of the present invention long.
3. the analgesic activity of pair rat local wound electricity irritation:
Experiment selects healthy wister rat, body weight 160--180g, male and female half and half, female unpregnancy.After each rat abdomen center depilation, under ether light anaesthesia, after the sterilization of abdominal part center, otch reaches abdominal cavity, and in the bipolar implanted electrode of the subcutaneous implantation of otch before sew up wound, two electrode distances are about 0.8cm, and subcutaneous length is about 0.8cm, then conventional sew up wound.Art finishes after animal is naturally clear-headed, is divided into blank group at random, excipient matched group, the Chinese medicine external membrane matched group of morphine hydrochloride matched group (lot number: 950812 manufacturers: Shenyang No. 1 Pharmaceutical Factory) and embodiment 1.Each group lie on the back fixing after electrode is pressed on the multiplex instrument of YSD-4 type pharmacology Physiological Experiment respectively, stimulate with linear boost voltage, till shouting appears in rat, continuous three times, average is as the starting voltage (V) before administration.Then press the administration of table 8 dosage local wound, and 1,2,4,8,12 and 24 hour after administration measures (V) number of threshold of pain reaction respectively with same method, each time period surveys three times, and every minor tick 5 minutes, averages.The relatively change of the threshold of pain before and after administration, result through statistical procedures rank rear in table 10:
Table 10. Chinese medicine external membrane of the present invention is to rat abdomen wound electrostimulation analgesic activity (X ± SD)
Compare with blank group with before administration: * P<0.05, * * P<0.01.(note: morphine intramuscular injection)
Table 10 shows: the local electrical stimulation method of Chinese medicine external membrane of the present invention to wound mouth has more obvious analgesic activity, onset in a hour after medication, sustainable more than 12 hours.
Embodiment 4: the research of Chinese medicine external membrane analgesia mechanism
1. Chinese medicine external membrane effective component extracts Human fetuses of the present invention effect:
Get Kunming mouse, body weight 18-20g, male and female half and half, its afterbody is placed in 48 DEG C of hot water 5cm, with its TFL for resurveying once after pain indicator reaction 5min, get Mean square value as the front threshold of pain of medication, spinal cord injection (ith) normal saline (NS) or by after reagent 15,30 and 45min after survey TFL respectively again.(note: n=10)
Table 11. Chinese medicine external membrane of the present invention effective component extracts spinal cord injection is on the impact (X ± S) of mice hot water TFL
Compare with NS, * * P<0.01; Compare with before medication, ##<0.01.
Shown in table 11: compare with before Ns matched group and medication, 25mg.kg -2after Chinese medicine external membrane effective component extracts ith of the present invention 30,45min can significant prolongation mice TFL in the hot water, illustrates: Chinese medicine external membrane effective component extracts spinal cord of the present invention administration has certain analgesic activity.
2. the impact of Chinese medicine external membrane effective component extracts rabbit ear topical KCl induced pain of the present invention effect:
The impact of Chinese medicine external membrane effective component extracts rabbit ear topical KCl induced pain of the present invention effect:
Select rabbit 2.0 ± 0.5kg, male and female half and half, block and both sides, drain rabbit ear back auricular vein after, the ear medium-sized artery 1/2 place antegrade blood flow hit exactly in hard of hearing portion is to injection 1.5%kcl0.4ml, to cause after the ANIMAL PAIN reaction 5min such as (get rid of head, shout, struggle) same injection location normal saline (NS) or by reagent, after medication 10,20min injects 1.5%KCl 0.4ml respectively, observes ANIMAL PAIN reaction and whether occurs.
Table 12. Chinese medicine external membrane of the present invention crude drug is to k +to the impact of rabbit ear pain
Compare with matched group, * * P<0.01.Bracket inner digital is the suppressed number of animals of pain.
As shown in table 12, significantly can suppress K after the rabbit ear intra-arterial injection of 200mg/kg Chinese medicine external membrane of the present invention effective component extracts local +induced pain reaction, illustrate that Chinese medicine external membrane effective component extracts topical application of the present invention can resist K +induced pain effect.
3. Chinese medicine external membrane effective component extracts of the present invention is to PGE in rabbit midline incision flushing liquor 2and K +the impact of content:
The preparation of 3.1 rabbit midline incision flushing liquors: rabbit 1.5--2.2kg, male and female are regardless of, spinal column both sides, back depilation 5 × 4cm 2after 24 hours, in depilation, district makes long 3cm, dark 0.7cm otch, and left side sticked Chinese medicine external membrane of the present invention after 8 hours, threw off tablet, rinsed otch with 1mlNS, collects flushing liquor, puts 40 DEG C of following indexs to be measured.
3.2.K +the aas determination of content: the otch flushing liquor getting 200ul, be added in 9ml 3% nitric acid, digestion is spent the night, and surveys K by literature method POLARIZED180-80 type atomic absorption spectrophotometer +content.
3.3. prostaglandin E 2(PGE 2) ultraviolet method mensuration (4): the 0.5N KOH--methanol solution adding 2ml in 0.5ml otch flushing liquor, in juxtaposition 50 DEG C of water-baths after isomerization 20min, add methanol 2.5ml, shake up rear centrifugal (2500rpm, 10min) and get supernatant and measure at 751--UV detector 278nm place.
Table 13. Chinese medicine external membrane of the present invention after 8 hours to rabbit midline incision flushing liquor PGE 2and K +the impact (X ± S) of content
Group n K +Content (ug.ml -1) PGE2 content (ug.ml -1)
Blank group 6 54.2±19.1 4.1±0.9
Chinese medicine external membrane of the present invention 6 23.4±11.5* 2.4±1.6*
Compare with matched group, * P<0.05.
As shown in table 13, K in blank group otch flushing liquor +and PGE 2content is respectively 54.2 ± 19.1 and 4.1 ± 0.9ug.ml -1, Chinese medicine external membrane effective component extracts of the present invention then reduces to 23.9 ± 11.5 and 2.4 ± 1.6ug.ml -1, two groups of difference all have significance (P<0.05).Illustrate: Chinese medicine external membrane effective component extracts of the present invention can reduce PGE in incision tissue 2and K +content (infer and for promoting organization healing, or may reduce PGE by its mechanism 2release).
Embodiment 5: Chinese medicine external membrane treatment open wound (comprising surgical incision) and closed trauma pain relieving, antiinflammatory promote wound healing clinical observation on the therapeutic effect
Chinese medicine external membrane treatment open wound (comprising surgical incision) of the present invention and closed trauma pain relieving, antiinflammatory, detumescence do 205 examples (whole inpatient) altogether comprising Chinese medicine external membrane checking group 123 example of the present invention, surgical dressing matched group 82 example; Male 115 example, women 90 example, two groups of age levels all 18-65 year.Range of operation: body surface is performed the operation, abdominal operation, takes parallel even counter point to select case, and Ji Liangjia hospital checking group and matched group case are than being 1:1, and the 3rd hospital is that open checking group carries out clinical verification.
Clinical efficacy criterion is according to the classification of comprehensive WHO pain intensity and improvement visual analogue scales (VAS), in conjunction with overall merit pain palliation efficacies such as the number of patient's postoperative use opioid analgesic dolantin and dosage and the postoperative patient mental status (quiet, quieter, dysphoria, perspiration).Two groups of the results: checking group postoperative analgesia curative effect is 86.99% (effective 34.15%, effective 52.84%, invalid 13.01%).Matched group is (naturally not bitterly) 10.98% (effective nothing, effective 10.98%, invalid 89.02%) effectively; Dolantin number of users and dosage: checking group 88.62% does not adopt dolantin, 11.38% uses dolantin, and total amount 1100mg, all measures 8.94mg; Matched group 18.3% does not use dolantin, and 81.17% uses dolantin, and total amount 5100mg all measures 62.2mg.Postoperative mental state: checking group patient is postoperative be in peace and quiet or quieter be 87.00%, matched group patient is postoperative be in peace and quiet or quieter be 10.98%.Above result statistical procedures illustrates: Chinese medicine external membrane postoperative analgesia curative effect of the present invention is obviously better than matched group.
1. clinical observation:
Physical data: select the post-surgical incisions external applications such as body surface, abdominal cavity, thoracic cavity respectively, Chinese medicine external membrane of the present invention is checking group 123 example, and surgical dressing group is matched group 82 example, totally 205 examples.
1.1. sex: this group patient male 115 example, women 90 example, man: female=1.28:1.Two groups of Sex distribution situations are in table 14:
Table 14. liang group case gender comparison [example (%)]
Group Number of cases Man Female Man: female
Checking group 123 72(58.54) 51(41.46) 1.41：1
[0176]
Matched group 82 43(52.44) 39(47.56) 1.10：1
Note: two groups of case gender comparison: through X 2inspection: X 2=0.7428P>0.05
Two groups of gender comparison no significant differences, have comparability.
1.2. the age: checking group age 18--65 year, 44.63 ± 14.88 years old mean age, matched group age 18--65 year, 47.59 ± 12.27 years old mean age.Two groups of age distribution situations are in table 15:
Table 15. liang group case age comparison sheet [example (%)]
Note: two groups of age bracket distributions are analyzed through Ridit, u=0.6286, P>0.05, and the mean age is checked through t, #t=1.4940, P>0.05.Two groups of ages compare no significant difference comparability.
All kinds of operation names of 1.3 surgery and operative site distribution are in table 16,17,18:
Table 16. liang group thoracic surgery distribution and incision length compare
Note: #t=0.2805, P>0.05. two groups of thoracic surgery case incision lengths compare no significant difference, have comparability.
The title of table 17. liang group abdominal part and body surface operation and incision length
Note: Operation incision length is through statistical procedures #t=0.6776, P>0.05.
Table 17 illustrates: checking group 92 example, incision length average out to 12.89 ± 5.2cm, with the routine otch average length of matched group 51 13.16 ± 6.58cm, P>0.05., two groups of no significant differences, have comparability.
Table 18. liang group each position operative incision length [ratio (%)], (cm, X ± S) distribution table
Note: two groups of X 2inspection *x 2=3.7034, t=0.6137, P>0.05; *x 2=0.1605, *t=0.1033, P>0.05; * *x 2=0.1778, * *t=1.8399, P>0.05.
Illustrate: in checking group, thoracic surgery otch is maximum, average 31.77 ± 2.46cm; Abdominal operation incision length, average 12.78 ± 7.6cm; Body surface operative incision length, average 9.89 ± 6.71cm; Maximum 32.19 ± the 2.19cm of thoracic surgery otch in matched group, body surface operative incision average length is 14.41 ± 9.29cm, is greater than abdominal operation average cuts length 12.63 ± 5.63cm, because of wherein mammary cancer radical operation and bilateral thyroid surgical incision larger therefore.
Two groups of thoracic surgeries, abdominal operation, body surface operative incision length are through statistical procedures P>0.05.No significant difference.
1.4. two groups of average operative incision lengths compare, in table 19:
Table 19. Operation otch compares [example (%), (cm, )]
Note: two groups of incision length distributions analyze u=1.5703, P>0.05 through Ridit; Two groups of otch average lengths check t=0.0391 through t, P>0.05.Operation incision length no significant difference, has comparability.
1.5. two groups of anesthesias compare, and see the following form:
A table 20. liang group anesthesia compares [example (%)]
Group Local anaesthesia Continuous epidural Check anesthesia
Checking group (n=123) 31(25.20) 58(47.2) 34(27.64)
Matched group (n=82) 7(8.53) 39(47.6) 36(43.90)
Note: according to the checking group of the attached institute of the scheme traditional Chinese medical science and Bang Yifu institute with matched group case than 1:1, general anesthesia 34:36, connects hard 41:39, local anaesthesia 8:7, through statistical procedures, P>0.05.3rd hospital is for expanding checking group (not establishing matched group), and based on emergency treatment, outpatient service, body surface operation, therefore anesthesia is based on local anaesthesia; Local anaesthesia 23 example, connect hard 17 examples, without general anesthesia.
Table 20 anesthesia comparison range is checking group 125 example, matched group 82 example.
In sum, checking group and matched group patient, compare no significant difference through statistics, P>0.05 at age, sex, operative site, operation kind, anesthesia, incision length etc., two groups have comparability.
2. clinical efficacy:
2.1. Chinese medicine external membrane dosage of the present invention, in table 21:
Table 21. Chinese medicine external membrane of the present invention dosage compares (g, X ± S)
Note: checking group Chinese medicine external membrane of the present invention dosage average out to 34.83 ± 16.85.
Checking group effective 42 examples of Chinese medicine external membrane of the present invention, effective 65 examples, invalid 6 examples.
2.2. two groups of postoperative wound analgesic therapies compare:
Table 22. liang group WHO pain intensity comparison sheet [example (%)]
Group 0 grade I level II grade III grade Total effective rate
Checking group (n=123) 42(34.15) 65(52.84) 13(10.57) 3(2.44) 107(86.99)
Matched group (n=82) Nothing 9(10.98) 56(68.29) 17(20.73) 9(10.98)
Note: two groups through X 2inspection (0+1) x 2=87.6483, P<0.01 verifies that incision analgesic curative effect is obviously better than matched group.
Table 23. liang group pain intensity is to improve VAS analog vision point system comparison sheet [example (%)]
Group 0--2 divides 2--4 divides 4--6 divides 6--8 divides Total effective rate
Checking group (n=123) 42(34.15) 65(52.84) 13(10.57) 3(2.44) 107(86.99)
Matched group (n=82) Nothing 9(10.98) 56(68.29) 17(20.73) 9(10.98)
Note: two groups through X 2inspection (0--4 divides) x 2=87.6483, P<0.01 verifies that incision analgesic curative effect is obviously better than matched group.
Table 24. liang group pain relieving comprehensive therapeutic effect comparison sheet [example (%)]
Group Effective Effectively Invalid Total effective rate number of cases and effective percentage
Checking group (n=123) 42(34.15) 65(52.84) 16(13.01) 107(86.99)
Matched group (n=82) Nothing 9(10.98) 73(89.02) 9(10.98)
Note: two groups of total effective rates are through X 2inspection, x 2=87.6483, P<0.01.Checking incision analgesic curative effect is obviously better than matched group.
The table 25. liang different operative site comparitive study table of group [example (%)]
Note:
1.n 1represent checking group, n 2represent matched group;
2. checking group and matched group Ridit analyze * u=5.3247, P<0.05; * u=6.6374, P<0.01;
* * u=4.406, P<0.05; More than illustrate that two groups of thoracic cavities, abdominal cavity, body surface operative effect all have notable difference, checking group is obviously better than matched group.
3. checking group: thoracic operation and abdominal operation analyze u=0.5289 through Ridit, P>0..05, after thoracic operation and abdominal operation medication are described, pain palliation efficacy no significant difference; Thoracic operation and body surface operation analyze u=1.7496, P>0..05 through Ridit, after thoracic operation and body surface operation medication are described, and pain palliation efficacy no significant difference; Abdominal operation and body surface operation analyze u=1.3290, P>0.05 through Ridit, after abdominal operation and body surface operation medication are described, and pain palliation efficacy no significant difference.
Table 26. operative incision length and therapeutic effect relationship [example (%)]
Note: checking group and matched group are analyzed through Ridit: incision length≤10cm*u=6.478, P<0.05; Incision length 10--20cm**u=4.9312, P<0.05; Incision length >20cm***u=5.0429, P<0.05;
Illustrate: there were significant differences for checking group curative effect and matched group curative effect, checking group is evident in efficacy is greater than matched group.
Checking group is analyzed through Ridit :≤10cm compares u=2.9506, P>0.05 with >=20cm,
Illustrate :≤10cm otch curative effect and >=20cm otch curative effect are similar to;
≤ 10cm and 10--20cm compares u=2.3062, P>0.05,
Illustrate :≤10cm otch curative effect and 10--20cm otch curative effect are similar to;
10--20cm and >20cm compares u=0.5495, P>0.05,
Illustrate: 10--20cm and >20cm curative effect is similar to.
More than illustrate: incision length and curative effect are without obvious relation.
2.3. two groups of postoperative pain persistent period compare, and see the following form:
A table 27. liang group postoperative pain persistent period compares (h, )
Note: check the average pain persistent period through t, t=10.54, P<0.01. for two groups
The checking group postoperative pain persistent period is significantly short compared with matched group.
2.4. postoperative opioid analgesics:
The table 28. liang postoperative use opioid analgesics dolantin of group [example (%) (X ± S) mg]
Group Do not use dolantin Use dolantin Total amount (mg) All measure (mg)
Checking group (n=123) 109(88.62) 14(11.38) 1100 8.94
Matched group (n=82) 14(18.30) 68(81.70) 5100 62.24
[0248]note: two groups by dolantin number through X 2inspection X 2=104.93, P<0.01.
Checking group postoperative dolantin number is obviously less than matched group (two groups of postoperative dolantin pain relieving persons are all as Ineffective Cases statistics).
2.5. postoperative mental state:
Table 29. liang group postoperative mental epidemic situation comparison [example (%)]
Group Quiet Quieter (or frowning time movable) Dysphoria is perspired
Checking group (n=123) 42(34.15) 65(52.85) 16(13.00)
Matched group (n=82) Nothing 9(10.98) 73(89.02)
Note: analyze through Ridit for two groups, u=6.0243, P<0.01.
Checking group postoperative mental state be in peace and quiet and comparatively rest state be significantly greater than matched group.
The relation [example (%)] of table 30. sex and curative effect
Note: n 1for man, n 2for female;
Two groups of total effective rate X 2inspection, X 2=112.3491, P<0.01. checking group curative effect is obviously better than matched group.
Checking group boys and girls analyze through Ridit, u=0.5019, P>0.05, and checking group curative effect and sex are without obvious relation.
Matched group boys and girls analyze through Ridit, u=0.1872, P>0.05, and matched group and postoperative wound are without obvious relation.
The relation [example (%)] of table 31. age and curative effect
Note: n 1>=45 number of cases, n 2<45 number of cases
Two groups of total effective rates are through X 2inspection, X 2=143.5373, P<0.05.Checking group curative effect is obviously better than matched group.
Checking group >=45 and≤45 are analyzed through Ridit, u=1.8144, P>0.05, and checking group curative effect and age are without obvious relation; Matched group u=0.6586, P>0.05, matched group post-operative incisional pain and age are without obvious relation.
2.6 liang of group postoperative rehabilitation situations compare, and see the following form:
A table 32. liang group abdominal operation restoration of gastrointestinal function compares (h, ) ###
Note: check * t=2.0876 through t, P<0.05, * * t=2.0857, P<0.05 for two groups,
#t＝1.8578，P>0.05，##t＝2.3245，P<0.05，###t＝2.1100，P<0.05，
The statistical procedures such as the postoperative borborygmus recovery of checking group, passage of gas by anus, feed, out-of-bed activity, obviously early than matched group, though checking group defecation time is shorter than matched group, no difference of science of statistics.
Only select abdominal operation to observe, observe gastrointestinal function because of body surface operation and have little significance.
A table 33. liang group postoperative wound healing state compares [example (%)]
Group Red and swollen Ooze out After splitting Infect The first phase heals The second phase heals
Checking group n 1＝45 3(2.44) 0 0 1 122(99.19) 1(0.8)
Matched group n 2＝39 1 1 0 1 81(98.78) 1(1.22)
Note: two groups through X 2inspection, Affiliated Hospital of P>0.05. Wannan Medical College, after the medication of checking group, otch redness more takes a turn for the better after change dressings immediately without infecting, Wound healing by first intention.Through statistical procedures two groups of wound healing no significant differences.
Before and after two groups of medications, general medical condition, routine blood test, hepatic and renal function change comparison sheet 34,35,36
Routine blood test change before and after table 34. liang group medication:
Before and after table 35. liang group medication, liver function compares:
Before and after table 36. liang group medication, renal function situation compares:
3. safety evaluatio:
3.1 untoward reaction:
Chinese medicine external membrane checking group of the present invention is totally 123 examples, and wherein (otch both sides mild redness in 24 hours after 2.44% medication, without erythra and ooze out for 3 examples, more Wound healing by first intention after change dressings, thoracic surgery one example, the wound infection second phase heals, and two groups are compared no significant difference.
3.2 toxic reactions:
123 routine checking group patients wherein 3 routine otch have mild redness, and disappear after change dressings, otch is Wound healing by first intention, remaining without other untoward reaction.
3.3 cases reject situation:
The routine second operation of checking group one.Postoperative hemorrhage, as rejecting case;
Checking group and matched group is a case each does not meet because of the age, all as rejecting case.
3.4 model cases:
[case 1]. Tang, man, 55 years old, diagnosing liver cancer (B ultrasonic and CT diagnosis), blood routine examination after being admitted to hospital:
WBC3.6×10 9L，RBC4.23×10 12/L,PIt112×10 9/L,Hb130g/L.
Liver function: ALP59.9u/L ALT 6.5u/L, AST64.4u/L, γ-GT56.3u/L, albumin 42g/L
Globulin 28.6g/L, bilirubin 30.01umol/L.
Renal function: BuN8.29mmol/L Cr100umol/L, improves various preparation.
Left hemihepatectomy (II, III, IV section) roof shape long incision 24cm is below right costal margin carried out, anesthesia consumption 2% lignocaine 20ml, 1% tetracaine 8ml under the continuous spinal dura mater anesthesia of what.Cotton ball soaked in alcohol sterilization otch after the abdomen of pass.Award Chinese medicine external membrane of the present invention (10 × 3 × 0.12 × 3) sheet, change after 20 hours once, remove after 50 hours, change common dressing.Clinical follow patient's condition, Who Pain Grading 1 grade; Improvement VAS marks 3 points; Durante dolors 16 hours; But only dull pain does not affect rest, do not use analgesic dolantin, spirit is in rest state; Restoration of gastrointestinal function is good, passage of gas by anus, defecation after 48 hours.Take food after 59 hours; Out-of-bed activity after 65 hours.Wound healing is good, within postoperative 10 days, takes out stitches.Otch without red and swollen, ooze out, split and infect, classification II/Wound healing by first intention.Leave hospital after postoperative inspection is normal.
[case 2]: Lee, man, 58 years old, Diagnosis of Gastric carcinoma of gastric cardia, routine of being admitted to hospital did various Preoperative Method and inspection.In balanced anesthesia descending stomach carcinoma of gastric cardia radical operation.The long 16cm of epigastrium median incision.Anesthesia consumption 1% procaine 1g (complex liquid).Operation after cotton ball soaked in alcohol antiinflammatory, is pasted Chinese medicine external membrane (10 × 3 × 0.12) cm × 2 slice of the present invention, is changed pad pasting once, remove after 48 hours, change common dressing after 19 hours after terminating the abdomen stitching of rear pass.Clinical follow edge of a knife pain condition: Who pain divides 1 grade; Improve VAS and mark 3.2 points; Durante dolors 15 hours, belonging to dull pain does not affect rest, does not use analgesic, and restoration of gastrointestinal function 48 hours borborygmus recover, and 72 hours passage of gas by anus, defecations, take food after 76 hours, within 48 hours, get final product out-of-bed activity; Wound healing situation: take out stitches for postoperative 9 days, otch without red and swollen, ooze out, split and infect.Classification II grade/Wound healing by first intention.Clinical recovery is left hospital.
[case 3] 5 certain, female, 37 annual income institutes are diagnosed as cervical region thyroid tumor.Preoperative routine examination and preparation.(1%l lignocaine+0.2% tetracaine mixed liquor) row left side thyroidectomy under cervical plexus nerve block, operative incision 8cm, operation is well on, after terminating wound suture, and otch Chinese medicine external membrane of the present invention external application (10 × 3 × 0.12) cm a slice.Postoperative wound, without pain, does not use opioid analgesic.WHO 0 grade, VAS 0 grade, effective, within 24 hours, observe wound without oozing out, totally, within 36 hours, throwing off pad pasting, change common dressing into and leave hospital for 72 hours.
[case 4]. Chen, female 48 years old, because right newborn fibroma requires excision.Conventional preoperative every laboratory examination after being admitted to hospital.Excise right mastofibroma under local anaesthesia, long incision 4cm, operation smoothly, after myometrial suture, pastes Chinese medicine external membrane of the present invention external application (10 × 3 × 0.12) cm a slice.Postoperative wound is without pain, and do not use opiates and other analgesic, the edge of a knife does not ache, quiet sleep.WHO 0 grade, VAS 0 grade, effective.The recovery from illness of wound healing 1/ first class is left hospital.
[case 5], takes certain, and man, 49 years old, AD was esophageal carcinoma hypomere.Conventional preoperative planning and preparation is done in being admitted to hospital.Enter breast at descending left breast Esophageal cancer left-external side the 7th intercostal incision of the quiet general anesthesia of oxygen, otch is about 34cm operation through smooth, and 1.4.P.D.S intravenous anesthesia maintains.Cotton ball soaked in alcohol sterilization otch after closing breast also pastes Chinese medicine external membrane of the present invention external application (10 × 3 × 0.12) cm × 4 slice.Analgesic effect is good.The clinical follow state of an illness is as follows: WHO pain is 0 grade; Improvement VAS marks 2 points; Durante dolors 18 hours, dull pain, can quietly have a rest; Do not use the analgesic drug products such as dolantin; Spirit is in rest state; Wound healing situation: take out stitches for postoperative 14 days, otch without red and swollen, ooze out, Wound healing by first intention is left hospital.
[case 6]: Jiang, man, 48 annual income institutes are diagnosed as esophageal carcinoma hypomere.Carry out conventional preoperative planning and preparation.In the descending esophageal carcinoma of general anesthesia, the excision of hypomere pars cardiaca cancerous protuberance adds Reconstructive alimentary canal.Operation is well on, and sees that lump is positioned at esophagus hypomere and invades muscle layer in art, and with general anesthesia in art, perform the operation and to terminate to 13:30 from morning 9,14 tube drawings send ward back to safely.Postoperatively spread on operative incision outward with Chinese medicine external membrane of the present invention external application (10 × 3 × 0.12) cm × 4 slice.After operation in patients 16 completely clear-headed.18 points--24 patients have mild pain but can stand, and sleep unaffected, sleep soundly to peace and quiet next day and have a rest, breathe freely, without any discomfort.Within postoperative 8 hours, can stand up, cough without obvious pain, postoperative not with analgesic such as dolantins, local edge of a knife recovery from illness is good.
4. discuss:
4.1. curative effect general introduction:
4.1.1. illustrate that all kinds of open wound of Chinese medicine external membrane external application surgery of the present invention (operative incision) has good analgesic effect by clinical 205 examples (checking group: 123 examples, matched group: 82 examples): show: the evaluation result of comprehensive WHO grading and VAS scoring and postoperative use opioid analgesics.Its checking group incision analgesic curative effect total effective rate reaches 86.99% (effective 34.15%, effective 52.84%, invalid 13.01%); Matched group: effective nothing, naturally not bitterly 10.9%, invalid 89.02%; Two groups have notable difference P<0.01 through statistical procedures, and the pain relieving of checking group is clearly better than matched group.Chinese medicine external membrane research on maximum utilized quantity 4 (64.92g crude drug) of the present invention, minimum amount 1 (16.23g crude drug).
4.1.2. the post-operative incisional pain persistent period: checking group: 13.37 ± 7.04 hours; Matched group: 26.70 ± 11.07 hours, two groups of statistical procedures durante dolorses have notable difference P<0.01, and checking group pain time comparatively matched group highly significant shortens.
4.1.3. postoperative opioid analgesics: checking group 88.62% does not use dolantin, 11.38% uses dolantin, all measure: 8.94mg, matched group: 81.7% uses dolantin, 18.3% does not use dolantin, all measure: 62.20mg, two groups have notable difference P<0.01 through statistical procedures.The postoperative dolantin number of checking group is clearly less than matched group.
4.1.4. postoperative mental state: checking group: peace and quiet and quieter 87.00%, dysphoria, perspiration 13.00%; Matched group: quiet and quieter 10.98%, dysphoria 89.02%, two groups of statistical procedures have notable difference, and P<0.05. checking group postoperative mental state is in peace and quiet and more quiet number obviously more than matched group.
4.1.5. analgesia effect and incision length relation: Chinese medicine external membrane result of the present invention illustrates that operative incision and curative effect are without obvious relation, postoperative wound≤10cm total effective rate is 96.30%, 10--20cm total effective rate is 84.62%, >=20cm total effective rate is 76.74%.Through statistical procedures, P>0.05, not statistically significant.
4.1.6. the relation of analgesia effect and sex: illustrate that this group analgesia effect and sex are without obvious relation.
4.1.7. the relation at analgesia effect and age: this organizes Chinese medicine external membrane of the present invention for patient's incision analgesic effective percentage below <45 year is 92.16%, patient's incision analgesic effective percentage of >=45 years old is 83.33%, through statistical procedures P>0.05, without significant difference.Result illustrates: analgesia effect and age are without obvious relation.
4.18. Chinese medicine external membrane of the present invention can promote the early recovery of postoperative patient, find expression in: the postoperative borborygmus of checking group recover average time comparatively matched group shift to an earlier date 17.90%, checking group passage of gas by anus average time, comparatively matched group shifted to an earlier date 18.50%, checking group eating time comparatively matched group shifts to an earlier date 21.06%, and checking group out-of-bed activity average time, comparatively matched group shifted to an earlier date 23.55%.Two groups of statistical procedures have more than notable difference P<0.05. to illustrate the postoperative digestive function of Chinese medicine external membrane of the present invention recovers to have more obvious facilitation, be conducive to rehabilitation.Defecation time two groups of no difference of science of statistics.
4.2. safety evaluatio overview:
During Chinese medicine external membrane external application surgical incision position of the present invention, except 3 routine otch rednesses, without other untoward reaction.
5. conclusion:
Clinical observation result shows:
5.1. Chinese medicine external membrane external application operative incision (open wound face) of the present invention has good pain palliation efficacy, can partly replace or reduce the application of postoperative application central analgesia medicine dolantin, avoid or reduce the dependence of patient to opioid analgesics.Certain reality and positive role is had to treating narcotic addiction.
5.2. all kinds of operative incision of Chinese medicine external membrane external application surgery of the present invention can promote the recovery of postoperative digestive function and gastrointestinal function.Postoperatively can recover borborygmus, passage of gas by anus, feed and out-of-bed activity ahead of time, be conducive to rehabilitation.
5.3. Chinese medicine external membrane external application operative incision of the present invention is to whole body and otch local all without obvious adverse reaction and toxic and side effects, uses simply, facilitates.
5.4. Chinese medicine external membrane treatment surgical incision pain relieving feature of the present invention:
5.4.1 Chinese medicine external membrane content of dispersion of the present invention is large up to 68% release amount of medicine, and rate of release is fast, and percutaneous absorbtion dose is many, and blood drug level is high, the effect of the effective disease therapy of energy.
5.4.2 Chinese medicine external membrane of the present invention not with skin adhesion, do not affect local skin homergy and post-surgical incisions punishment secretion eliminating.
Implement 6: the clinical impact for easing pain after craniocerebral operations on pain mediator in human body cerebrospinal fluid (CSF) and inflammatory mediator of Chinese medicine external membrane.
1. summarize:
The Chinese medicine external membrane animal test of pesticide effectiveness of the present invention; The application of animal analgesia, antiinflammatory study mechanism and open clinical sexual trauma (post-surgical incisions) all illustrates that this pad pasting all has the effect of obvious analgesia, antiinflammatory to surgery open wound, is the mechanism of more its analgesia of further investigated, antiinflammatory.We select craniocerebral operations otch to apply with the patient of Chinese medicine external membrane of the present invention for this reason.Postoperative collection cerebrospinal fluid (CSF) detects the content of wherein induced pain, anti-pain and inflammatory mediator and preoperative contrast.So as to observing the change of these materials and the dependency with analgesia, antiinflammatory action.Its possible mechanism of further discussion.
Method: select craniocerebral operations patient 38 example, random point of checking group 22 example, blank group 16 example.Customary diagnostic waist is worn and postoperative 24 hours in the preoperative--within 36 hours, respectively gather CSF2--3ml, detect β-END (β-Nei calf peptide), L-ENR (enkephalin), analgesic matter and the SP materials such as LBSA (nerve sheath candy ester), algogenic substance and TNFa (tumor necrosis factor-ɑ) 1L-1 such as CGRP (calcitonin generelated peptide), NO (nitric oxide) b(interleukin-1 b) and the change of the inflammatory mediator quality such as NO (nitric oxide).
Result: Chinese medicine external membrane experimental group of the present invention is β-END (β-Nei calf peptide) compared with matched group, and L-ENR (enkephalin), LBSA (nerve sheath candy ester) content all increases or increase trend; SP material, CGRP (calcitonin generelated peptide), TNFa (tumor necrosis factor-ɑ) 1L-1 b(interleukin-1 b) content all comparatively matched group reduction or reduction trend; NO experimental group is postoperative than preoperative obvious decline.Conclusion Chinese medicine external of the present invention membrane has good postoperative antiinflammatory, analgesic activity, and its mechanism can by the increase of the anti-pain material of maincenter, and the reduction of algogenic substance, the suppression of inflammatory mediator realize.
2. method and material:
2.1 object of study: object of study is the patient accepting cerebral surgery operation treatment, sick kind comprises meningioma, glioma and chronic epidural and intracranial hematoma.Without endocrine, metabolic system disease; Other important organ no appreciable disease, does not preoperatively take or injects analgesics; Adult men and women does not limit.The patient selected to each example records its name, sex, age, body weight, operation names, anesthesia method, Anesthesia medicine amount, hepatic and renal function and electrocardiogram respectively.
The collection of 2.2 cerebrospinal fluid (CSF): spinal fluid samples all in the preoperative diagnostic waist is worn and postoperative (24--36 hour), observe intracranial hemorrhage etc. to need to take advantage of the occasion to gather, a 2--3mlCSF, be placed in the plastic test tube adding the aprotinin of 200 units in advance, put into-20 DEG C of refrigerators to keep in, after drying to be frozen, be placed in-80 DEG C of cryogenic refrigerators preservations in order to measuring.
β-END (β-Nei calf peptide) in 2.3 cerebrospinal fluid, L-ENK (enkephalin), SP material, CGRP (calcitonin generelated peptide) assay.Instrument is LDR4--84 DEG C of refrigerated centrifuge (Beijing Medical Centrifugal Machine Factory's production), ria-determination medicine box wherein β--END, L--ENK are provided by the large neural biological study room of Shanghai two army F1--2008P automatic γ immunity enumerator (state-run 262 factories produce); SP, CGRP are provided by PLA General Hospital development in science and technology center.
2.4 cerebrospinal fluid TNFa (tumor necrosis factor-ɑ), 1L---1 b(interleukin-1 b), NO (nitric oxide) assay: every part of lyophilizing sample 200ul distilled water redissolves, and measure content above-mentioned in pipe with double antibodies sandwich enzyme-linked method (ELISA), reagent kit is provided by Shenzhen Jing Mei biological engineering company limited.
The assay method of ganglioside lipid-bound sialic acid (LBSA) content in 2.5 cerebrospinal fluid, improvement isophthalic acid method, in experimentation, the acid of agents useful for same desalivation is Sigma company, outside providing, other is biochemical teaching and research group of Wannan Medical College and provides for oneself, and instrument is 80--1 centrifuge (Shanghai Surgical Operation Equipment Factory).ZFQ85A rotary evaporator (Shanghai Special Medical Appliances Factory).
3. date processing:
3.1. the data of each group represent with means standard deviation (X ± S), statistics between different group compares with ANOVA, continue with Newmankalls inspection, perioperative difference adopts paired t-test, using P<0.05 as the standard of statistical significance.
3.2 results:
3.2.1 patient's ordinary circumstance:
Participate in the Patients after Receiving Craniocerebral Operation totally 38 of research, wherein male 24, women 14, maximum 65 years old, minimum 17 years old, 40 years old mean age, be divided into the routine postoperative wound application of experimental group (E) 22 Chinese medicine external membrane of the present invention at random, the routine postoperative wound of matched group (C) 16 only uses Mobil dressing.
After grouping they sex, age, body weight, sick to plant, anesthesia and following group of observation index, experimental group and matched group pre-operative data add up P>0.05, without significant difference.
3.2.2. Chinese medicine external membrane induced pain of the present invention, anti-pain index content are observed.
The change of induced pain and anti-pain mediator in preoperative, the postoperative CSF of table 37.
(unit: be that mg/L outside all the other be ng/L. except NO is umol/L, LBSA)
Note: *: induced pain and the perioperative difference of anti-pain material are matched t and checked P<0.05;
*: induced pain and the perioperative difference of anti-pain material are matched t and checked P<0.01.
The change of matched group difference (postoperative, preoperative) induced pain and anti-pain mediator in table 38.CSF:
(unit: be that mg/L outside all the other be ng/L. except NO is umol/L, LBSA)
Pain mediator Experimental group Matched group
β-END －2.72±9.52 Δ －9.86±13.43
L-ENK 7.72±19.47 Δ －3.00±19.03
LBSA 0.43±1.55 Δ －0.48±1.47
SP 0.24±1.17 ΔΔ 1.80±1.43
CGRP －18.42±28.51 ΔΔ 7.84±34.35
NO 6.85±12.70 －2.98±23.82
Note: Δ: induced pain and anti-pain material experimental group and matched group adopt ANOVA, P<0.05
Δ Δ: induced pain and anti-pain material experimental group and matched group adopt ANOVA, P<0.01
The postoperative β of experimental group-END content is 14.99 ± 8.31ng/L, preoperative 17.71 ± 6.05ng/L, postoperatively have dropped 15.3% than preoperative, not statistically significant; The postoperative β of matched group-END content is 11.25 ± 4.98ng/L, preoperative 21.11 ± 12.69ng/L, postoperatively have dropped 46.70% than preoperative, has highly significant difference.Experimental group matched group difference β-END content is-2.72 ± 9.52ng/L; Matched group is-9.86 ± 13.43ng/L, and experimental group is more relative than matched group exceeds 72.40%, has statistical significance.
The postoperative L-ENK content of experimental group is 49.08 ± 19.42ng/L, and preoperative is 40.45 ± 14.6ng/L, has postoperatively exceeded 21.33% than preoperative, has statistical significance; The postoperative L-ENK content of matched group is 45.91 ± 17.76ng/L, preoperative 48.91 ± 17.73ng/L, postoperatively have dropped 6.10% than preoperative, on a declining curve, not statistically significant.Experimental group matched group difference L-ENK content is 7.72 ± 19.47ng/L; Matched group is-3.00 ± 19.03ng/L, and experimental group is more relative than matched group exceeds 3.57 times, and there were significant differences.
The postoperative LBAS content of experimental group is 3.56 ± 2.03mg/L, and preoperative is 3.13 ± 1.79mg/L, has postoperatively exceeded 13.74% than preoperative, in rising trend, not statistically significant; The postoperative LBSA content of matched group is 3.03 ± 1.74mg/L, preoperative 3.51 ± 1.66mg/L, postoperatively have dropped 13.68% than preoperative, on a declining curve, not statistically significant.Experimental group matched group difference LBSA content is 0.43 ± 1.55mg/L; Matched group is-0.48 ± 1.47mg/L, and experimental group exceeds 1.88 times than matched group, has significant difference.
The postoperative SP content of experimental group is 2.60 ± 0.64ng/L, and preoperative is 2.22 ± 1.08ng/L, has postoperatively exceeded 17.12% than preoperative, not statistically significant in rising trend; The postoperative SP content of matched group is 3.7 ± 1.48ng/L, preoperative 1.91 ± 0.61ng/L, postoperatively exceeds 93.70% than preoperative, has highly significant difference.Experimental group matched group difference SP content is 0.24 ± 1.17ng/L; Matched group is 1.80 ± 1.43ng/L, and experimental group is more relative than matched group have dropped 86.67%, has highly significant difference.
The postoperative CGRP content of experimental group is 37.60 ± 27.58ng/L, and preoperative is 56.02 ± 30.98ng/L, postoperatively have dropped 32.83% than preoperative, has highly significant difference; The postoperative CGRP content of matched group is 58.16 ± 33.20ng/L, preoperative 50.31 ± 30.81ng/L, has postoperatively exceeded 15.60% than preoperative, in rising trend, not statistically significant.Experimental group matched group difference CGRP content is-18.42 ± 28.51ng/L; Matched group is 7.84 ± 34.35ng/L, and experimental group have dropped 3.35 times than matched group, has highly significant difference.
3.2.3. Chinese medicine external membrane of the present invention is observed inflammatory mediator content:
The change (unit: except NO is umol/L, all the other are ng/L.) of inflammatory mediator in preoperative, the postoperative CSF of table 39.
Note: *: inflammatory mediator perioperative difference paired t-test P<0.05
*: inflammatory mediator perioperative difference paired t-test P<0.01.
The change (unit: except NO is umol/L, all the other are ng/L.) of matched group difference (postoperative-preoperative) inflammatory mediator in table 40.CSF
Inflammatory mediator Experimental group Matched group
TNFa 0.59±1.97 ΔΔ 3.55±3.26
IL-1 B －14.27±30.25 ΔΔ 37.50±40.50
NO －6.85±12.70 －2.98±23.82
Note: Δ: inflammatory mediator experimental group and matched group adopt ANOVA, P<0.05
Δ Δ: inflammatory mediator experimental group and matched group adopt ANOVA, P<0.01.
The postoperative TNFa content of experimental group is 8.24 ± 2.11ug/L.Preoperative is 7.65 ± 1.47ng/L, postoperatively exceeds 7.71% than preoperative, not statistically significant in rising trend; The postoperative TNFa content of matched group is 10.90 ± 4.09ng/L, and preoperative is 7.63 ± 1.79ng/L, postoperatively exceeds 42.86% than preoperative, has highly significant difference.Experimental group matched group difference TNFa content is 0.59 ± 1.97ng/L, and matched group is 3.55 ± 3.26ng/L, and experimental group is more relative than matched group have dropped 83.38%, has highly significant difference.
The postoperative IL-I of experimental group bcontent is 168.67 ± 26.57ug/L.Preoperative is 182.94 ± 33.23ng/L, postoperatively have dropped 7.80% than preoperative, has statistical significance; The postoperative 1L-I of matched group bcontent is 213.04 ± 46.32ng/L, and preoperative is 175.54 ± 26.51ng/L, postoperatively exceeds 21.36% than preoperative, has highly significant difference.Experimental group matched group difference 1L-I bcontent is-14.27 ± 30.25ng/L, and matched group is 37.5 ± 40.50ng/L, and experimental group is more relative than matched group have dropped 1.38 times, has highly significant difference.
The postoperative NO content of experimental group is 47.28 ± 11.12umol/L.Preoperative is 54.14 ± 13.61umol/L, postoperatively have dropped 12.67% than preoperative, has statistical significance; The postoperative NO content of matched group is 42.40 ± 12.37umol/L, and preoperative is 45.38 ± 17.94umol/L, postoperatively have dropped 6.57% than preoperative, not statistically significant on a declining curve.Experimental group matched group difference NO content is-6.85 ± 12.70u mol/L, and matched group is-2.98 ± 23.82umol/L, though experimental group have dropped 1.30 times than matched group, has downward trend not statistically significant through statistics.
4 discuss:
Surgery open wound (Post operation is one wherein) can produce two kinds of noxious stimulations, is first skin, muscle, blood vessel, neural comprehensive damage; Next is cutting part inflammatory reaction.They discharge K +, H +, the algogenic substance such as SP, 5-Ht, PGS imports cornu dorsale medullae spinalis or spinal nucleus of trigeminal nerve into through the teleneuron of A δ and C centripetal fiber, causes dorsal horn or corresponding neuronal excitation, release G/u, SP, GABA, 5-Ht, ENK, CGRP, NK 1deng, have activated NMDA and non-NMDA receptor makes nervus centripetalis granting constantly strengthen, easily changed noxious stimulation, bring out Dorsal Horn Neurons reaction.Reaction impulsion passes on lateral nuclear group in thalamus along on membrane of spinal cord lateral funiculus, causes the Hyperalgesia of periphery and maincenter.
There is β-lipase hormone in known nucleus arcuatus hypothalami, hypophysis, reticular formation of brain stem, periaqueductal gray, nucleus raphes dorsalis--β-END--ACTH nervous system, can synthesize β-END and ACTH, wherein nucleus arcuatus hypothalami hypophysis contains a large amount of β-END.Containing enriching the opioid such as enkephalin (ENK), dynorphin (DYN) in volt core, outside, septal area, corpus amygdaloideum.When the noxious stimulation of skin and internal organs import into can activate above central nuclei and discharge β-END, ENK, DYN concentrate and flow to PAG (periaqueductal gray).Cornu dorsale medullae spinalis can be passed to by descending nerve by nucleus raphes magnus (DRM), 5-Ht, suppress the transmission of pain signal.There is opioid peptide to coexist in some 5-Ht serotonergic neuron, discharge from tip after assigning spinal cord simultaneously; In addition, the prominent enkephalin serotonergic neuron of major axis to be gone directly spinal cord by PAG, and enkephalin release produces obvious anti-pain effect.Affected the activity of nucleus of thalamus (PF) unit by nucleus raphes dorsalis (DR), 5-Ht energy Ascending Fiber, thus realize the suppression to PF unit pain-related response.Recent study find, periphery noxious stimulation, can make cornu dorsale medullae spinalis c-fos expression product Fos increase and can suppress by OLS (opioid).Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH2 (SP) is a kind of excitatory transmitter of injury primary afferent termination release, transmits the effect of pain sensation information in spinal cord, and therefore noxious stimulation can bring out SP and increases, cause pain reaction and cornu dorsale medullae spinalis c-fos expression.Nearest isolated experiment also finds that falling calcium causes local pain sensation transmission because procatarxis related peptides (CGRP) can promote the release of primary afferent nerve fibers tip SP.
Ganglioside (GLS) is for containing sialic acidic glycosphingolipids.The difference of the sialic acid residues number contained by it, can be divided into GM 1, GD, GT, GQ etc., it is almost present in mammal nervous tissue, especially the highest with content in cerebral gray matter, mainly be distributed in generation and electric discharge that neurocyte plasma membrane outer page periphery noxious stimulation triggers the action potential of dystopy, abnormal sympathetic nerve change, can cause the transposition of cornu dorsale medullae spinalis I-VI layer of Protein kinase C (PKC) and activate increases, also cornu dorsale medullae spinalis NMDA/ non-NMDA receptor excessive activation can be caused, have activated receptor, promote the release of EAA in spinal cord on the one hand, cascade in active cell, comprises Ca in born of the same parents on the other hand 2increasing of concentration, PKC transposition activates to be increased, and makes the pain sensation sensitization of maincenter.
GM 1ganglioside be a kind of PKC transposition and activation born of the same parents in inhibitor, peripheral nervous can be weakened and CNS trauma institute induced pain is quick, for three days on end, intrathecal injection GM once a day 1ganglioside can prevent membrane of spinal cord in conjunction with the increase of PKC, also can prevent the generation of nociception behavior reaction, is a kind of analgesic matter.
LBSA can represent and reflect the content of GLS, and GM in the content of GLS 1be main component, therefore also reflect GM 1changes of contents, the data measured by this experiment show that experimental group LBSA content is apparently higher than matched group, and there were significant differences.The reinforcement of anti-pain effect is also described.
As everyone knows, NO-CGMP makes Ca in cell because noxious stimulation causes primary afferent fiber tip to discharge excitatory amino acid activation nmda receptor 2+concentration rising have stimulated NO synzyme (NOS) and acts on L-arginine (L-Arg) and generate NO.NO have activated sGC (GC-S) and causes target cell CGMP concentration to increase, protein phosphorylation, the conductance of ion channel changes, cause vasodilation, permeability increases, make inflammatory mediator and algogenic substance arrive site of action, indirectly facilitate the transmission of noxious stimulation.Local gives NO biosynthesis inhibitor N g-nitro-L arginine methyl esters (L-NAmE) suppresses the synthesis of NO, can the second stage of sole of the foot injection after dose-dependent inhibition formalin rat react analgesic and act on.Detection display in this group patient CSf: reduce obviously in the postoperative concentration of experimental group, and matched group reduces not obvious, the reduction of illustrative experiment group NO, the i.e. reduction of inflammation algogenic substance.Thus the enhancing of anti-pain effect is indirectly reflected.
Authors etc. detect in patient CSf before and after operative incision application Chinese medicine external of the present invention membrane has the β-END of anti-pain, L-ENK, LBSA and induced pain effect: the index that SP, CGKP, NO bis-kinds is contrary, found that experimental group postoperative β-END, L-ENK, LBSA compared with matched group all have increase or increase trend, and SP, CGKP, NO all have reduction or reduction trend.Thus author etc. think that the analgesic activity of Chinese medicine external membrane of the present invention may be to be absorbed the drug the release increase of the anti-pain material of the maincenter that excites and the reduction of algogenic substance by otch skin, caused by the expression suppressing cornu dorsale medullae spinalis C-fos.
NO, except mediating the transmission of the pain sensation, also tool promotes the effect of inflammatory reaction, makes vasodilation, increases inflammatory exudation, forms local swelling and erythema.At acute inflammation position, can induce to anti-inflammatory agent and inflammatory mediator and increase NO synthesis and release, by increasing regional flow, what promote blood plasma oozes out the formation with edema.This effect can by NG-monomethyl-L-arginine (L-NMMA) and L-NAMF to suppress and L-Arg can strengthen it.
Immunohistochemical study proves that the materials such as CGRP and SP, somatostatin, cholecystokinin coexist, promote the pain sensation transmission of spinal levels, promote the release of SP, it is not only maincenter and peripheral nervous system mediator, and is Anti-inflammatory mediator, in the CSF of this group patient, postoperative content checking group reduces and matched group increases, illustrate: CGRP with NO is the same, promote inflammatory reaction--local swelling, increase mediator--the pain of noxious stimulation.
Tumor necrosis factor (TNFa) is a kind of endogenous polytropism (Pleiotropic) protein factor produced by the Monocytes/Macrophages activated, it is one of important inflammatory cytokine, it has biological effect widely in vivo, and inducing inflammatory reaction participates in the effects such as Organism immunoregulation.Interleukin-1 (1L-1 b) be a kind of low-molecular-weight polypeptide class medium, participate in Growth of Cells, differentiation, inflammation, immunity and repair, equally with TNFa to be produced by intravascular cells neutrophilic leukocyte, mononuclear cell and lymphocyte, discharge primarily of paracrine or autocrine mode, play a role within the scope of a few cell.Already proved, TNFa and 1L-1 bthe equal adhesion that can promote vascular endothelial cell centering granulocyte (PmN).
Conclusion:
This group patient experimental group and matched group are than TNFa, the 1L-1 in postoperative CSf b, NO content all have reduction or reduction trend.Take a broad view of these three indexs to illustrate: Chinese medicine external membrane of the present invention may be play antiinflammation by the suppression to inflammatory cytokine and inflammatory mediator.
Inflammation and pain closely related to one another, reciprocal causation.Inflammation is secondary to tissue injury sexual stimulus; Inflammatory seep exacerbates again the transmission of noxious stimulation, finally cause operative incision local and maincenter hyperpathia, and Chinese medicine external membrane of the present invention may make maincenter algogenic substance reduce just, anti-pain material strengthens, the reduction of inflammatory mediator and the suppression of inflammatory reaction and play analgesia detumescence effect.
What induced pain, antiinflammatory and the inflammatory mediator index great majority measured herein were discharged by nerve nucleus in brain acting on cornu dorsale medullae spinalis by many synapses or flowing into the ventricles of the brain by hypophyseal portal system, therefore thinks that CSF makees sample more direct and reflect that it changes exactly than peripheral blood.
Conclusion:
Clinical verification shows:
Chinese medicine external membrane of the present invention has obvious postoperative antiinflammatory, analgesic activity.

Claims (9)

1. the application of pharmaceutical composition in preparation treatment surgery opening or closed injury, in described pharmaceutical composition, the weight proportion of each crude drug is:
2. application according to claim 1, in described pharmaceutical composition, the weight proportion of each crude drug is:
3. application according to claim 2, in described pharmaceutical composition, the weight proportion of a crude drug is:
4. treat the Chinese medicine external membrane of surgery opening or closed injury for one kind, comprise by weight: active ingredients of traditional Chinese medicine 60%-75%, film former 20%-32%, plasticizer 5%-10%, wherein active ingredients of traditional Chinese medicine is that the component comprising following weight portion Chinese crude drug is made:
5. the Chinese medicine external membrane for the treatment of surgery opening as claimed in claim 4 or closed injury, wherein active ingredients of traditional Chinese medicine is that the component including following weight portion Chinese crude drug is made:
6. the treatment surgery opening as described in claim 4-5 or the Chinese medicine external membrane of closed injury, comprise active ingredients of traditional Chinese medicine 71%, film former 23%, plasticizer 6% by weight.
7. the treatment surgery opening as described in claim 4 or 6 or the Chinese medicine external membrane of closed injury, it is characterized in that film former is selected from polyvinyl alcohol, Pioloform, polyvinyl acetal, polyvinylpyrrolidone a kind of or two kinds or multiple combination, preferably polyethylene alcohol.
8. the Chinese medicine external membrane of the open or closed injury for the treatment of surgery as described in claim 4 or 5, it is characterized in that plasticizer be selected from glycerol, triacetyl glycerine, ethylene glycol, sorbitol phthalic acid ester one or more, preferably glycerine.
9. the preparation method of the Chinese medicine external membrane of the open or closed injury of arbitrary treatment surgery in claim 4-8, is characterized in that it comprises the following steps:
Step one, in proportion the 15 taste medical materials such as Rhizoma Chuanxiong, Lignum Santali Albi, Radix Curcumae, Lignum Aquilariae Resinatum, Rhizoma Cyperi, Lignum Dalbergiae Odoriferae, Olibanum, Myrrha, Flos Chrysanthemi, Flos Caryophylli, the Radix Aucklandiae, Radix Angelicae Sinensis, the Radix Angelicae Dahuricae, Bulbus Allii Macrostemonis, Rhizoma Acori Graminei in prescription are added 2.5-4 times of water, with extraction by steam distillation volatile oil a;
Step 2, filtered by the water cooking liquid after above-mentioned extraction by steam distillation volatile oil, medicinal residues b is for subsequent use; Filtrate being condensed at 60 DEG C thick relative density is 1.12-1.15, add 1.7 times of 95% ethanol, make ethanol content be 60%, be stirred well to completely evenly, leave standstill 24 hours, draw supernatant, sediment fraction filters, and is reduced pressure by filtrate, reclaims ethanol, be condensed into magma c (relative density 1.15-1.17, temperature 60 C);
Step 3, Radix Salviae Miltiorrhizae, Radix Puerariae, Benzoinum, the Radix Astragali, Radix Paeoniae Rubra, Rhizoma Corydalis 6 taste medicine are added in the medicinal residues b in above-mentioned steps two, with 9 times amount alcohol reflux twice, 90% ethanol for the first time, second time 80% ethanol, filters, and twice filtrate is merged distilling under reduced pressure, be condensed into the thick paste d that relative density is 1.15-1.17, temperature 45-60 DEG C;
Step 4, depend on pine torch, Caulis Polygoni Multiflori is ground into coarse powder (crossing 20 mesh sieves), according to the percolation under fluid extract and extractum item, use 90% ethanol, about 10-12 times amount dipping 24h carries out percolation, collect percolate, reclaim ethanol, be condensed into thick paste e (relative density 1.15-1.17);
Step 5, by the thick paste e in the magma c in step 2, the thick paste d in step 3, step 4, i.e. c, d, e three thick paste mixing and stirring, add the volatile oil a in step one, then add Radix Notoginseng powder, Borneolum Syntheticum powder and Storax oil, whole mixing and stirring, make the total compound of active drug, be positioned in blender and stir, mixing homogenizing, makes medicine make the molecule of ultrafine particle.Leave standstill about 10-20 minute, remove minute bubbles after colloid mill, disappear completely to bubble, obtain active ingredients of traditional Chinese medicine f;
Step 6, mixs homogeneously the active ingredients of traditional Chinese medicine f manufactured in step 5 with film former and plasticizer, inserts masking in moulding machine medicine groove, dry rear demoulding;
Step 7, cuts into the specification that clinical wound area varies in size, to obtain final product.
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