CN103251627A - Application of carbenoxolone or salt thereof in preparation of medicine for treating inflammatory diseases - Google Patents
Application of carbenoxolone or salt thereof in preparation of medicine for treating inflammatory diseases Download PDFInfo
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- CN103251627A CN103251627A CN2013101734667A CN201310173466A CN103251627A CN 103251627 A CN103251627 A CN 103251627A CN 2013101734667 A CN2013101734667 A CN 2013101734667A CN 201310173466 A CN201310173466 A CN 201310173466A CN 103251627 A CN103251627 A CN 103251627A
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Abstract
The invention relates to application of carbenoxolone or salt thereof in preparation of a medicine for treating inflammatory diseases, and particularly discloses novel application of the carbenoxolone or the medically accepted salt thereof in preparation of the medicine for treating whole-body infected or whole-body inflammatory diseases, in particular septicemia and septicopyemia. Furthermore, the invention also discloses application of the arbenoxolone or the medically accepted salt thereof in preparation of an inhibitor for inhibiting the protein kinase depended by double-stranded RNA and/or a medicine for treating the diseases mediated by the protein kinase depended by the double-stranded RNA. By the method and the medicine, the whole-body infected or whole-body inflammatory diseases can be effectively treated, in particular the septicemia and the septicopyemia; and the method and the medicine have wide clinical application and market development prospect.
Description
Technical field
The present invention relates to medical technical field, relate to the application in the medicine of the diseases associated with inflammation of the infection for preparing the treatment general or general of carbenoxolone or its pharmaceutically acceptable salt particularly.
Background technology
Septicemia or pyemia are a kind of high-intensity inflammatory reactions of the general to severe infection.The difference of it and endotoxemia is that a large amount of endotoxins is not only arranged in the blood samples of patients, and the source of disease microorganism is arranged.The animal model of endotoxemia generally is to form by the direct injection bacterial endotoxin, because this model do not cause zoogenetic infection, therefore can not effectively copy the various signs of septicemia and is not considered to desirable septicemia model.So at present the most frequently used and widely accepted septicemia or pyemia animal model are by the ligation vermiform appendix and cause perforation to cause that serious abdominal cavity infection sets up.
Septicemia or pyemia are still the main cause of death of serious symptom ward patient in the hospital so far.For example: septicemia is annual about 1000 people that cause death in Taiwan. and there are 750,000 people to suffer from septicemia in the U.S., wherein 20% septicemia patient death.The septicemia sickness rate is up to about 10% among the patient who infects in Chinese Hospitals.The Therapeutic Method of septicemia or pyemia mainly is supportive at present, and often invalid.Therefore, it is very necessary to continue to seek effective treatment way.
Since several centuries, Radix Glycyrrhizae is used to treat similar gastric ulcer in traditional medicine, hepatitis and bronchitic diseases associated with inflammation.The antiinflammatory action of Radix Glycyrrhizae is given the credit to its main component glycyrrhizic acid.Evidence suggests glycyrrhizic acid in influenza, hepatitis, toxemia is useful in the animal model of pulmonary infection and enteritis.With succinic acid substitute glucuronic acid in the glycyrrhizic acid produce new molecule be called carbenoxolone (carbenoxolone, CBX).Carbenoxolone salt is a kind of prescription drugs that is used for the treatment of esophageal ulcer and inflammation.The biological effect of carbenoxolone and glycyrrhizic acid is different.Such as, glycyrrhizic acid can not be blocked the slit interface channel, and ischemic animal is not had protective effect, and carbenoxolone can suppress the slit interface channel effectively and protect newborn rat brain ischemic injuries.And up to the present, do not report that also whether carbenoxolone (salt) has protective effect to the animal of the septicemia of suffering from lethal.
Summary of the invention
The purpose of this invention is to provide a kind of known compound-carbenoxolone or its pharmaceutically acceptable salt new purposes in the medicine of the diseases associated with inflammation of the infection for preparing the treatment general or general.
A first aspect of the present invention provides the purposes of a kind of carbenoxolone or its pharmaceutically acceptable salt, and it is for the preparation of the medicine of the diseases associated with inflammation of the infection for the treatment of general or general.
In another preference, the infection of described general or the diseases associated with inflammation of general are at the disease or the symptom that are selected from down group: septicemia, pyemia, the diseases associated with inflammation that is caused by antibacterial or antibacterial composition.
In another preference, the infection of described general or the diseases associated with inflammation of general are septicemia and/or pyemia.
In another preference, described medicine also is used for the activity of the protein kinase of inhibition double stranded RNA dependence.
In another preference, described medicine is compositions.
In another preference, the content of carbenoxolone or its pharmaceutically acceptable salt is 0.001-99.9wt% in the described compositions, by the gross weight of compositions.
In another preference, the content of carbenoxolone or its pharmaceutically acceptable salt is preferably 0.01-95wt% in the described compositions, and more preferably 0.1-90wt% is by the gross weight of compositions.
In another preference, described carbenoxolone or its pharmaceutically acceptable salt be natural separation or chemosynthesis.
In another preference, before using described medicine, simultaneously or afterwards, be used the active substance of the diseases associated with inflammation of the infection of other treatment general or general.
In another preference, the subject of described medicine is mammal, and is preferred human.
In another preference, the dosage form of described medicine is selected from: peroral dosage form, injection or lyophilized preparation.
In another preference, the dosage form of described medicine is injection.
In another preference, the drug administration by injection mode comprises: intravenous injection, intramuscular injection, subcutaneous injection, intracavitary administration.
In another preference, described medicine comprises:
(i) carbenoxolone or its pharmaceutically acceptable salt;
(ii) pharmaceutically acceptable carrier.
The (iii) active substance of the diseases associated with inflammation of the infection of Ren Xuan one or more other treatment generals or general.
In another preference, described active substance is selected from down one or more of group: the medicine of antibiotic, the medicine that suppresses infection, inflammation-inhibiting reaction.
In another preference, the medicine that described inhibition is infected is hormone medicine.
In another preference, the medicine of described inflammation-inhibiting reaction is hormone medicine.
A second aspect of the present invention provides the purposes of another kind of carbenoxolone or its pharmaceutically acceptable salt, its for the preparation of
(a) suppress the inhibitors of protein kinases that double stranded RNA relies on; And/or
(b) treatment is by the medicine of the disease of the protein kinase mediation of double stranded RNA dependence.
In another preference, described inhibitor or medicine also are used for the treatment of the infection of general or the diseases associated with inflammation of general.
A third aspect of the present invention provides the method for the diseases associated with inflammation of a kind of infection for the treatment of general or general, and described method comprises step: the object that needs is used carbenoxolone or its pharmaceutically acceptable salt of safe and effective amount.
In should be understood that within the scope of the present invention, above-mentioned each technical characterictic of the present invention and can making up mutually between specifically described each technical characterictic in below (eg embodiment), thus constitute new or optimized technical scheme.As space is limited, this tired stating no longer one by one.
Description of drawings
Fig. 1 has shown the survival rate of septicemia animal when the amount of application of carbenoxolone sodium is respectively 1.2 and 3.0 milligrams/kg body weight.
Fig. 2 has shown the survival rate of septicemia animal when the amount of application of carbenoxolone sodium is 6.0 milligrams/kg body weight.
Fig. 3 has shown that bacteria lipopolysaccharide is to the expression of the protein kinase of double stranded RNA dependence and the stimulation of phosphorylation in the macrophage.
The specific embodiment
The inventor is through extensively and profoundly research, be surprised to find that known compound carbenoxolone or its pharmaceutically acceptable salt are to the infection of general or the diseases associated with inflammation of general, particularly septicemia and pyemia had the obvious treatment effect, and almost there is not toxic and side effects, can cure above-mentioned disease safely and effectively, the inventor has developed the diseases associated with inflammation medicine of septicemia and pyemia particularly that can be used for preparing the infection for the treatment of general or general thus.Finished the present invention on this basis.
Carbenoxolone or its pharmaceutically acceptable salt are to therapeutic activity and the application of the diseases associated with inflammation of the infection of general or general
The invention provides carbenoxolone or its pharmaceutically acceptable salt at the infection for the treatment of general or the diseases associated with inflammation of general, the new purposes in treatment septicemia and pyemia particularly, carbenoxolone or its pharmaceutically acceptable salt among the present invention, perhaps contain this compounds as composition of active components, can play the effect for the treatment of septicemia and pyemia effectively.
Be not limited to theory, carbenoxolone of the present invention or its pharmaceutically acceptable salt can be treated septicemia and pyemia by following mechanism:
By suppressing bacterial endotoxin lipopolysaccharide (lipopolysaccharide, the activity of the protein kinase that the double stranded RNA of LPS) inducing relies on.The activity increase of the protein kinase that the double stranded RNA that bacterial endotoxin causes relies on is the key link of hyperphlogosis reaction, bacteria lipopolysaccharide can stimulate expression (PKR) and the phosphorylation (P-PKR) of the protein kinase of the interior double stranded RNA dependence of inflammatory cell (macrophage), expression and the phosphorylation of the protein kinase that the double stranded RNA that carbenoxolone or its pharmaceutically acceptable salt can suppress to be excited by bacteria lipopolysaccharide relies on, thereby the activity of the protein kinase that the inhibition double stranded RNA relies on.
Therefore, carbenoxolone or its pharmaceutically acceptable salt, and contain carbenoxolone or its pharmaceutically acceptable salt can be used for preparing the disease that suppresses the protein kinase mediation that inhibitors of protein kinases that double stranded RNA relies on or treatment rely on by double stranded RNA as composition of active components medicine.In addition also can be for the preparation of the medicine for the treatment of septicemia and pyemia, with the present supportive Therapeutic Method of effective treatment septicemia and the pyemia that can't cure.
Medicine and application process
Medicine of the present invention can be compositions (medicine), it contains carbenoxolone or its pharmaceutically acceptable salt of effective dose, pharmaceutically acceptable carrier or excipient, and the active substance of the diseases associated with inflammation of the infection of optional other treatment general or general.
As used herein, term " contain " or " comprising " comprised " comprising ", " basically by ... constitute " and " by ... constitute ".As used herein, the composition of term " pharmaceutically acceptable " is applicable to people and/or animal and does not have excessive bad side reaction (as toxicity, stimulation and allergy), the material of rational benefit/risk ratio is namely arranged.As used herein, term " effective dose " refers to and can produce function or amount active and that can be accepted by people and/or animal to people and/or animal.
As used herein, term " pharmaceutically acceptable carrier " refers to be used for the treatment of the carrier of agent administration, comprises various excipient and diluent.This term refers to some medicament carriers like this: they itself are not necessary active component, and do not have undue toxicity after using.Suitable carriers is well known to those of ordinary skill in the art." Lei Mingdun pharmaceutical science " (Remington ' s Pharmaceutical Sciences, Mack Pub.Co. can find discussing fully about pharmaceutically acceptable excipient in N.J.1991).
Carbenoxolone as herein described or its pharmaceutically acceptable salt can obtain or obtain by chemosynthesis through natural separation.
In the compositions of the present invention, the effective ingredient of carbenoxolone or its pharmaceutically acceptable salt accounts for the 0.001-99.9wt% of composition total weight; Being preferably the 0.01-95wt% of composition total weight, more preferably is 0.1-90wt%, and surplus is materials such as pharmaceutically acceptable carrier and other additive.
In a preferred embodiment of the present invention, described medicine can also be various topical administration formulations or other gastrointestinal tract external administration preparation, as injection except being the various dosage forms (for example comprising tablet, capsule, pill etc.) of suitable for oral administration administration.
Medicine of the present invention can also be made lyophilized formulations.Can dilute it before use, by the gross weight of dilution, the content of carbenoxolone or its pharmaceutically acceptable salt is 0.01-99.9%.
In another preference of the present invention, use medicine of the present invention once a day or repeatedly, for example 1,2,3,4,5 or 6 time.Wherein route of administration includes, but are not limited to: oral administration, drug administration by injection, intracavitary administration, transdermal administration; Preferred drug administration by injection comprises: intravenous injection, intramuscular injection, subcutaneous injection, intracavitary administration.
When using medicine of the present invention, concrete dosage also should be considered factors such as route of administration, patient health situation, and these are all within the skilled practitioners skill.The safe and effective amount of carbenoxolone or its pharmaceutically acceptable salt is usually at least about 0.5mg/ kg body weight/sky, and in most of the cases is no more than about 30 mg/kg body weight/day.Dosage preferably is about 2-10mg/ kg body weight/sky.
Before using medicine of the present invention, simultaneously or afterwards, can also be used the active substance of the diseases associated with inflammation of the infection of other treatment general or general.As long as can reach the purpose for the treatment of, other active substances can be selected from the diseases associated with inflammation of the infection for the treatment of general commonly used or general antibiotic, suppress the medicine that infects or the medicine of inflammation-inhibiting reaction.Wherein, the medicine of inhibition infection is hormone medicine.The medicine of inflammation-inhibiting reaction is hormone medicine.
Compared with prior art, major advantage of the present invention comprises:
(i) the present invention finds that first carbenoxolone or its pharmaceutically acceptable salt can effectively treat the infection of general or the diseases associated with inflammation of general, particularly treats septicemia and pyemia, thereby provides new approach for the treatment of septicemia and pyemia.
(ii) the invention provides and contain carbenoxolone or its pharmaceutically acceptable salt as the compositions of effective ingredient, said composition is very effective for treatment septicemia and pyemia, can cure present supportive Therapeutic Method septicemia and the pyemia that can't cure.
(iii) the present invention uses cell biology method, disclosed the mechanism of carbenoxolone or its pharmaceutically acceptable salt treatment septicemia and pyemia: expression and the phosphorylation of the protein kinase that the double stranded RNA that is excited by bacteria lipopolysaccharide by inhibition relies on, thereby suppress the activity of the protein kinase of double stranded RNA dependence, thereby effectively treat septicemia and pyemia.
The above-mentioned feature that the present invention mentions, or the feature that embodiment mentions can combination in any.All features that this case description discloses can with any composition forms and usefulness, each feature that discloses in the description, the alternative characteristics that can anyly be provided identical, impartial or similar purpose replaces.Therefore except special instruction is arranged, the feature that discloses only is the general example of equalization or similar features.
Below in conjunction with specific embodiment, further set forth the present invention.Should be understood that these embodiment only to be used for explanation the present invention and be not used in and limit the scope of the invention.The experimental technique of unreceipted actual conditions in the following example is usually according to normal condition or the condition of advising according to manufacturer.
Unless otherwise defined, the same meaning that employed all specialties and scientific words and one skilled in the art are familiar with in the literary composition.In addition, any method similar or impartial to described content and material all can be applicable in the inventive method.The usefulness that preferable implementation method described in the literary composition and material only present a demonstration.
The survival rate of septicemia mice is suffered from the raising of embodiment 1 carbenoxolone sodium dose dependent
Reagent: carbenoxolone sodium is available from Sigma-Aldrich company (carbenoxolone sodium article number: C4790).
Balb/C mice septicemia model: according to vermiform appendix by ligation and the perforation (cecal ligation and puncture, CLP) method is set up, method for building up sees document J.Vis.Exp. (62) for details, e3926, doi:10.3791/3926 (2012).The animals survived time finishes from operation and begins to calculate.
Medication: carbenoxolone sodium is dissolved in normal saline, and passes through lumbar injection by following described dosage.Administration for the first time is behind the CLP 24 hours.Be administered once every 24 hours then.3 times altogether.Dosage is respectively per kilogram of body weight 1.2,3.0 and 6.0 milligrams.Volume is 0.2 milliliter.
Matched group is only injected the normal saline of same volume.
Fig. 1 is different experimental grouies with Fig. 2.Fig. 1 shows that the carbenoxolone sodium of 1.2 and 3.0 milligrams/kg body weight brings up to 50% and 57% the 8th day survival rate from 21% with the septicemia animal respectively.Fig. 2 shows that the carbenoxolone sodium of 6.0 milligrams/kg body weight brings up to 85% with the survival rate of septicemia animal from 42%.These results show that carbenoxolone sodium can be cured and suffer from serious septicemia mice.
The activity of the protein kinase that the double stranded RNA that embodiment 2 carbenoxolone sodium inhibition bacterial endotoxin causes relies on
Turnover of Mouse Peritoneal Macrophages is collected and the following document of cultured method reference: ((a) Biochemical Pharmacology, 81,9,1152-1163, (b) Nature488,670-674.(c)PLoS?One.2011Feb8;6(2):e16945.doi:10.1371/journal.pone.0016945。(d)J.Vis.Exp.(62),e3926,doi:10.3791/3926(2012))。
Intervention to cell is to carry out and lasting 16 hours in Dole uncle section minimum essential medium.The concentration of bacteria lipopolysaccharide be 0.5 mcg/ml (bacteria lipopolysaccharide article number: L2630, Sigma-Aldrich, U.S.A.).The concentration of carbenoxolone sodium is 10 little rubbing.Expression and the phosphorylation of the protein kinase that double stranded RNA relies in the cell are to determine by Western blotting.The total amount of the protein kinase that double stranded RNA relies on is the antibody (trade name: mouse-anti Mus protein kinase R monoclonal antibody with a kind of protein kinase of anti-double stranded RNA dependence.Article number: SC-6282, manufacturer: Santa Cruz Biotechnology) detect.The protein kinase that the double stranded RNA of phosphorylation relies on is the antibody (trade name: the protein kinase R antibody of the anti-people's phosphorylation of rabbit with a kind of protein kinase of double stranded RNA dependence of anti-phosphorylation.Article number: 07-886.Manufacturer: Millipore U.S.A.) detects.Fig. 3 shows that bacteria lipopolysaccharide can stimulate expression (PKR) and the phosphorylation (P-PKR) of the protein kinase that double stranded RNA relies in the macrophage.And expression and the phosphorylation of the protein kinase that the double stranded RNA that carbenoxolone sodium can significantly suppress to be excited by bacteria lipopolysaccharide relies on.These results show that carbenoxolone can suppress the activity of the protein kinase of double stranded RNA dependence.
All quote in this application as a reference at all documents that the present invention mentions, just quoted as a reference separately as each piece document.Should be understood that in addition those skilled in the art can make various changes or modifications the present invention after having read above-mentioned teachings of the present invention, these equivalent form of values fall within the application's appended claims institute restricted portion equally.
Claims (10)
1. the purposes of a carbenoxolone or its pharmaceutically acceptable salt is characterized in that, for the preparation of the medicine of the diseases associated with inflammation of the treatment infection of general or general.
2. purposes as claimed in claim 1 is characterized in that, the infection of described general or the diseases associated with inflammation of general are at the disease or the symptom that are selected from down group: septicemia, pyemia, the diseases associated with inflammation that is caused by antibacterial or antibacterial composition.
3. purposes as claimed in claim 1 is characterized in that, described medicine also is used for the activity of the protein kinase of inhibition double stranded RNA dependence.
4. purposes as claimed in claim 1 is characterized in that, described medicine is compositions.
5. purposes as claimed in claim 4 is characterized in that, the content of carbenoxolone or its pharmaceutically acceptable salt is 0.001-99.9wt% in the described compositions, by the gross weight of compositions.
6. purposes as claimed in claim 1 is characterized in that, the dosage form of described medicine is selected from: peroral dosage form, injection or lyophilized preparation.
7. purposes as claimed in claim 1 is characterized in that, described medicine comprises:
(i) carbenoxolone or its pharmaceutically acceptable salt;
(ii) pharmaceutically acceptable carrier;
The (iii) active substance of the diseases associated with inflammation of the infection of Ren Xuan one or more other treatment generals or general.
8. purposes as claimed in claim 7, described active substance are selected from down one or more of group: antibiotic, suppress the medicine that infects, the medicine of inflammation-inhibiting reaction.
9. the purposes of a carbenoxolone or its pharmaceutically acceptable salt is characterized in that, for the preparation of
(a) suppress the inhibitors of protein kinases that double stranded RNA relies on; And/or
(b) treatment is by the medicine of the disease of the protein kinase mediation of double stranded RNA dependence.
10. purposes as claimed in claim 9 is characterized in that, described inhibitor or medicine also are used for the treatment of the infection of general or the diseases associated with inflammation of general.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111773228A (en) * | 2020-06-09 | 2020-10-16 | 中山大学附属第五医院 | Application of carbenoxolone in preparation of anti-Zika virus drugs |
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Non-Patent Citations (2)
| Title |
|---|
| BEN LU ET AL.: "Novel role of PKR in inflammasome activation and HMGB1 release. Ben Lu et al.Nature 2012,488,670-674", 《NATURE》 * |
| W. LI ET AL.: "Carbenoxolone protects mice against severe sepsis by inhibiting HMGB1 release and activities. W. Li et al. SHOCK. Wolters Kluwer,Lippincott Williams & Wilkins.June 2012, volume37,P31-119,Abstracts.", 《SHOCK》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111773228A (en) * | 2020-06-09 | 2020-10-16 | 中山大学附属第五医院 | Application of carbenoxolone in preparation of anti-Zika virus drugs |
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