CN109394746A - Ethyl sulfuric acid ammonium is in preparation for preventing or treating the application in diseases associated with inflammation drug - Google Patents
Ethyl sulfuric acid ammonium is in preparation for preventing or treating the application in diseases associated with inflammation drug Download PDFInfo
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- CN109394746A CN109394746A CN201710694358.2A CN201710694358A CN109394746A CN 109394746 A CN109394746 A CN 109394746A CN 201710694358 A CN201710694358 A CN 201710694358A CN 109394746 A CN109394746 A CN 109394746A
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- sulfuric acid
- acid ammonium
- ethyl sulfuric
- ethyl
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/255—Esters, e.g. nitroglycerine, selenocyanates of sulfoxy acids or sulfur analogues thereof
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- Health & Medical Sciences (AREA)
- Emergency Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention discloses ethyl sulfuric acid ammonium preparation inflammation, fever, diarrhea, cough and as NF- kB inhibitor drug in terms of using, preparation method and composition.
Description
Technical field
The present invention relates to ethyl sulfuric acid ammonium in preparation for preventing or treating the application in diseases associated with inflammation drug.
Background technique
Ethyl sulfuric acid is also known as acid ethylsulfate (ethyl bisulfate) or ethyl sulfuric acid (ethyl-sulfuric
acid).280 DEG C of boiling point (decomposition).Relative density 1.316.Heat or its fortified aqueous are decomposed into toxic sulphur oxidation when boiling
Object (SOx) smog, has strong and stimulating, strong corrosive to skin, eyes, mucous membrane.The product and ethyl alcohol are etherified, and can obtain aether pronarcosi；
Ethyl sulfuric acid ammonium can be obtained with ethyl sulfuric acid in ammonium hydroxide, discovery ethyl sulfuric acid ammonium has medical usage at present.
Summary of the invention
Applicant has found that ethyl sulfuric acid ammonium can be used for preparing diseases associated with inflammation, bring down a fever, diarrhea or NF- κ B inhibition unexpectedly
New application in terms of agent drug.
First invention purpose of the invention provides ethyl sulfuric acid ammonium in preparation for preventing or treating diseases associated with inflammation drug
The application of aspect.
One of preferred embodiment, the diseases associated with inflammation are selected from infective inflammation or non-infectious inflammation, including
But being not limited to may be by bacterium, caused by the pathogen such as virus, or the inflammation disease as caused by autoimmunity.
One of preferred embodiment, the inflammation disease is including but not limited to esophagitis, enteritis, thyroiditis, bone
Inflammation, stomatitis, pleurisy, dermatitis, pneumonia, vaginitis, cystitis, bronchitis, inflammatory swelling etc..
One of which is more highly preferred to embodiment, and the inflammatory swelling includes but is not limited to that phorbol exters cause Mice Auricle swollen
Swollen, Carrageenan causes foot swelling, granuloma induced by implantation of cotton pellets etc..
Second goal of the invention of the invention provides application of the ethyl sulfuric acid ammonium in terms of preparing for antipyretic.
Third goal of the invention of the invention provides ethyl sulfuric acid ammonium in terms of preparation is for preventing or treating anti-diarrhea drug
Using.
4th goal of the invention of the invention provides ethyl sulfuric acid ammonium in preparation for preventing or treating cough medicine object space face
Using.
5th goal of the invention of the invention provides ethyl sulfuric acid ammonium drug in terms of preparing for NF- kB inhibitor drug
Application.
6th goal of the invention of the invention provides a kind of preparation method of ethyl sulfuric acid ammonium:
Ethyl alcohol is added in a kettle, under stiring be added sulfuric acid ethyl alcohol, control reaction temperature at 5~40 DEG C, reaction 1~
72 hours, ethyl alcohol is added, is 5.5~8.5 with ammonium hydroxide tune pH, separation.
7th goal of the invention of the invention, provides a kind of pharmaceutical composition comprising the ethyl sulfuric acid ammonium of therapeutically effective amount
And pharmaceutically acceptable auxiliary material；
Described pharmaceutical composition can be used for preparing diseases associated with inflammation, bring down a fever, the drugs such as diarrhea or NF- kB inhibitor.
In described pharmaceutical composition, the pharmaceutically acceptable auxiliary material may include pharmaceutically acceptable carrier, dilution
Agent and/or excipient.
According to therapeutic purposes, pharmaceutical composition can be made to various types of administration unit dosage forms, such as tablet, pill, powder
Agent, liquid, suspension, lotion, granule, capsule, suppository and injection (solution and suspension) etc., preferred liquid, suspension, cream
Liquid, suppository and injection (solution and suspension) etc..
In order to shape the pharmaceutical composition of tablet form, it can be used this field any known and widely used figuration
Agent.For example, carrier, such as lactose, white sugar, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, avicel cellulose and silicon
Acid etc.；Adhesive, such as water, ethyl alcohol, propyl alcohol, common syrup, glucose solution, starch solution, gelatin solution, carboxymethyl cellulose
Element, lac, methylcellulose and potassium phosphate, polyvinylpyrrolidone etc.；Disintegrating agent, such as dried starch, mosanom, agar powder and sea
Band powder, sodium bicarbonate, calcium carbonate, the aliphatic ester of polyethylene sorbitan, lauryl sodium sulfate, stearic acid monoglycerides,
Starch and lactose etc.；Disintegration inhibitor, such as white sugar, glycerol tristearate, coconut oil and hydrogenated oil and fat；Adsorption enhancer, such as season
Amine base and lauryl sodium sulfate etc.；Wetting agent, such as glycerol, starch；Adsorbent, such as starch, lactose, kaolin, bentonite
With colloid silicic acid etc.；And lubricant, such as pure talcum, stearate, boric acid powder and polyethylene glycol etc..It can also be according to need
Select common coated material be made sugar coated tablet, apply gelatin film tablet, enteric coated tablets, film coated tablets, duplicature tablet and
Multilayer tablet.
In order to shape the pharmaceutical composition of pill, it can be used this field any of and widely used figuration
Agent, for example, carrier, such as lactose, starch, coconut oil, hardened vegetable oils, kaolin and talcum powder etc.；Adhesive, such as Arabic tree
Rubber powder, tragacanth gum powder, gelatin and ethyl alcohol etc.；Disintegrating agent, such as agar and Kelp Powder.
In order to shape the pharmaceutical composition of suppository form, it can be used this field any known and widely used inborn nature
Agent, for example, polyethylene glycol, coconut oil, higher alcohol, the ester of higher alcohol, gelatin and semi-synthetic glyceride etc..
In order to prepare the pharmaceutical composition of injection form, (suitable chlorine can will be preferably added after solution or suspension liquid disinfectant
Change sodium, glucose or glycerol etc.), it is made and the isotonic injection of blood.When preparing injection, it is possible to use in the art any
Common carrier.For example, water, ethyl alcohol, propylene glycol, the isooctadecanol of ethoxylation, the isooctadecanol and polyethylene of polyoxy
The aliphatic ester etc. of anhydro sorbitol.In addition, common lytic agent, buffer and analgesic etc. can also be added.
In the present invention, content of the composition in pharmaceutical composition is without specifically limited, wherein the ethyl sulfuric acid
Ammonium can be selected in a wide range, safely, effectively dosage according to the age for the treatment of object, weight, the state of an illness, the course of disease,
The concrete conditions such as administration route determine, generally can be the 5-95% of mass percent, preferably mass percent 30-
80%.
In the present invention, the medication of described pharmaceutical composition is not particularly limited.Can according to patient age, gender and its
Its condition and symptom select the preparation of various dosage forms to be administered.For example, tablet, pill, solution, suspension, lotion, granule or
Capsule oral administration；Injection can be administered alone, or mixed with injection conveying liquid (such as glucose solution and amino acid solution)
Conjunction is injected intravenously；Suppository is to be administered into rectum.
The present invention also provides the ethyl sulfuric acid ammoniums and one or more other type therapeutic agents to be used to prepare and control
Treat the application in anti-inflammatory drugs.
The therapeutic agent of other types can with the ethyl sulfuric acid ammonium or described pharmaceutical composition, be made into it is single to
The therapeutic dosage forms of medicine, or it is taken up in order of priority the therapeutic dosage forms of administration.
Advantageous effects of the invention:
Ethyl sulfuric acid ammonium of the invention has good anti-inflammatory effect, can effectively treat diseases associated with inflammation, experiments have shown that:
Ethyl sulfuric acid ammonium can significantly inhibit the auricle edema of auris dextra in 50~200mg/kg dosage range, 50~
Foot swelling is significantly inhibited in the equal dose dependent of 3~7h in 200mg/kg dosage range, in 22.5~160mg/kg dosage range
The relative weight (P < 0.05 or P < 0.01) of granuloma induced by implantation of cotton pellets is inside significantly inhibited, and dose dependent is presented.
Ethyl sulfuric acid ammonium has the activity for improving bronchitis；The ethyl sulfuric acid in 31.25~125mg/kg dosage range
Ammonium can significantly extend the citric acid spraying caused incubation period coughed and cough number (P < 0.05 or P < 0.01), and have dosage
Dependence.
Ethyl sulfuric acid ammonium can significantly inhibit mouse lung inflammation caused by LPS, improve injury of lungs；Inhibit inflammatory infiltration and each
Inflammatory factor (IL-1, TNF-α, IL-6, IL-4, IL-5, IL-17) expression；Inhibit NF- kB activation；With improvement bronchitis
Activity；The citric acid spraying caused incubation period coughed and cough number can significantly be extended.
Ethyl sulfuric acid ammonium has significant antipyretic effect, and single-dose can significantly reduce saccharomycete and cause fever rat or endotoxin
Cause the body temperature of fever rabbit；Antipyretic effect works quickly, persistently, and 0.5h begins with significant hypothermal effect upon administration, and continues
To 8h.
Ethyl sulfuric acid ammonium can prevent or treat cough, as ethyl sulfuric acid ammonium can be shown in 31.25~120mg/kg dosage range
It writes and extends the citric acid spraying caused incubation period coughed and cough number (P < 0.05 or P < 0.01), and there is dose-dependant
Property.
In addition, 50~200mg/kg of ethyl sulfuric acid ammonium can obviously lower its Scours index；The ethyl sulphur of 25~200mg/kg
Sour ammonium can significantly inhibit mouse Intestinal pushing (P < 0.05 or P < 0.01).
Without prejudice to the field on the basis of common sense, above-mentioned each optimum condition, can any combination to get the present invention it is each preferably
Example.
The reagents and materials used in the present invention are commercially available.
Medicine or pharmaceutical field those of ordinary skill under the premise of not doing related experiment, can not predict ethyl sulfuric acid in advance
Ammonium has medical application of the present invention.
Detailed description of the invention
Fig. 1: ethyl sulfuric acid ammonium inhibits the infiltration of the Pneumonia Mice lung tissue medium size lymphocyte of LPS induction；
Fig. 2: the administration of ethyl sulfuric acid ammonium inhibits the water of inflammatory factor in the Pneumonia Mice lung-douching fluid and serum of LPS induction
It is flat；
Fig. 3: the administration of ethyl sulfuric acid ammonium inhibits the mRNA expression of inflammatory factor in the Pneumonia Mice lung tissue of LPS induction；
Fig. 4: ethyl sulfuric acid ammonium improves the Pneumonia Mice lung tissue lesion of LPS induction；
Fig. 5: the administration of ethyl sulfuric acid ammonium inhibits the NF- κ B signal access of LPS induction.
Specific embodiment
The present invention is further illustrated below by the mode of embodiment, but does not therefore limit the present invention to the reality
It applies among a range.In the following examples, the experimental methods for specific conditions are not specified, according to conventional methods and conditions, or according to quotient
The selection of product specification.
FL-21 represents ethyl sulfuric acid ammonium in the present invention.
Embodiment 1: the preparation of ethyl sulfuric acid ammonium
Quantitative ethyl alcohol is added in a kettle, 6 times of amount ethanol solution of sulfuric acid, control reaction kettle temperature are slowly added dropwise under stiring
Degree continues stirring esterification 24 hours at 38 DEG C.Ethyl alcohol is added, stirs evenly, is 7.0 with 10% ammonium hydroxide tune pH, 95% second is added
Alcohol makes alcohol content up to 85% or more, ethyl alcohol is recovered under reduced pressure, aqueous solution is through adsorption resin column chromatography, with water: ethanol gradient is washed
It is de-, eluent is collected, ethyl sulfuric acid ammonium is crystallized.
Embodiment 2: ethyl sulfuric acid ammonium causes the influence of mice auricle swelling to phorbol exters
Experimental method
ICR mouse, half male and half female, 6-8 week old, 18~22g of weight are randomly divided into 6 groups of (model groups, ethyl sulfuric acid ammonium five
A dosage group).20 μ L TPA solution equably are smeared in every mouse right ear with 20 μ L liquid-transfering guns.1h presses 0.l mL/ after modeling
The volume of 10g is injected intravenously ethyl sulfuric acid ammonium, and dosage is respectively 12.5,25,50,100,200mg/kg.It is taken off after modeling 6h
Cervical vertebra puts to death mouse, lays round auricle at the same position of two auricles respectively with diameter 8mm punch, electronic balance weighing is pressed
Formula calculates auricle swelling degree and swelling inhibiting rate.Swelling (%)=(auris dextra quality-left ear quality)/left ear quality × 100%.
Data analysis
All data indicate that statistical difference is examined using Tukey ' s between group with means ± S.D.P value is less than 0.05
It is considered having significant difference.
Experimental result
Ethyl sulfuric acid ammonium can be significantly inhibited in 50~200mg/kg dosage range auris dextra auricle edema (P < 0.05 or P <
0.01), and swelling inhibiting rate is 35% or more.
Influence of the ethyl sulfuric acid ammonium to the TPA auricle edema induced
Note: compared with model group,*P < 0.05,**P<0.01
Embodiment 3: the influence of ethyl sulfuric acid ammonium Carrageenan cause rat paw edema
Experimental method
Wistar rat, 200~220g are randomly divided into 6 groups (normal group, four model groups, ethyl sulfuric acid ammonium dosage groups).
After chloral hydrate anesthesia, in addition to normal group is given the physiological saline of equivalent, other each group right hind foot of rat plantar subcutaneous injections are sterile
0.5h is injected intravenously respectively after 1% carrageenan physiological saline suspension 0.1mL causes inflammation, cause scorching gives various dose ethyl sulfuric acid ammonium
Or physiological saline, administered volume 1mL/100g.The measurement of water capacity area method cause it is scorching before and cause it is scorching after 1,3,5, vola pedis is held behind the right side of 7h
Product calculates swelling rate and swelling inhibiting rate.Swelling rate (%) is expressed as (Vt-Vn)/Vn*100, and it is scorching that Vn and Vt respectively indicate cause
Sufficient volume that is preceding and causing the response time after inflammation.Swelling inhibiting rate (%), indicate (model group be averaged swelling rate-administration group averagely swell
Swollen rate)/model group is averaged swelling rate * 100.
Data analysis
All data indicate that statistical difference is examined using Tukey ' s between group with means ± S.D.P value is less than 0.05
It is considered having significant difference.
Experimental result
5h or so reaches swelling peak value after carrageenin injection.Ethyl sulfuric acid ammonium in 50-200mg/kg dosage range
3,5,7h equal dose dependents significantly inhibit foot swelling (P < 0.05 or P < 0.01 or P < 0.001), and the swelling inhibiting rate of 5-7h reaches
30-70%.
The influence of the different time foot swelling of ethyl sulfuric acid ammonium Carrageenan induction
Note: compared with normal group,##P < 0.01,###P<0.001；Compared with model group,*P < 0.05,**P < 0.01,***P<
0.001。
Inhibiting rate of the different time ethyl sulfuric acid ammonium to foot swelling
Embodiment 4: influence of the ethyl sulfuric acid ammonium to swollen hyperplasia of rat granuloma
Experimental method
SD rat, 200g or so are raised in 22 ± 2 DEG C of environment, are freely ingested and drink water.With random after adapting to 3 days
It is divided into 5 groups (four model group, ethyl sulfuric acid ammonium dosage groups).After rats by intraperitoneal injection chloral hydrate anesthesia, sterile working is in abdomen
Portion makees a small notch, and the 20mg cotton balls implantation rat two sides upper limb groin after high pressure sterilization is dried is subcutaneous, sutures immediately
Skin.Start to be administered in postoperative next day, continuous 7 days, sacrificed by exsanguination rat after weighing in the 8th day removes and takes out cotton balls granulation group
It knits and (rejects adipose tissue), weigh after being placed in 60 DEG C of drying in oven to constant weight, subtract raw cotton ball weight, as granuloma weight
Amount calculates inhibiting rate.
Data analysis
All data indicate that statistical difference is examined using Tukey ' s between group with means ± S.D.P value is less than 0.05
It is considered having significant difference.
Experimental result
As a result shown in following table, relative to model group, the significant suppression in 25~200mg/kg dosage range of ethyl sulfuric acid ammonium
The relative weight (P < 0.05 or P < 0.01) of granuloma induced by implantation of cotton pellets processed, and dose dependent is presented.
Influence of the ethyl sulfuric acid ammonium to granuloma induced by implantation of cotton pellets relative weight (granuloma dry weight/weight)
Note: compared with model group,*P < 0.05,**P<0.01
Integrated embodiment 2~4 is it is found that ethyl sulfuric acid ammonium has a better effect nonspecific inflammation tool:
1) auricle edema (P < 0.05 or P < 0.01) of auris dextra can be significantly inhibited in 50~200mg/kg dosage range, and
Swelling inhibiting rate is 30% or more.
2) ethyl sulfuric acid ammonium Carrageenan induction different time influence, in 50~200mg/kg dosage range
3,5,7h equal dose dependents significantly inhibit foot swelling (P < 0.05 or P < 0.01 or P < 0.001), and the swelling inhibiting rate of 5-7h reaches
30-70%.
3) significantly inhibited in 25~200mg/kg dosage range granuloma induced by implantation of cotton pellets relative weight (P < 0.05 or P <
0.01), and dose dependent is presented.
Embodiment 5: ethyl sulfuric acid ammonium causes the drug efficacy study of rat fever to saccharomycete
Experimental method
Wistar rat, 150g or so are raised in 22 ± 2 DEG C of environment, are freely ingested and drink water.Adaptation 3 days, daily
Rat-rectum temperature is monitored, the rat that body temperature is abnormal or variation is big is rejected.12h is deprived of food but not water before modeling.1h is surveyed before modeling
It measures every rat temperature 2 times, takes mean value as every rat basal body temperature.
Rat neck 15% yeast bacteria suspension 10mL/kg of dorsal sc injection below, causes rat fever.Massage injection
Position is so that suspension is subcutaneously being spread.Room temperature should be maintained at 22~24 DEG C.Rectal temperature is recorded after modeling 5h, rejects body temperature not
The rat for reaching 38 DEG C, is grouped according to body temperature, is divided into normal group, model group, ethyl sulfuric acid ammonium (22.5mg/mL, 45mg/
ML, 90mg/mL, 160mg/mL) group.Be administered at once after grouping, and after administration 0.5,1,2,4,6,8, measurement is big again after 10h
Mouse rectal temperature.
Data analysis
All data indicate that statistical difference is examined using Tukey ' s between group with means ± S.D.P value is less than 0.05
It is considered having significant difference.
Experimental result
Ethyl sulfuric acid ammonium has significant antipyretic effect, and single-dose can significantly reduce the body temperature that saccharomycete causes fever rat；It moves back
Heat effect works quickly, persistently, and 0.5h begins with significant hypothermal effect upon administration, and continues to 8h.
Ethyl sulfuric acid ammonium causes the temperature influence of fever rat to saccharomycete
Note: compared with normal group,#P < 0.05,##P < 0.01；Compared with model group,*P < 0.05,**P < 0.01.
Embodiment 6: the drug efficacy study of ethyl sulfuric acid ammonium induced by endotoxin cause fever in rabbits
Experimental method
Male regular grade rabbit, 2.0kg or so, quality certification number: SCXK (Soviet Union) 2012-0008 is raised in 22 ± 2 DEG C of ring
In border, freely ingests and drink water.Raising 3 days is adapted to, daily measurement body temperature 2 times, rejects the rabbit that body temperature is abnormal and variation is big.
12h is deprived of food but not water before testing.It tests the same day to detect body temperature 3 times, takes mean value as basic body temperature.With pyrogen-free physiological saline
The LPS of purification is diluted to 2mg/L, except for the normal group, remaining each group injects LPS through auricular vein by 1mL/kg；Normal group
Pyrogen free, physiological salt water is injected by 1mL/kg auricular vein.After lps injection 30min, measurement animal rectal temperature (rejects body temperature liter
0.8 DEG C of rabbit of high <), random sub-model group, each dosage of ethyl sulfuric acid ammonium (8.75,17.5,35,70mg/kg) group.By 1mL/kg
Auricular vein injects the ethyl sulfuric acid ammonium salt solution of various dose, and normal group and model group give isometric physiological saline, surveys
0.5h, 1h, 2h, 3h, 5h and 8h rabbit anus temperature after fixed administration compare the difference (Δ T) of different time points anus temperature and basic anus temperature
For the index of Temperature changing.
Data analysis
All data indicate that statistical difference is examined using Tukey ' s between group with means ± S.D.P value is less than 0.05
It is considered having significant difference.
Experimental result
Ethyl sulfuric acid ammonium has significant antipyretic effect, and single-dose can significantly reduce the body temperature that endotoxin causes fever rabbit；It moves back
Heat effect works quickly, persistently, and 0.5h begins with significant hypothermal effect upon administration, and continues to 8h.
Ethyl sulfuric acid ammonium induced by endotoxin causes the temperature influence of fever rabbit
Note: model group compared with normal group,##Indicate extremely significant (P < 0.01)；Test group compared with model group,*It indicates
Significant difference (P < 0.05),**Indicate extremely significant (P < 0.01).
Embodiment 7: ethyl sulfuric acid ammonium causes the influence of bronchitis to LPS
Experimental method
ICR mouse, male, 6~8 week old, 18~22g of weight are raised in 22 ± 2 DEG C of environment, are freely ingested and drink
Water.Subsequent experimental research is used for after adapting to raising 3 days.6mg/mL LPS normal saline solution is instilled with nasal cavity with liquid-transfering gun, even
Continuous to instill 3 days, 2 or 6h is administered after the 3rd day collunarium, for three days on end, the 5th day execution animal.Mouse separates tracheae after putting to death, and is intubated
And it is fixed.Divide normal group, model group, each dosage of ethyl sulfuric acid ammonium (25,50,100,200mg/kg) group at random.Use 0.5mL/10g
Physiological saline, point 2 progress bronchoalveolar lavages recycle BAL fluid, carry out inflammatory cell counting.
Data analysis
All data indicate that statistical difference is examined using Tukey ' s between group with means ± S.D.P value is less than 0.05
It is considered having significant difference.
Experimental result
White blood cell count(WBC) (P < 0.01) in mouse bronchial bronchoalveolar lavage fluid can significantly be increased within the modeling of LPS collunarium 3 days；Regardless of
It is that 2h or 6h starts to be administered after last modeling, relative to model group, ethyl sulfuric acid ammonium can be significant in 50-200mg/kg dosage
White blood cell count(WBC) (P < 0.05 or P < 0.01) in BAL fluid is reduced, and has dose dependent.Prompt ethyl sulfuric acid
Ammonium has the activity for improving bronchitis.
Influence of the ethyl sulfuric acid ammonium to the LPS tracheitis mouse bronchial bronchoalveolar lavage fluid white blood cell count(WBC) induced
Note: compared with normal group,##P < 0.01；Compared with model group,*P < 0.05,**P < 0.01.
Embodiment 8: ethyl sulfuric acid ammonium causes the influence of guinea pig cough to citric acid
Experimental method
Cavy, half male and half female, weight 250-300g are raised in 22 ± 2 DEG C of environment, are freely ingested and drink water.Yu Shi
It tests first 1 day, cavy is placed in the closed glass bell jar of 4L volume, sprayed into using 980-A type ultrasonic atomizer pre-configured
17.5% citric acid recorded the cough number of cavy in 5min with maximum spray amount spraying 10 seconds, number of coughing is less than 10 times
Person's reject.The cavy by primary dcreening operation is taken, model group and each administration group of ethyl sulfuric acid ammonium, successive administration 5d are randomly divided into.Last is given
Cavy is placed in the glass bell jar of 4L volume by 30min after medicine, is sprayed into using 980-A type ultrasonic atomizer pre-configured
17.5% citric acid, it is 10 seconds spraying with maximum spray amount, record number of coughing in guinea pig cough's incubation period and 5min.The cough of cavy
It coughs fullness of tone, to hear cough as calculating standard.
Data analysis
All data indicate that statistical difference is examined using LSD between group with means ± S.D.P value is recognized less than 0.05
To there is significant difference.
Experimental result
Ethyl sulfuric acid ammonium can significantly extend the latent of the spraying caused cough of citric acid in 31.25~125mg/kg dosage range
Volt phase and cough number (P < 0.05 or P < 0.01), and there is dose dependent.
Ethyl sulfuric acid ammonium causes the influence in guinea pig cough's incubation period and number of coughing to citric acid
Note: compared with model group,*P < 0.05,**P<0.01。
Embodiment 9: ethyl sulfuric acid ammonium causes the drug efficacy study of pneumonia to LPS
Test method: C57BL/6 mouse, 6~8 week old, female, 20 ± 2g of weight.Mouse is exposed to the LPS of atomization
(2 times, primary every 1h) progress modelings of (0.25mg/ml) 40min；It is infused respectively by 5,10, the abdominal cavity 20mg/kg after LPS sucking
It penetrates and gives ethyl sulfuric acid ammonium, investigate ethyl sulfuric acid ammonium intraperitoneal injection to pulmonary inflammatory improvement result.
Detection method and index:
1) bronchoalveolar lavage and cell count
BAL fluid is collected in mouse trachea cannula, PBS lavation, 0.3ml × 1 time；4 DEG C of refrigerated centrifuge 500g
×5min；Collect supernatant, -20 DEG C of cell factors to be checked.Cell precipitation is resuspended in 300 μ l PBS, inhales 20 μ l and adds 80 μ l fixers solid
Determine technology.Remaining is divided into two parts fluidic cell dyeing identification of cell classification and ratio (CD3-FITC, CD11b-APC, Gr1+-
PE)。
2) it is horizontal to detect inflammatory factor in mice serum and BAL fluid by ELISA
Mouse anesthesia, eyeball take blood, and 3000r/min is centrifuged 15min, and serum is taken to grasp according to ELISA kit specification
Make, the level of detection serum IL -1, IL-6 and TNF-α.
3) lung tissue inflammatory factor detects
It takes a fritter lung tissue (about 1mg) to be soaked in 1ml Trizol, is homogenized, extracted total RNA.By RNA reverse transcription at
CDNA: primer information is as follows:
β-actin forward 5’-TGCTGTCCCTGTATGCCTCT-3’,
β-actin forward 5'-TTTGATGTCACGCACGATTT-3'；
tnf-αforward 5'-CGAGTGACAAGCCTGTAGCCC-3'；
tnf-αreverse 5'-GTCTTTGAGATCCATGCCGTTG-3'；
il-1βforward 5'-CTTCAGGCAGGCAGTATCACTC-3'；
il-1βreverse 5'-TGCAGTTGTCTAATGGGAACGT-3'；
il-6 forward 5'-ACAACCACGGCCTTCCCTAC-3'；
il-6 reverse 5'-TCTCATTTCCACGATTTCCCAG-3'；
il-4forward 5'-GTCTGCTGTGGCATATTCTG-3'；
il-4 reverse 5'-GGCATTTCTCATTCAGATTC-3'；
il-5forward 5'-GGCTACACAGAGAAACCCTGT-3'；
il-5 reverse 5'-CATGCATACACAGGTAGTTCA-3'；
il-17 forward 5'-TCGAGAAGATGCTGGTGGGT-3'；
il-17 reverse 5'-CTCTGTTTAGGCTGCCTGGC-3'；
4) pathologic slice and H&E dyeing
Cervical dislocation puts to death mouse, takes its inferior lobe of right lung, is fixed with 10% formaldehyde, dehydration of alcohol, routine paraffin wax embedding,
Slice carries out H&E dyeing.
5) to the influence of NF- kB activation
Lung tissue paraffin section, dewaxing, xylene soak, ethanol gradient elution；The penetrating tissue of 1%Triton X100
1min.3% lowlenthal serum room temperature closes 1h；Room temperature incubates primary antibody p-p65 (1:50) 90min respectively, secondary antibody is incubated for 1h；Bush uniformly dyeing
Core 30S, distilled water flushing 2 times, each 5min；Dehydration.Neutral gum mounting, microscope are taken pictures.
Statistical method:
As a result indicated with mean ± SEM, first use one-way analysis of variance (ANOVA), it is variant after ratio between two groups
Compared with using Student ' s-t test to examine, comparison more than two is examined using Dunnett ' s test, and P < 0.05 is thought to have aobvious
Difference is write, P < 0.01 thinks there is extremely significant difference.
Experimental result:
1) ethyl sulfuric acid ammonium significantly inhibits the infiltration of lung tissue medium size lymphocyte
Each group mouse sucking LPS causes inflammatory model, and various dose ethyl sulfuric acid ammonium intraperitoneal injection is primary.It puts to death small
Lung perfusion is carried out after mouse, collect the lymph in irrigating solution and carries out fluidic cell staining analysis, is counted.As a result with mean ±
SEM expression, n=8, * P < 0.05, * * P < 0.01vs.LPS, ##P < 0.01vs.normal.
As shown in Figure 1, in the Pneumonia Mice BAL fluid (BALF) caused by LPS, model group (LPS) mouse
Total cell number be significantly higher than normal group；After giving ethyl sulfuric acid ammonium, the total cell number in BALF can obviously reduce；Further
Streaming Coloration experiment the results show that the CD3T+ cell infiltrated in lung tissue after the treatment of ethyl sulfuric acid ammonium, macrophage CD11b+
And the infiltration of neutrophil cell (Gr1+) is all remarkably decreased.
2) ethyl sulfuric acid ammonium significantly inhibits the level of inflammatory factor in serum and BAL fluid
Each group mouse irrigating solution and serum are acquired, it is horizontal that ELISA measures each inflammatory factor.As a result it is indicated with mean ± SEM,
N=8, * P < 0.05, * * P < 0.01vs.LPS, ##P < 0.01vs.normal.
As shown in Fig. 2, after LPS Neulized inhalation, TNF-α in model group mouse bronchial bronchoalveolar lavage fluid and serum, IL-6,
The level of IL-1 β is significantly raised.Inflammation in serum and bronchoalveolar lavage fluid is dose-dependently reduced after the administration of ethyl sulfuric acid ammonium
Factor level.
3) ethyl sulfuric acid ammonium significantly inhibits the mRNA level in-site of inflammatory factor in lung tissue
Each group mouse lung tissue is acquired, extracts RNA, it is horizontal that Q-PCR measures each inflammatory factor.As a result with mean ± SEM
It indicates, n=8, * P < 0.05, * * P < 0.01vs.LPS, ##P < 0.01vs.normal.
Q-PCR is the results show that model group mouse lung tissue inflammatory factor il-1, il-4, il-5, il-6, il-17 and tnf-
The gene expression of α is significantly raised, and each dosage administration of ethyl sulfuric acid ammonium can all significantly inhibit the expression (Fig. 3) of said gene.
4) ethyl sulfuric acid ammonium is obviously improved pathologic damage
Each group mouse lung tissue is acquired, it is fixed to carry out paraffin section and H&E dyeing and histopathology scoring.As a result with mean
± SEM expression, n=6, * P < 0.05, * * P < 0.01vs.LPS, ##P < 0.01vs.normal.
As shown in figure 4, H&E coloration result is shown, oedema occurs for model group (LPS) lung thin vessels peripheral tissue edema, scorching
Cellular infiltration increases.After giving ethyl sulfuric acid ammonium, mitigate pathological score, pulmonary lesion is obviously improved.
5) ethyl sulfuric acid ammonium significantly inhibits NF- κ B signal signal pathway activated
Each group mouse lung tissue is acquired, it is fixed to carry out paraffin section and immunohistochemical staining.
LPS stimulation can activate NF- κ B access in lung cells, be mainly shown as the phosphorylation of NF- κ B, such as Fig. 5, immune group
The phosphorylation level for changing the p65 in impaired lung cells as the result is shown increases, and a large amount of brown particles are distributed in nucleus.Second
Mouse lung tissue substantially resumes to normal morphology after base ammonium sulfate is administered, and the level of phosphorylation p65 also reduces in nucleus.
As a result:
1) ethyl sulfuric acid ammonium intraperitoneal injection can significantly inhibit the infiltration of pulmonary inflammatory cell and reduce pulmonary lavage liquid
And the content of the inflammatory factor (IL-1, TNF-α and IL-6) in serum；
2) ethyl sulfuric acid ammonium intraperitoneal injection can significantly inhibit damage and the inflammatory factor mRNA of lung tissue caused by LPS
The expression of (il-6, tnf- α, il-4, il-5, il-17 and il-1)；
3) ethyl sulfuric acid ammonium intraperitoneal injection can significantly reduce the activation of NF- κ B access in lung tissue, realize to small
The protection of mouse lung tissue.
Embodiment 10: ethyl sulfuric acid ammonium causes the influence of diarrhea of mouse to folium sennae
Experimental method
ICR mouse, half male and half female, 6~8 week old, 18~22g of weight are randomly divided into 5 groups.Test group presses 0.l mL/10g
Volume intravenous injection various dose ethyl sulfuric acid ammonium salt solution, model group and normal group give the physiological saline of same volume；Between
After 15min, except for the normal group, other each groups press the volume stomach-filling cassia angustifolia leaf decoction of 0.15ml/10g, and are individually placed on and are covered with
Observation gavages after folium sennae mouse stool and diarrhea situation, statistics loose stools number, total just number, loose stools in 6h in the small mouse cage of filter paper
Grade, and calculate Scours index (product of loose stool rate and loose stools grade).
A. diarrhea rate: the percentage of the number of animals of passage of loose stools and this group of animal number in one group of animal.
B. loose stool rate: the loose stools number and total just the ratio between number that every animal is arranged.
C. loose stools grade: the degree of loose stools is indicated.The size deciding grade and level of stain area is formed with loose stools pollution filter paper.
| Series | 1 | 2 | 3 | 4 |
| Stain diameter (cm) | <1 | 1~1.9 | 2~3 | >3 |
Data analysis
All data indicate that statistical difference is examined using Tukey ' s between group with means ± S.D.P value is less than 0.05
It is considered having significant difference.
Experimental result
Relative to normal group, 1-6h can cause the significant raising (P < 0.01) of model group Scours index after folium sennae stomach-filling；
Ethyl sulfuric acid ammonium 50-200mg/kg can obviously lower its Scours index (P < 0.01).
The influence for the diarrhea of mouse index that ethyl sulfuric acid ammonium induces folium sennae
Note: compared with normal group,##P < 0.01；Compared with model group,*P < 0.05,**P < 0.01.
Embodiment 11: influence of the ethyl sulfuric acid ammonium to mouse Intestinal pushing
Experimental method
ICR mouse, half male and half female, 6~8 week old, 18~22g of weight.It is randomly divided into 11 groups.Animal fasting 18h, is pressed respectively
The volume intravenous injection Xiyanping and ethyl sulfuric acid ammonium of 0.l mL/10g, is spaced after 15min and fills again by the volume of 0.l5mL/10g
Stomach gives Insta-Char, and section small intestine is rounded after 30min, and traction is not added and is laid on glass plate.Pylorus is measured to blind
The small intestine overall length of intestines and pylorus to carbon powder forward position distance.Pylorus is accounted for caecum portion overall length with the distance in pylorus to carbon powder forward position
Percentage be Intestinal propulsive rate.
Data analysis
All data indicate that statistical difference is examined using Tukey ' s between group with means ± S.D.P value is less than 0.05
It is considered having significant difference.
Experimental result
The ethyl sulfuric acid ammonium of 25~200mg/kg can significantly inhibit mouse Intestinal pushing (P < 0.05 or P < 0.01).
The influence that ethyl sulfuric acid ammonium promotes mouse carbon powder
Note: compared with the control group,*P < 0.05,**P<0.01。
Claims (7)
1. ethyl sulfuric acid ammonium is in preparation for preventing or treating the application in diseases associated with inflammation drug.
2. application as described in claim 1, which is characterized in that the diseases associated with inflammation is selected from esophagitis, enteritis, thyroid gland
Inflammation, osteitis, stomatitis, pleurisy, dermatitis, pneumonia, vaginitis, cystitis, bronchitis, inflammatory swelling.
3. ethyl sulfuric acid ammonium is in preparation for the application in antipyretic.
4. ethyl sulfuric acid ammonium is in preparation for preventing or treating the application in anti-diarrhea drug.
5. ethyl sulfuric acid ammonium is in preparation for preventing or treating the application in cough drug.
6. ethyl sulfuric acid ammonium is in preparation for the application in NF- kB inhibitor drug.
7. a kind of pharmaceutical composition comprising ethyl sulfuric acid ammonium is preparing diseases associated with inflammation, is bringing down a fever, diarrhea, cough or NF- κ B suppression
Application in preparation medicine.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109381453A (en) * | 2017-08-14 | 2019-02-26 | 江西青峰药业有限公司 | Potassium ethyl sulfate is in preparation for preventing or treating the application in diseases associated with inflammation drug |
| CN109381452A (en) * | 2017-08-11 | 2019-02-26 | 江西青峰药业有限公司 | Application of ethyl sulfuric acid class compound and preparation method thereof |
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| CN109381453A (en) * | 2017-08-14 | 2019-02-26 | 江西青峰药业有限公司 | Potassium ethyl sulfate is in preparation for preventing or treating the application in diseases associated with inflammation drug |
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