Four, the specific embodiment
Below in conjunction with concrete condition the specific embodiment of the present invention is elaborated.
Provide by such scheme, the present invention in force, be to adopt to make by Rhizoma Coptidis 40-45g, Herba Hedyotidis Diffusae 130-150g, Fructus Forsythiae 100-110g, Radix Ilicis Pubescentis 130-150g, Radix Astragali 130-150g, Rhizoma Atractylodis Macrocephalae 100-110g, Radix Rehmanniae 130-150g, Herba Plantaginis 100-110g, Cortex Cinnamomi 40-45g and Radix Glycyrrhizae 80-88g, wherein that Fructus Forsythiae, Cortex Cinnamomi and the Rhizoma Atractylodis Macrocephalae is cataclasm, use vapor distillation, the device preservation is standby in addition to collect volatile oil and Aromatic water; Aqueous solution after medicinal residues and the distillation adds Rhizoma Coptidis, Herba Hedyotidis Diffusae, Radix Ilicis Pubescentis, the Radix Astragali, the Radix Rehmanniae, Herba Plantaginis and Radix Glycyrrhizae, add the water boiling and extraction 3 times of 6-10 times of medicine gross weight volume, each 1.5 hours, merge 3 times decoction liquor, filter, filtrate is concentrated in right amount, adds to concentrate 3 times of long-pending amount ethanol of liquid and leave standstill and made precipitation in 24 hours, gets the supernatant decompression recycling ethanol, adding water stirs evenly, leave standstill, get supernatant and filter, filtrate is concentrated into relative density greater than 1.04, add standby volatile oil and Aromatic water, add an amount of antiseptic, transfer to total amount, stir evenly, filter, fill, sterilization, promptly.
In concrete production, the present invention adopts Rhizoma Coptidis 42g, Herba Hedyotidis Diffusae 140g, Fructus Forsythiae 105g, Radix Ilicis Pubescentis 140g, Radix Astragali 140g, Rhizoma Atractylodis Macrocephalae 105g, Radix Rehmanniae 140g, Herba Plantaginis 105g, Cortex Cinnamomi 42g and Radix Glycyrrhizae 84g to make, wherein that Fructus Forsythiae, Cortex Cinnamomi and the Rhizoma Atractylodis Macrocephalae is cataclasm, use vapor distillation, the device preservation is standby in addition to collect volatile oil and Aromatic water 250ml; Aqueous solution after medicinal residues and the distillation adds Rhizoma Coptidis, Herba Hedyotidis Diffusae, Radix Ilicis Pubescentis, the Radix Astragali, the Radix Rehmanniae, Herba Plantaginis and Radix Glycyrrhizae decoct with water and extract 3 times, add water 10230ml and fry in shallow oil 1.5 hours for the 1st time, add water 8184ml the 2nd time and the 3rd time fried in shallow oil 1 hour at every turn, merge 3 times decoction liquor, filter, filtrate is concentrated into density greater than 1.04, the ethanol of 3 times of amounts of concentrated solution adding volume leaves standstill and made precipitation in 24 hours, get the supernatant decompression recycling ethanol, add water and stir evenly, leave standstill, getting supernatant filters, filtrate is concentrated into relative density greater than 1.04, adds above-mentioned standby volatile oil and Aromatic water, and adds an amount of antiseptic, adjust total amount to 1000ml, stir evenly, filter fill, sterilization, promptly.
In said medicine, the Rhizoma Coptidis bitter cold is gone into heart spleen two warps, and the merit of rushing down accumulation of heat in the heart and spleen is clearly arranged, thus be monarch drug, long-pending evanescence of heat then fire not scorching on, aphtha spontaneous recovery; Intimately clearly then heat is not disturbed the heart, and the mind is from peace, with Herba Hedyotidis Diffusae, Fructus Forsythiae helps the Rhizoma Coptidis heat-clearing and toxic substances removing, because of pyretic toxicity decocts nutrient blood, the pyrogenicity stasis of blood is handed over knot, more uses the Radix Ilicis Pubescentis heat clearing away again, both principal drug assistance heat-clearing and toxic substances removing, the purgation of spleen excess that clears away heart-fire again can blood circulation promoting and blood stasis dispelling, doublely control the hot stasis of blood, three medicines share and are ministerial drug, again because of heat impairing vital QI the moon, so use the Radix Astragali, Rhizoma Atractylodis Macrocephalae replenishing QI to invigorate the spleen, the blood stasis dispelling of Radix Rehmanniae removing heat from blood YIN nourishing, to cause small intestinal in small intestinal damp and hot because of heat in the heart moves again, so use the Herba Plantaginis clearing away heat and promoting diuresis, it is descending to lead heart-fire, the hot temperature of Cortex Cinnamomi, but the burnt yang-energy of relaxing the bowels with purgatives of warm nature, restoring normal coordination between the heart and kidney, both helped the Radix Astragali, the Rhizoma Atractylodis Macrocephalae, Radix Rehmanniae benefiting QI and nourishing blood is with promoting tissue regeneration and ulcer healing, draw heart-fire again and assign in kidney, more than four medicines be adjuvant drug altogether, Radix Glycyrrhizae is mended in the earth culture, coordinating the actions of various ingredients in a prescription, merit is held concurrently to help and is made, and all medicine compatibilities are supported mutually, play clearing away heat-fire altogether, eliminating toxic substances to remove stasis is held back skin ulcer, and the merit of supplementing QI and nourishing YIN cures mainly accumulation of heat in the heart and spleen, deficiency of both QI and YIN, the aphtha of type of hyperactivity of fire caused by deficiency of YIN.
Medicine of the present invention has clearing away heat-fire, supplementing QI and nourishing YIN, and skin ulcer is held back in blood stasis dispelling, cure mainly accumulation of heat in the heart and spleen, deficiency of both QI and YIN, type of hyperactivity of fire caused by deficiency of YIN aphtha, clinically see aphtha of the mouth and tongue, erosion and pain, thirsty flushed complexion, vexed insomnia, faint low voice, urine yellow skin, the few tongue of dimly red tongue, thready and rapid pulse without strength has unique curative effect for treatment oral ulcer of AIDS and recurrent oral ulceration, and has been obtained fully proving by clinical data.Relevant clinical data is as follows:
One, selects the standard of case
The recurrent oral ulceration clinical manifestation is that oral mucosa festers repeatedly, aphtha of the mouth and tongue, erosion and pain, thirsty flushed complexion, vexed insomnia, the few tongue of dimly red tongue, thready and rapid pulse without strength is not prolongedly healed, thereby influences functions such as diet, language, and ulcer has periodicity, recurrent, self limiting and painful, and all have the diagnosis and treatment patient of above-mentioned symptom all as the standard of selecting case.
Two, diagnostic criteria
Recurrent oral ulceration (claiming aphtha again) can be divided into minor aphtha, periglandular aphthae according to incidence, and its diagnostic criteria is:
Minor aphtha: the little and shallow number of ulcer is few, 1-3, the 1-2mm size more shallow, redness is outstanding, neat in edge has blush, substrate is recessed slightly smooth, healing in general 7-10 days, healing preventing from scar.
The stomatitis aphtha: claim herpetic aphtha again, the ulcer table is shallow smooth irregular, can go out the small rice grain size to the Semen Viciae fabae size, and number can reach dozens of, can merge mutually, has yellow to ooze out, and congested on every side obviously scope is big, and pain is obvious.
Periglandular aphthae: claim huge aphtha again, ulcer exists greatly and deeply, is cratering, and the ulcer area can reach above normal isolated generation of 1cm, also can several take place simultaneously, the edge is high to be risen obviously, and hyperemia is work or apparent dark red not, the long indolence of the course of disease can reach 1 month to the several months, and it is good to leave scar after the healing.
Diagnosis basis:
The ulcer of single or several diameters 3-5mm occurs with oral mucosa, scorching hot pain is cardinal symptom; Examination of mouth: stomatocace is circular or oval, 1-2 at least of quantity, and individual surplus in the of 10 at most, the surface has faint yellow secretions to adhere to, and mucosa is congested mostly around the ulcer.
Primary symptom: ulcer, spontaneous pain, excitation pain.
Inferior disease: vexed impetuous, mouthful hot xerostomia, yellowish urine dry stool.
Check: stomatocace contrafluxion edema, pseudomembrane is oozed out on the ulcer surface, and the neat in edge base is smooth, and ulcer is rounded or oval, has blush to center on every side.
Dialectical foundation:
Accumulation of heat in the heart and spleen, deficiency of both QI and YIN, type of hyperactivity of fire caused by deficiency of YIN
Primary symptom: disease is seen aphtha of the mouth and tongue, erosion and pain, thirsty flushed complexion, vexed insomnia, faint low voice.
Inferior disease: dizziness, headache, cardiopalmus, five heat in the heart, spontaneous sweating, weak breath, dryness of the mouth and throat, urine yellow skin.
Tongue fur: the few tongue of dimly red tongue.
Pulse condition: count accurately unable.
Three, therapeutic scheme
Every day, oral mixture of the present invention was 3 times, and each 10-20ml when taking, contains 3-5 minute with mixture earlier in mouth, and under the clothes, 5 days is a course of treatment then.
Four, efficacy assessment standard
1, recurrent aphtha efficacy assessment standard
Clinical recovery: medication 3 days obviously alleviates with interior symptom, sign, and medication 5 days is with interior symptom, not levy disappearance.
Produce effects: medication 5 days obviously alleviates with interior symptom, sign, and integration reduces 〉=70%.
Effectively: medication 5 days alleviates with interior symptom, sign, and integration reduces 〉=30%.
Invalid: medication 5 days does not all have obvious improvement with interior symptom, sign, even increase the weight of, integration reduces less than 30%.
2, recurrent aphtha disease and sign curative effect determinate standard
Clinical recovery: individual event symptom, sign medication 3 days obviously alleviate with interior symptom, sign, and medication 5 days disappears with interior symptom, sign, and integration reduces 〉=95%.
Produce effects: individual event symptom, sign medication 5 days obviously alleviate with interior symptom, sign, and integration reduces 〉=70%.
Effectively: individual event symptom, sign medication 5 days alleviate with interior symptom, sign, and integration reduces 〉=30%.
Invalid: individual event symptom, sign medication 5 days all do not have obvious improvement with interior symptom, Signs, even increase the weight of, integration reduces less than 30%.
Annotate: computing formula (nimodipine method): [integration 1 * 100% before (integration one treatment back integration before the treatment) ÷ treatment].
3 traditional Chinese medical science aphtha efficacy assessment standards
Cure: oral ulcer healing, local no sense of discomfort;
Take a turn for the better (effectively): though recur sometimes in the oral cavity, quantity reduces, and degree alleviates;
Do not heal (invalid): oral cavity symptom and ulcer do not have significant change.
Five, statistical procedures
A, to oral ulcer of AIDS treatment situation, all be Han nationality through 60 people's MethodsThe cases enrolled, occupation is complete to be the peasant, medical history provides by the patient, all be to infect through the blood approach, male 14 people are organized in treatment, women 16 people, age is 42.8 ± 5.4 years old, matched group man 17 people, women 13 people, the age is 44.7 ± 6.2 years old, through checking two groups of sexes, age isobase data difference not statistically significant (P>0.05), its line unanimity.
Treatment group: mixture of the present invention, every bottle of 100ml, each 30ml, every day three times, buccal.
Matched group: the nystatin sheet, every 500,000 unit, each 1, every day three times, oral; External nystatin suspension rinse, each 5ml contains 5 minutes, every day three times.
1 week was 1 course of treatment, observed 2 courses of treatment continuously, and 2 weeks followed up a case by regular visits to after the drug withdrawal.
Curative effect relatively sees the following form between two groups:
Group |
n |
Recovery from illness |
Produce effects |
Take a turn for the better |
Invalid |
Effective percentage (%) |
Total effective rate (95%CI) |
The treatment group |
30 |
24 |
6 |
0 |
0 |
100 |
100 |
Matched group |
30 |
12 |
5 |
7 |
6 |
80 |
77.4-82.6 |
The effective percentage that shows the treatment group in the table is 100%, and total effective rate (95%CI) is 100%; The effective percentage of matched group is 80%, and total effective rate (95%CI) is 77.4-82.6%.The difference that curative effect constitutes between group has significant statistical significance (P<0.05) on α=0.05 level, can think that mixture of the present invention is better than the nystatin sheet to this ground oral ulcer of AIDS curative effect.
B, warp are to recurrent aphtha (ulcer) patient 128 examples, male 48 examples (37.5%), women 80 examples (62.5%); Age 14-70 year, maximum 70 years old, minimum 14 years old, wherein 14-20 year 8 examples (6.3%), 21-30 year 36 examples (28.1%), 31-40 year 32 examples (25.0%), 41-50 year 24 examples (18.6%), 51-60 year 20 examples (15.6%), 61-70 year 8 examples (6.3%), 39 ± 14 years old mean age; The course of disease is the longest to be 6 years, and the shortest is 1 day, 100 examples (78.1%) below 3 months wherein, 8 examples (6.3%) in 3 months-3 years, 20 examples (15.6%) in 3 years surplus-6 years, average course of disease 323 ± 585 days; The maximum gross area of ulcer is 60mm
2, minimum is 2mm
2, 2-20mm wherein
248 examples (3.8%), 21-40mm
256 examples (43.8%), 41-60mm
228 examples (21.9%), the average gross area is 27 ± 15mm
2Ulcer quantity mostly is 6 most, and minimum is 1,1-3 56 examples (43.8%) wherein, and 4-6 72 examples (56.3%), mean number is 3 ± 1; Differential diagnosis in tcm belongs to accumulation of heat in the heart and spleen 120 examples (93.8%), resistance prosperous 8 examples of asthenic fire (6.3%).Carried out antibiotic therapy among the 128 routine patients and do not have a positive effect 60 examples (46.9%) are arranged, above-mentioned case is selected from July, 2005 to 2006 a year outpatient service in the February patient that seeks medical advice.
By above-mentioned therapeutic scheme, its statistical result such as following table:
As seen from the above table, the present invention is effective good medicine of treatment recurrent oral ulceration, and clinical meaning is outstanding.
Six, zoopery situation
In order to guarantee that curative effect and patient take safety, the present invention utilizes animal to do necessary test, and its situation is as follows:
1, to the bullate influence of mice auricular concha caused by dimethylbenzene xylene
Get 50 of body 18-21g male mices; evenly be divided into 5 groups at random; be respectively big; in; low dose of mixture (20g/kg of the present invention; 10g/kg; 5g/kg; 1g/ml; 0.5g/ml; 0.25g/ml 0.2ml/10g is equivalent to 20 times of clinical consumption respectively; 10 times; 5 times); kouyanqing granules suspension (3.3g/kg; 0.167g/ml 0.2ml/10g is equivalent to 10 times of clinical consumption) and with the normal saline of volume; administration every day 1 time; successive administration 3 days, 1h after last 1 administration, every Mus auris dextra are coated with dimethylbenzene 0.04ml (the positive and negative 0.02ml that all is coated with); 4h after giving dimethylbenzene; take off cervical vertebra and put to death mice, cut ears, alignment; lay the ears auricle with the 9mm card punch; use rapidly scales/electronic balance weighing, and calculate the swelling degree, result such as following table (swelling degree=auris dextra heavy-left ear weight).
Group |
Number of animals |
Dosage (the g crude drug in whole/kg) |
Swelling degree (mg) |
The normal saline group |
10 |
|
7.0±1.6 |
The kouyanqing granules group |
10 |
3.3 finished product |
3.6±1.5
** |
The routed clever mixture group of heavy dose of Chinese mugwort |
10 |
20 |
2.3±1.5
** |
The routed clever mixture group of middle dosage Chinese mugwort |
10 |
10 |
3.5±1.5
** |
The routed clever mixture group of low dose of Chinese mugwort |
10 |
5 |
4.7±1.4
** |
* represent with the normal saline group than P<0.01, the Chinese mugwort clever mixture of bursting is mixture of the present invention, and is as follows.
As seen from the above table, respectively organize no significant difference (P>0.05) between the rat normal foot sole of the foot volume before the administration, illustrate that grouping evenly.Compare with normal saline, the routed clever mixture group of heavy dose of Chinese mugwort all can significantly suppress rat Ovum Gallus domesticus album pedal swelling (P<0.01) at administration 30-360min; The routed clever mixture group of middle dosage Chinese mugwort can obviously suppress rat Ovum Gallus domesticus album pedal swelling (P<0.05) at administration 30min, 120min and 240min, all can obviously suppress rat Ovum Gallus domesticus album pedal swelling (P<0.05) at administration 60min and 360min; The routed clever mixture group of low dose of Chinese mugwort all can obviously suppress rat Ovum Gallus domesticus album pedal swelling (P<0.05) at administration 30-360min; The kouyanqing granules group all can obviously suppress rat Ovum Gallus domesticus album pedal swelling (P<0.05) at administration 30-360min.
Mixture of the present invention is given mouse gavaging for three days on end, and it is swollen significantly to suppress mice auricular concha caused by dimethylbenzene xylene; Give rats gavaged for three days on end, can significantly suppress rat Ovum Gallus domesticus album pedal swelling.
2, to the influence of Cavia porcellus oral ulcer model
Get 60 of 270-300g Cavia porcelluss, male and female half and half, be divided into 6 groups at random, wherein make the oral ulcer model, method for 5 groups: use the etherization Cavia porcellus, it is glass tubing 1 end (making it concordant with the mouth of pipe) of 5mm that one cotton pellet is placed diameter, again glass pipe close cotton balls one end is dipped in 90% phenol solution, calcination Guinea Pig Left side cheek 60sec observes behind the 24h, the ulcer that all occurs diameter 5mm on the Cavia porcellus oral mucosa illustrates and makes the film success.After other gets the anesthesia of 10 Cavia porcelluss, be placed on Guinea Pig Left side cheek 60sec after dipping in normal saline with the glass tubing of filling in cotton balls, as the blank group.With 5 groups of modeling type, be coated with the routed clever mixture (1g/ml, 0.5g/ml, 0.25g/ml) of large, medium and small dosage Chinese mugwort 1 time every day respectively, be placed on the Cavia porcellus oral ulcer 3min of place after dipping in corresponding medicinal liquid 0.5ml with Disinfectant absorbent cotton, gavage with regard to medicinal liquid by 1ml/100g respectively then; Kouyanqing granules suspension group as stated above; after dipping in corresponding medicinal liquid 0.5ml with absorbent cotton; be placed on the 3min of oral ulcer place; gavage for then Cavia porcellus again by 1ml/100g; after model group is dipped in the 0.5ml normal saline with Disinfectant absorbent cotton; apply at the Cavia porcellus oral ulcer 3min of place; gavage normal saline then with volume; administration every day 1 time, continuous use 5 days was in the 1st day; 3 days; photographed Cavia porcellus oral ulcer situation (focal length 3cm with the digital picture head in 5 days; photograph is apart from 2cm); be used to calculate the ulcer area, in the 1st; 2; 3; 4; 5 days, press the ulcer level judgment criteria every day and estimate Cavia porcellus oral ulcer situation.2h after medication in last 1 day, after judgment criteria evaluation Cavia porcellus oral ulcer degree, put to death Cavia porcellus, take off the oral ulcer part, 10% formalin fixed, the embedding of stone vinegar, section, microscopy is observed and is respectively organized Cavia porcellus oral cavity tissue form situation (the blank group is got the local organization of the position of corresponding oral ulcer), and the result is:
The ulcer level judgment criteria
" 0 " no ulcer, oral mucosa is normal;
" I " has ulcer, the no obvious pseudomembrane in ulcer surface;
There is thin one deck yellow-white pseudomembrane on " II " ulcer surface, does not have edema on every side;
" III " ulcer surface pseudomembrane is thicker, and on every side with inflammatory edema;
" IV " ulcer surface pseudomembrane is thick, on every side with obvious inflammatory edema.
To the influence of Cavia porcellus oral ulcer model ulcer area (x ± s)
* represent with model group than P<0.05, * * represent with model group than P<0.01
As seen from the above table, the blank group does not have ulcer, and with blank group ratio, model group ulcer is (P<0.01) significantly, and the success of modeling ulcer model is described.The 1st day, except that the blank group, each organized no significant difference between the ulcer area, illustrated respectively to organize institute's modeling type basically identical, and grouping evenly.Compare with model, all can make the ulcer area significantly reduce (P<0.01) in medication the 3rd day, the routed clever mixture group of large, medium and small dosage Chinese mugwort and kouyanqing granules group; Medication the 5th day, heavy dose of Chinese mugwort clever mixture group of bursting can make the ulcer area significantly reduce (P<0.01), in, burst clever mixture group and kouyanqing granules group of low dose of Chinese mugwort make the ulcer area obviously reduce (P<0.05).
Mixture of the present invention is to the influence of Cavia porcellus oral ulcer model tissue morphology
"-" oral mucous epithelia is complete, and mucosa is that squamous epithelial cancer covers, and tela submucosa is loose connective tissue, is muscular tissue below the hair follicle body of gland; "+" stomatocace dwindles 2/3, and 1/3 the ulcer area of surplusing is repaired by new life's granulation tissue; " ++ " stomatocace dwindles 1/2, and 1/2 the ulcer surface of surplusing is repaired by new life's granulation tissue; " +++" stomatocace dwindles 1/3, or does not dwindle, and 2/3 the ulcer surface of surplusing is repaired by new granulation tissue.
Find out from last table, check through Ridit, with blank group ratio, model group oral ulcer lesion tissue serious (P<0.01), illustrate and make the success of Cavia porcellus oral ulcer model,, check through Ridit with the model group ratio, clever mixture group and kouyanqing granules group oral ulcer histopathology minimizings (P<0.01) that be changed significantly of bursting of dosage big or middle Chinese mugwort, the low dose of Chinese mugwort clever mixture group of bursting also has the trend that alleviates the variation of oral ulcer pathology.
3, toxicity test
Get 20 of mices, male and female half and half, body weight 18-22g, fasting (can't help water) 12h before the experiment, the maximum volume (0.4ml/10g) that can gavage by mice is irritated the Chinese mugwort that can gavage concentration with maximum clever mixture suspension (the 4.667g crude drug in whole/ml), and connected and irritate each 8h at interval 3 times of bursting within 1 day.Give animal with normal diet then, observed continuously 7 days, it is dead not see that mice occurs.Rarely seen animal has minimizing just for the medicine activity slightly, and the activity of the 2nd time and the 3rd time administration reduces, and mice is movable behind the general administration 2-3h recovers normal; The jaundice slightly of the 1st day visible mice urine, stool rubicundity, rare slightly, diet and drinking-water reduce; Visible mice stool color was rubescent slightly, rare slightly in the 2nd day, but was shaped, and diet and drinking-water reduce slightly; The 3rd day mice is complete to recover normal, do not see diet is arranged, hair color, two just, autonomic activities etc. obviously unusual.Weigh behind the 7th day mice fasting (the can't help water) 12h, put to death, dissect mice again, the obviously unusual of macroscopic liver, the heart, spleen, lung, kidney, stomach, intestinal, brain etc. do not arranged.
From the above, mixture toxicity of the present invention is very little, the maximum volume that can gavage with mice is given the mixture suspension of the present invention of Cmax, death does not appear in mice, accumulating maximum tolerated dose its every day is 560g/kg, this medicine has been more than 540 times of clinical application amount, shows that fully mixture clinical drug safety of the present invention is nontoxic.
Seven, conclusion
Shown clearly that by above-mentioned clinical and zoopery mixture of the present invention is a treatment recurrent oral ulceration active drug, effective percentage is up to more than 99%, having no side effect, outstanding clinical meaning is arranged, is that one on the treatment by Chinese herbs oral ulcer disease invented greatly, apply, economic and social benefit is huge.