CN1179726C - Application of naringin in preparing medicine for supporting treatment of SARS - Google Patents
Application of naringin in preparing medicine for supporting treatment of SARS Download PDFInfo
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- CN1179726C CN1179726C CNB031269087A CN03126908A CN1179726C CN 1179726 C CN1179726 C CN 1179726C CN B031269087 A CNB031269087 A CN B031269087A CN 03126908 A CN03126908 A CN 03126908A CN 1179726 C CN1179726 C CN 1179726C
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- naringin
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- 239000001606 7-[(2S,3R,4S,5S,6R)-4,5-dihydroxy-6-(hydroxymethyl)-3-[(2S,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyloxan-2-yl]oxyoxan-2-yl]oxy-5-hydroxy-2-(4-hydroxyphenyl)chroman-4-one Substances 0.000 title claims abstract description 109
- DFPMSGMNTNDNHN-ZPHOTFPESA-N naringin Chemical compound O[C@@H]1[C@H](O)[C@@H](O)[C@H](C)O[C@H]1O[C@H]1[C@H](OC=2C=C3O[C@@H](CC(=O)C3=C(O)C=2)C=2C=CC(O)=CC=2)O[C@H](CO)[C@@H](O)[C@@H]1O DFPMSGMNTNDNHN-ZPHOTFPESA-N 0.000 title claims abstract description 109
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- 239000003814 drug Substances 0.000 title claims abstract description 48
- 201000003176 Severe Acute Respiratory Syndrome Diseases 0.000 title claims description 21
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- Medicinal Preparation (AREA)
Abstract
The present invention relates to the application of naringin to the preparation of a medicine for supporting the treatment of atypical pneumonitis. A naringin medicine which takes naringin as an effective component has the favorable functions of stop cough and relieving phlegm, and has a conspicuous curative effect on acute bronchitis, chronic bronchitis, chronic obstructive emphysema, severe respiratory failure syndrome, etc. without toxic and side effects. Therefore, the naringin medicine can be used for preparing a medicine for supporting the treatment of atypical pneumonitis.
Description
Technical field
The present invention relates to the purposes that naringin is used to prepare supportive treatment severe acute respiratory syndrome (SARS) medicine.
Background technology
Severe acute respiratory syndrome, full name are that (Severe Acute Respiratory Syndrome SARS), is called for short SARS to severe acute respiratory syndrome." atypical pneumonia " this speech just put forward as far back as 1938, had found abroad that at that time a kind of clinical manifestation is different from the pulmonary infection disease of common pneumonia fully.Usually pneumonia mainly is to be caused by streptococcus pneumoniae, shows as the hyperpyrexia shiver with cold, coughs a large amount of rust purulent sputums, dyspnea, and blood leukocytes raises, and the whole body poisoning symptom is serious, before antibiotic such as penicillin occur, is the very high serious symptom of a kind of case fatality rate.And newfound pneumonia mainly shows as slight respiratory tract infection symptom, as heating (low grade fever is main), dry cough, breathe hard, symptom is low weight, and there is the patch shape in rabat pulmonary, netted shade, leukocyte is not high yet, at that time its called after " atypical pneumonia ", to be different from typical streptococcus pneumoniae property pneumonia.Found to cause common the having of pathogen of this pneumonia afterwards: mycoplasma, chlamydia, legionella, adenovirus and some more rare viruses, as respiratory syncytial virus, parainfluenza virus etc.
Popular SARS is caused by coronavirus in China for the previous period.For severe acute respiratory syndrome,, will develop into the degree of respiratory failure as untimely treatment.Antiviral drugs commonly used, steroid medicine treatment and general Supporting Therapy, the course of treatment is more than 20 days, 96-97% prognosis bona.Poor prognosis person is the shortest, and sb.'s illness took a turn for the worse within 5 days, serious symptoms of pneumonia occurs, and mortality rate is at 5-10%.
The treatment severe acute respiratory syndrome does not temporarily have specific drug at present, and what take mainly is " supporting treatment " and " symptomatic treatment ".At first be to allow patient have a rest, liquid make-up has additional nutrients, and the close observation PD improves patient's self immunity and resistance.There are situations such as shade in the pulmonary of breaking forth if carrying out property dyspnea, hypoxemia, X-ray sheet have appearred in patient, and the doctor also can carry out the treatment of three aspects to it.At first, put on to patient and can support the face shield or the nose cup of ventilating to provide oxygen with certain pressure, to prevent further withering of alveolar.If patient's pulmonary infection continues to increase, except antiinflammatory, may also can add and use 17-hydroxy-11-dehydrocorticosterone.At last, in a single day insecondary bacterial infection appears in patient, also will adopt positive antibiotic therapy.Just treatment at present, the doctor can support that patient strengthens autoimmunity after taking said method, tide over onset peak period, and virus will fall after rise naturally afterwards, and patient also will fully recover gradually.The patient's great majority of leaving hospital of having fully recovered belong to this situation, and therefore present Therapeutic Method be we can say still effectively.”
" supporting treatment " has important effect in the treatment of severe acute respiratory syndrome, seek newly for the effective supportive medicine of severe acute respiratory syndrome, will have great importance to effective control and treatment severe acute respiratory syndrome.
The structural formula of naringin:
Summary of the invention
The purpose of this invention is to provide naringin is used for supportive treatment severe acute respiratory syndrome medicine in preparation application.
The present invention is through experiment confirm, and naringin is to acute and chronic bronchitis, and diseases such as cough with copious phlegm have tangible curative effect.
We test by pharmacological effect, to the experimentize cough-relieving experiment of animal white mice of naringin.The result shows: naringin causes the tolerance time of cough to stimulating mice, compares with the blank group, and significant prolongation is all arranged, and there were significant differences statistically; Compare with positive control medicine dextromethorphan hydrobromide tablets, tolerance time prolongs, and curative effect is remarkable than positive control medicine dextromethorphan hydrobromide tablets.
The naringin that experiment showed, of the present invention not only has the acute and chronic bronchitis of good treatment, the curative effect of cough with copious phlegm, and in mouse animal experiment, almost do not show toxicity.Zoopery shows, when the naringin oral administration animal of 900mg/kg dosage, animal does not see toxic reaction, and it is 3-8g naringin/kg body weight that this dosage is equivalent to people's taking dose.
In sum, illustrate that naringin has good cough-relieving, the effect of reducing phlegm, do not see toxic and side effects, can alleviate the symptom of SARS patient, therefore, can be used for preparing the medicine (naringin medicine) of supportive treatment severe acute respiratory syndrome.
The present invention above-mentioned said be the naringin medicine that is used for supportive treatment severe acute respiratory syndrome of effective ingredient preparation with the naringin, can contain the 0.1-100%wt. naringin in its composition.Said naringin medicine can be made up of the naringin monomer merely, perhaps is made up of with other effective ingredient or/and conventional pharmaceutical aids the naringin as effective ingredient.
Above-mentioned said naringin medicine can be fit to the conventional adjuvant of corresponding dosage form or not add adjuvant by selecting, and is prepared into the pharmaceutical preparation of required different dosage form with conventional method.The adjuvant that adds can be solid, semisolid or liquid substance, as carrier, excipient or the medium of naringin.Therefore, said naringin pharmaceutical preparation can be tablet, powder, sachets, elixir, suspensoid, Emulsion, solution, syrup, aerosol, soft or various dosage forms such as hard capsule, aseptic parenteral solution.
The capsule of above-mentioned said naringin medicine, its inclusions contains the naringin of 0.5-100%wt.; Usually can form by the naringin that is no less than 0.5%wt. and other effective ingredient or/and various conventional adjuvant.The tablet of said naringin medicine contains the naringin that is no less than 0.1%wt. in its composition; Can form by the naringin that is no less than 0.1%wt. and other effective ingredient or/and various conventional adjuvant.
To the treatment tracheitis, cough with copious phlegm has better curative effect to naringin medicine of the present invention in 0.1-500mg naringin/kg body weight/day, and preferred daily dose is about 1-100mg naringin/kg body weight.
Naringin medicine of the present invention has good cough suppressing effect, can effectively carry out Supporting Therapy to the severe acute respiratory syndrome patient.And have characteristics such as steady quality, dose is little, curative effect is rapid.
The said naringin of the present invention can be from containing the various medical materials of naringin, Fructus Aurantii for example, and Exocarpium Citri Grandis, Fructus Aurantii Immaturus, Citrus, Fructus Citri Limoniae, grapefruit, dried tangerine peel is extracted naringin crude product or the naringin monomer (pure product) that obtains in the various medical materials such as orange.The method of extracting can be carried out according to following steps: pulverizing medicinal materials, and one to multiple inferior through water extraction, filter merging filtrate; Filtrate is condensed into extractum, and upper prop or direct upper prop carry out post and separate the organic solvent eluting behind the extractum precipitate with ethanol; Eluent volatilizes solvent, gets the naringin crude product, and repeatedly recrystallization gets naringin monomer (pure product).
The said naringin of the present invention also can be according to Rosenmund (Rosenmund, Ber., 61,2608 (1958)) and Zemlen, and the method that Bognar (Ber., 75,648 (1942)) describes and other chemical method are synthesized and obtained.
The specific embodiment
The present invention is described further below in conjunction with embodiment.
Solid among each embodiment in the related solid mixture, the liquid in the liquid, and the solid percentage ratio in the liquid is respectively with wt/wt, and vol/vol, wt/vol calculates, except as otherwise noted.
The cough-relieving pharmacological experiment of embodiment 1. naringin medicines
1. laboratory animal: the NIH mice, male, body weight 18.2-21.7g, regular grade standard, totally 60.Earlier animal is weighed, numbering is selected healthyly, and body weight is totally 45 of the mices of 18.5-21.0g gram.By the ordering of body weight size, be divided into three groups with randomized blocks, 15 every group.If negative control group, positive controls and naringin drug sample group.
2. sample source and processing:
1) blank group: normal saline, NaCl content 0.9%.
2) positive controls: get two of dextromethorphan hydrobromides and be dissolved in 20 ml physiological salines, promptly get the positive control Dextromethorphan Hydrobromide Solution, dextromethorphan hydrobromide concentration is 1.5mg/ml.
3) naringin sample sets: it is an amount of to get naringin, and in volumetric flask, naringin concentration is 1.6mg/ml with the normal saline standardize solution.Used naringin sample is that purity is more than 95% according to the method noted earlier naringin monomer of medicinal material extract therefrom.
3. experimental technique: (strong aqua ammonia nebulization)
Behind the mouse stomach 1 hour, begin to accept spraying.Spray into the strong aqua ammonia aerosol by certain hour, spraying finishes, and takes out mice immediately, observes to have or not the cough reaction.Observe the number of times of coughing in a minute,, can be regarded as " cough is arranged " if occur typical case's cough action (abdominal muscle shrinks or the breast that contracts, and magnifies mouth simultaneously, can cough sound sometimes) person more than 3 times in 1 minute.Otherwise can be regarded as " not having cough ".
4. experimentation:
Obtain the spray time (EDT that causes the half mouse cough with sequential method (going up purgation)
50).Calculate the R value, if the R value greater than 130%, illustrates that medicine has antitussive action.If the R value is greater than 150%, then showing has significant antitussive action.Computing formula is as follows:
EDT
50=log
-1C/n, n is a number of animals in the formula, and c is the summation of rx value, and r is the number of animals of every dosage group, and x is the logarithm of dosage (being spray time).
5. experimental result:
By statistics, each sample sets half cough time and cough suppressing effect see Table 1.
The cough suppressing effect of each sample of table 1.
The group sample concentration
Dosage
The cough-relieving of R value
(mg/ml) EDT
50
Code name sample name (ml/20g)
(%) effect
(second)
1 normal saline group 0 40.52--
2 dextromethorphan hydrobromide groups 0.2 1.5 56.82 140.23 are effective
3 naringin medicine groups, 1.6 65.53 161.72 produce effects
From naringin sample and positive control medicine dextromethorphan hydrobromide, oral administration causes that to stimulating mice the tolerance time of cough compares, naringin has significant prolongation to the mice tolerance time, and longer than the tolerance time of positive control medicine dextromethorphan hydrobromide, there were significant differences statistically.Illustrate that naringin causes that to stimulating mice the tolerance time of cough and dextromethorphan hydrobromide compare, tolerance time prolongs, and is evident in efficacy.
The pharmacological experiment that reduces phlegm of embodiment 2. naringin medicines
1. animal:
The NIH mice, male, body weight 17.9-22.1g, the cleaning grade standard, the quality certification number: Guangdong probatio inspectionem pecuoarem word 2000A037 number, on January 8th, 2003 was provided by No.1 Military Medical Univ.'s Experimental Animal Center.Totally 60.Earlier animal is weighed, numbering is selected healthyly, and body weight is totally 50 of the mices of 17.9-22.1 gram.By body weight size ordering, be divided into five groups, 10 every group with district's group method of dividision into groups at random.If negative control, high, medium and low three the dosage groups of positive control and naringin medicine.All by oral administration of filling stomach amount of 10ml/kg body weight.
2. sample source and processing:
(1) naringin sample high dose group: it is an amount of to get naringin, and in volumetric flask, naringin concentration is 14.4mg/ml with the normal saline standardize solution.Used naringin sample is that purity is more than 95% according to the method noted earlier naringin monomer of medicinal material extract therefrom.Oral administration.
(2) dosage group in the naringin sample: it is an amount of to get naringin, and in volumetric flask, naringin concentration is 4.8mg/ml with the normal saline standardize solution.Used naringin sample is that purity is more than 95% according to the method noted earlier naringin monomer of medicinal material extract therefrom.Oral administration.
(3) naringin sample low dose group: it is an amount of to get naringin, and in volumetric flask, naringin concentration is 1.6mg/ml with the normal saline standardize solution.Used naringin sample is that purity is more than 95% according to the method noted earlier naringin monomer of medicinal material extract therefrom.
(4) positive drug adopts TANKEJING: powder, and get 0.2 gram and be dissolved in 10 ml physiological salines, promptly get positive control TANKEJING solution, concentration is 20mg/ml.Dosage is 200mg/kg.
(5) negative control group: normal saline, NaCL content are 0.9%.
3. experimental technique: (phenol red method)
(1) water 12h is can't help in the mice fasting.
(2) gastric infusion.By the animal order, stopped behind every mouse stomach 3 minutes, irritate other one again, interval is 3 minutes, 10 every group are irritated the stomach time altogether is 30 minutes.
(3) half an hour behind each Mus filling stomach is through lumbar injection 5% phenol red normal saline solution 0.2ml.In order, promptly each mouse peritoneal was injected phenol red back 3 minutes, injected other one again, 10 mices totally 30 minutes.
(4) half an hour behind each Mus lumbar injection, take off cervical vertebra in order and put to death mice, put to death interval 3 minutes.Behind the sacrifice of animal, face upward the position and be fixed on the operation plate, cut off neck center skin, separate trachea, prop trachea with pincet.
(5) draw normal saline flushing trachea outer wall with big syringe, phenol red in flush away blood and the trachea outer wall, filter paper blots washing liquid.
(6) cut trachea prior to the trachea bifurcation, cut trachea (the ring-type thyroid cartilage is included) in other end thyroid cartilage upper end again.
(7) each trachea section is put into the 5%NaHCO that fills 1.5ml in advance
3In the solution test tube.
(8) in 3 minutes, finish above-mentioned tracheorrhaphy from shearing work.Reuse is handled second mice with quadrat method.Method as above.
(9) each test tube is put on the vortex mixer concussion 2 minutes, made phenol red the discharging in the trachea section.
(10) solution in each test tube is surveyed the OD value in 721 type spectrophotometer 546nm places.
(11) the OD value of resurveying behind the 24h is spent the night in each test tube gassiness pipeline section placement.
(12) go out phenol red content according to regression equation calculation.Computing formula: Y=-0.135302794+14.19137583X.X is the OD value, and Y is phenol red content.
(13) calculate the phenol red content of correction according to phenol red content and the weight of animals, carry out variance analysis with the SPSS8.0 statistical software.
Proofread and correct phenol red content=phenol red content (ng)/mice body weight (kg)
4. the result judges: each group result is carried out variance analysis, and when overall when variant, if positive drug and matched group are relatively, phenol red content raises, and significant difference (P＜0.05) is arranged, and determines that experiment reliably.With each dosage group and matched group relatively, phenol red content obviously raises again, and when significant difference (P＜0.05) is arranged, thinks that this dosage group is effective.
5. experimental result:
By statistics, each dosage group phenol red output, see Table 2.
Table 2. Pericarpium Citri grandis is for the effect of reducing phlegm of medicine (X ± S)
Group
Dosage animal trachea is proofreaied and correct phenol red content
aThe rate of reducing phlegm
b
The P value
The phenol red content of code name sample name (mg/kg) (ng)
(ng/kg) (％)
1 normal saline 0 1.6792 ± 0.4379 84.7774 ± 21.0409--
2 TANKEJING 200 2.6073 ± 0.5986 132.0956 ± 32.0495 P＜0.05 155.78
3 naringin high dose group 144 3.1702 ± 0.7423 158.6855 ± 34.8674 P＜0.01 187.15
Dosage group 48 3.1267 in 4 naringins ± 1.4389 160.3666 ± 78.3494 P＜0.01 189.16
5 naringin low dose group 16 2.7414 ± 0.7917 139.6466 ± 42.4319 P＜0.05 164.72
A: proofread and correct phenol red content=phenol red content/the weight of animals
B: the rate of reducing phlegm=administration group/blank group * 100%
Phenol red cubage method (ng): OD value * 14.19137583-0.135302794
Naringin medicine of the present invention shows the experiment of reducing phlegm of laboratory animal mice, naringin medicine height of the present invention, in, the mouse bronchial juice is increased the low dose group gastric infusion and blank compares, and all significantly increases, and there were significant differences statistically.Compare with positive drug TANKEJING group, naringin medicine height, middle dosage group has remarkable increase to the mouse bronchial juice, and there were significant differences statistically.Show that the naringin medicine of the present invention effect of reducing phlegm is better than the positive drug TANKEJING.
The toxicological experiment of embodiment 3. naringin medicines
24 ± 1 ℃ temperature, under 65 ± 5% the damp condition, choose 7-8 age in week, 20 of healthy cleaning level NIH mices, male and female half and half, body weight is at 20-22g.With feedstuff and water sterilization, before the test and in the observation period of test, all raise by normal feedstuff condition.
Naringin is dissolved among the 0.5%Tween80, and concentration is 900mg/ml, and with this liquid oral administration mice, dosage is a 0.2ml/20g mice body weight.Observed after the administration 1,4,8,12 hours, observed once in later per 12 hours.Observe death condition, write down mice body weight change and other symptom every day.The 10th day, disconnected neck was put to death mice, gets each organ and carries out pathologic finding.
At the 10th day, all mice survivals, the naringin of 900mg/kg dosage is not seen toxic reaction.Each organ pathologic finding of mice is normal, does not find pathological changes, and the mice body weight is not seen and alleviated in 10 days.Therefore, illustrate that naringin medicine of the present invention do not see toxicity when the oral administration animal.
Embodiment 4. naringin capsule preparations
Be prepared into gelatine capsule by following composition proportion:
Naringin 100g
Dry starch 40g
Micropowder silica gel 10g
With adjuvant and naringin mix homogeneously, in the transparent capsule of packing into, promptly.Loading amount: 150mg/ capsule.
Embodiment 5. naringin tablets
Be prepared into tablet by following composition proportion:
Naringin 750g
Starch 722.5g
Starch slurry (14%) 25.0g
Magnesium stearate 2.5g
Amount to 1500g
With naringin and starch uniform mixing, add starch slurry continuation stirring and make into soft material, granulate with 10 order nylon mesh, 80-90 ℃ of aeration-drying, dry granular adds magnesium stearate, and through 12 mesh sieve granulate, mixing is pressed into tablet.Altogether 5000, every sheet heavily is about 0.3g.
Claims (10)
1. naringin is used for the application of supportive treatment severe acute respiratory syndrome medicine in preparation.
2. according to the described application of claim 1, it is characterized in that said naringin is to extract naringin crude product or the naringin monomer that obtains from the medical material that contains naringin.
3. according to the described application of claim 1, it is characterized in that the extracting method of said naringin is: pulverizing medicinal materials is one to multiple inferior through water extraction, filter merging filtrate; Filtrate is condensed into extractum, and upper prop or direct upper prop carry out post and separate the organic solvent eluting behind the extractum precipitate with ethanol; Eluent volatilizes solvent, gets the naringin crude product; Again through recrystallization repeatedly, the naringin monomer.
4. according to the described application of claim 1, it is characterized in that said naringin obtains by chemical method is synthetic.
5. according to claim 1,2,3 or 4 described application is characterized in that said naringin medicine is the medicine that contains the 0.1-100%wt. naringin in the composition.
6. according to claim 1,2,3 or 4 described application is characterized in that said naringin medicine is made up of simple naringin, perhaps by as the naringin of effective ingredient with other effective ingredient or/and conventional pharmaceutical aids form.
7. according to claim 1,2,3 or 4 described application is characterized in that said naringin medicine is a capsule, and its inclusions contains the naringin of 0.5-100%wt..
8. according to the described application of claim 7, it is characterized in that the inclusions of said naringin medicine capsule is made up of the naringin that is no less than 0.5%wt. and other effective ingredient or/and conventional adjuvant.
9. according to claim 1,2,3 or 4 described application is characterized in that said naringin medicine is a tablet, contains the naringin that is no less than 0.1%wt. in its composition.
10. according to the described application of claim 9, it is characterized in that the composition of said naringin medicinal tablet is made up of the naringin that is no less than 0.1%wt. and other effective ingredient or/and conventional adjuvant.
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| CNB031269087A CN1179726C (en) | 2003-06-18 | 2003-06-18 | Application of naringin in preparing medicine for supporting treatment of SARS |
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| CN102872004B (en) * | 2012-07-06 | 2017-07-14 | 吉林大学 | Application of the naringenin in treatment pneumonia medicine is prepared |
| CN103893197A (en) * | 2014-04-02 | 2014-07-02 | 苏薇薇 | Application for naringin in preparation for medicine preventing and treating respiratory diseases due to PM2.5 particles |
| CN110934855A (en) * | 2020-01-31 | 2020-03-31 | 中山大学 | Application of p-hydroxyphenylpropionic acid in preparing medicine for preventing and treating respiratory tract infection |
| CN114191419B (en) * | 2022-01-17 | 2023-06-23 | 中国医学科学院药用植物研究所 | Naringin nanometer inhalation powder spray with polylysine as carrier, and preparation method and application thereof |
| CN114533752A (en) * | 2022-04-01 | 2022-05-27 | 中山大学 | Application of naringin in preparing medicament for treating chronic obstructive pulmonary disease |
| CN115708553B (en) * | 2022-11-28 | 2024-01-26 | 广东李金柚农业科技有限公司 | Naringin-containing composition and application thereof in preparation of naringin-containing beverage |
| CN115813993A (en) * | 2022-12-16 | 2023-03-21 | 中山大学 | Application of phyllanthus emblica extract in preparation of medicine for treating chronic obstructive pulmonary disease |
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