CN104888189A - Novel application of 3-amino-2-hydroxy-4-phenyl-valyl-isoleucine analogue - Google Patents
Novel application of 3-amino-2-hydroxy-4-phenyl-valyl-isoleucine analogue Download PDFInfo
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- CN104888189A CN104888189A CN201510324171.4A CN201510324171A CN104888189A CN 104888189 A CN104888189 A CN 104888189A CN 201510324171 A CN201510324171 A CN 201510324171A CN 104888189 A CN104888189 A CN 104888189A
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Abstract
The invention provides application of a 3-amino-2-hydroxy-4-phenyl-valyl-isoleucine analogue conforming to a general formula (I) and serving as an active ingredient in preparation of a pharmaceutical preparation used for preventing and curing inflammatory diseases and inflammation-associated infections. The general formula (I) is as shown in the description, wherein R1 is isopropyl or methylpropyl, R2 is isopropyl, methylpropyl or 2-methylpropyl, R3 is carboxyl or a chemical group as shown in the description, and R4 is H, straight-chain or branched-chain C1-C4 alkyl, straight-chain or branched-chain C1-C4 hydroxyalkyl, straight-chain or branched-chain C1-C4 sulfydryl-alkyl, straight-chain or branched-chain C1-C4 alkyl-carboxyl, and C1-C4 alkyl-amido. The invention further provides a pharmaceutical preparation used for preventing and curing inflammatory diseases. The pharmaceutical preparation contains an active ingredient capable of treating effective dose and a pharmaceutically acceptable carrier or excipient, wherein the active ingredient is the 3-amino-2-hydroxy-4-phenyl-valyl-isoleucine analogue conforming to the general formula (I), an optical isomer of the analoge or a pharmaceutically acceptable salt of the analoge.
Description
Technical field
The invention belongs to field of medicaments, relate to 3-amino-2-hydroxy-4-phenylbutanoyl-valyl-isoleucine analog particularly as active component for the preparation of the new opplication in prevention and therapy inflammation disease and the pharmaceutical preparation caught relevant to inflammation.
Background technology
Inflammation is a kind of very common and important basic pathology process, any factor that can cause tissue injury, as the generation infected, non-infectious tissue injury (as wound, operation etc.) all can cause inflammation, and these inflammation have much similar feature (Barton GM.A calculated response:control of inflammation by the innate immune system.J.Clin.Invest., 2008,118:413-420).For the inflammation that bacteriological infection causes, the endotoxin (bacteria lipopolysaccharide lipopolysaccharides is called for short LPS) of bacterial secretory is the principal element that antibacterial is caused a disease, and can cause a series of inflammatory reactions of body.Inflammatory signals and Toll-like receptor (TLRs) family etc. of LPS induction are relevant.When body is subject to bacteriological infection, LPS acts on TLRs receptor on cell membrane, transmitted by intracellular signal, cascade gene expression changes, LPS can stimulate cytokine profiles in body to synthesize and discharge inflammatory factor (as NO, TNF-α, IL-6, IL-1 β etc.), systemic inflammatory reaction is caused to occur, cause toxic shock, inflammation disease (the Wang Xiaodongs such as systemic inflammatory response syndrome (SIRS) and multiple organ dysfunction syndrome (MODS), endotoxin neutralizing protein and the effect [J] in sepsis control thereof, foreign medical science physiology, pathology science and clinical fascicle, 2001, 21 (2): 144-146, beautiful grain husk, Wang Xingpeng, block the progress [J] of endotoxin signal transduction pathway treatment sepsis or septic shock, Chinese Journal of Emergency Medicine, 2003,12 (2): 135-137, Wang Ying, Guo Chen, the treatment [J] of septic shock, Chinese Applied Clinical Pediatrics magazine, 2007,22 (6): 403-405, the inflammatory reaction signal transduction pathway progress of Zhang Xuemei, Xiong Huanzhang, LPS induction, Chinese Veterinary Journal, 2010,46 (7): 45-47).Therefore, LPS can be considered the major virulent factor of antibacterial, plays a very important role in the pathogeny of bacteriological infection.Equally, when tissue injury, body can secrete a large amount of cytokine to repair damage, but when overresponse, also can cause the inflammation diseases such as SIRS, MODS.
Ubenimex (Ubenimex has another name called Bestatin) is common antitumour auxiliary drug, improving immunocompetence, for (Umezawa, H., the Aoyagi such as auxiliary treatment of anticancer chemotherapy, radiotherapy, T., Suda, H., Hamada, M. & Takeuchi, T. (1976) .Bestatin, an inhibitor of aminopeptidase B, produced by actinomycetes, (29) .Pp.97-99; Muskardin, D.T., Voelkel.N.F. & Fitzpatrick, F.A. (1994) .Modulation of pulmonary leukotriene formation and perfusion pressure by bestatin, an inhibitor of leukotriene A4 hydrolase. (48) .pp.131-137; Hirayama, Y; Sakamaki, S; Takayanagi, N; Tsuji, Y; Sagawa, T; Chiba, H; Matsunaga, T; Niitsu, Y. (2003). " Chemotherapy with ubenimex corresponding to patient age and organ disorder for 18 cases of acute myelogeneous leukemia in elderly patients-effects, complications and long-term survival " .Gan to kagakuryoho.Cancer & chemotherapy 30 (8): 1113-8).The chemical structural formula of ubenimex is:
3-amino-2-hydroxy-4-phenylbutanoyl-valyl-isoleucine is the new derivatives similar to ubenimex (Bestatin) structure, applicant of the present invention is this compound first public in the Chinese invention patent of 201110076554.6 at application number, and its chemical structural formula is:
Be further disclose the application of compound 3-amino-2-hydroxy-4-phenylbutanoyl-valyl-isoleucine as amastatin in the Chinese invention patent of 201110076555.0 at application number, its activity is better than ubenimex (Bestatin), can be used as oncotherapy or adjuvant therapy medicaments, there is immunological enhancement in better body, if strengthen T cell and lethal NK cytoactive and function etc., but they are to the effect in such as bacterial acute inflammation, and there is not been reported.
A series of analog that the present inventor further study it on the basis of 3-amino-2-hydroxy-4-phenylbutanoyl-valyl-isoleucine are to the effect in such as bacterial acute inflammation.
Summary of the invention
The serial analogs that the present inventor further study it on the basis of 3-amino-2-hydroxy-4-phenylbutanoyl-valyl-isoleucine is to the effect in such as bacterial acute inflammation, research finds, its serial analogs has obvious inhibitory action for the acute inflammation that LPS causes.Therefore, the object of the present invention is to provide the serial analogs of 3-amino-2-hydroxy-4-phenylbutanoyl-valyl-isoleucine as active component for the preparation of the new opplication in prevention and therapy inflammation disease and the pharmaceutical preparation caught relevant to inflammation.
For achieving the above object, the present invention is by the following technical solutions:
First aspect of the present invention is to provide 3-amino-2-hydroxy-4-phenylbutanoyl-valyl-isoleucine analog that one meets general formula (I) as active component for the preparation of the application in prevention and therapy inflammation disease and the pharmaceutical preparation caught relevant to inflammation;
Wherein, R1 is isopropyl or methyl-propyl, and R2 is isopropyl, methyl-propyl or 2-methyl-propyl, R3 be carboxyl or
Wherein, R
4be selected from: the C1-C4 alkyl of H, straight or branched, the C1-C4 hydroxyalkyl of straight or branched, the C1-C4 mercaptoalkyl of straight or branched, the C1-C4 alkyl carboxyl of straight or branched and C1-C4 alkylamidoalkyl.
Further, the inflammation etc. that described inflammation disease and catch relevant to inflammation comprise bacteriological infection, uncomplicated cystitis, bronchitis, wound, Postoperative inflammatory reaction, unexpected injury, myocardial infarction, tuberculosis or sarcoidosis, sepsis, metastatic tumo(u)r, Active Rheumatoid Arthritis, seronegative spondylarthritis, immune vasculitis, polymyalgia rheumatica, segmental enteritis, dvt are formed.
The present invention have rated the antiphlogistic effects of 3-amino-2-hydroxy-4-phenylbutanoyl-valyl-isoleucine serial analogs, inventor selects mouse monokaryon-macrophage system Raw264.7 to test, the inflammatory factor NO detecting LPS induction expresses and release, find after detecting, the burst size of the inflammatory factor NO of LPS induction significantly reduces.
Second aspect of the present invention is to provide a kind of for prevention and therapy inflammation disease and the pharmaceutical preparation that catches relevant to inflammation, containing the treatment active component of effective dose and pharmaceutically acceptable carrier or excipient, described active component for described in meet acceptable salt on the 3-amino-2-hydroxy-4-phenylbutanoyl-valyl-isoleucine analog of general formula (I), its optical isomer or its materia medica.
Preferably, the dosage form of described pharmaceutical preparation comprises tablet, capsule, oral liquid, granule or injection (as lyophilized injectable powder).
On materia medica, acceptable salt can pharmacologically with on its materia medica all accept.Can be pharmacologically alkali metal salt or alkali salt with acceptable salt on its materia medica, particular certain cancers, potassium salt, magnesium salt or calcium salt.
Described pharmaceutical preparation relates to (as transdermal medicine preparation) dosage form of (such as oral, the sublingual administration or rectally) through intestinal, parenteral or local.The organic or inorganic thing do not reacted with active component can as carrier, saccharide, magnesium stearate, Talcum or the celluloses such as Ru Shui, oil, benzyl alcohol, Polyethylene Glycol, glycerol triacetate or other fatty glyceride, gelatin, lecithin, cyclodextrin, lactobiose or starch.Oral medication preferred tablet, dragee, capsule, powder, syrup, concentrating agents or drop, the preferred suppository of rectally, parenteral preferred aqueous solutions or oil solution, or lyophilized preparation.Also can use suspensoid, Emulsion or implant, local application can with patch or ointment.Parenteral use pharmaceutical preparation comprise reactive compound sterile, aqueous or without water injection, at the solution that this is preferably isotonic with cipient blood.
These pharmaceutical preparatioies can contain stabilizing agent, the additive controlling pharmaceutically active compound release, antioxidant, buffer agent, antibacterial and the adjuvant for the preparation of isosmotic solution.Moisture and anhydrous sterile suspensions can contain suspendible additive and thickening agent.Pharmaceutical preparation can be divided in single dose or multi-dose container as in sealant bottle, also can preserve as the goods through lyophilizing, as needs, and can with sterile liquid as water or saline solution preparation during use.Sterile powder, granule or tablet can also be used in the same way.
Described pharmaceutical preparation can be used for prevention and therapy inflammation and inflammation related disease in humans and animals.
Accompanying drawing explanation
In Figure 1A Raw264.7 cell that to be 3-amino-2-hydroxy-4-phenylbutanoyl-valyl-isoleucine serial analogs induce LPS, twice immunoblot results chart of iNOS protein expression;
Figure 1B is in the Raw264.7 cell of LPS induction, the quantitative analysis chart of iNOS protein expression;
Fig. 2 is the testing result chart that Griess method detects NO burst size in culture supernatant.
Detailed description of the invention
Carry out detailed and concrete introduction below by specific embodiment to the present invention, to make better to understand the present invention, but following embodiment does not limit the scope of the invention.
One, examples of compounds
Present embodiments provide the serial analogs of 3-amino-2-hydroxy-4-phenylbutanoyl-valyl-isoleucine, meet following general formula (I):
Wherein, R1 is isopropyl or methyl-propyl, and R2 is isopropyl, methyl-propyl or 2-methyl-propyl, R3 be carboxyl or
Wherein, R
4be selected from: the C1-C4 alkyl of H, straight or branched, the C1-C4 hydroxyalkyl of straight or branched, the C1-C4 mercaptoalkyl of straight or branched, the C1-C4 alkyl carboxyl of straight or branched and C1-C4 alkylamidoalkyl.
The examples of compounds meeting above-mentioned general formula (I) comprises:
Two, Application Example
The concrete operations of the detection method used in following Application Example are as follows:
1, the acute inflammation model of LPS induction is built:
By C57/BL mice group, often organize at least 5, weigh, the LPS of normal saline (negative control group) and 5mg/kg (inflammation group) is used to carry out Intratracheal administration respectively, at lps injection first 12 hours, after 10 minutes and give the lumbar injection (except negative control group) of compound 1 ~ 6 after 12 hours, 0, put to death after 4,24 hours, heart extracting blood, repeatedly pulmonary is rinsed with the PBS of 1ml, get lung tissue after collecting washing liquid, prepare tissue slice, the expression of cytokine and inflammatory factor in fluorescence quantitative PCR detection lung tissue.
2, quantitative fluorescent PCR (QPCR):
Trizol cell lysis, extracting RNA, reverse transcription PCR obtains cDNA, carries out quantitative fluorescent PCR as template, the DNA transcriptional level change of the inflammation-associated cytokine of inducing before and after inspection drug effect and inflammatory molecule etc.
3, immunoblotting (Western Blot):
Cracking collecting cell, degenerative treatments, SDS electrophoresis 80V 2 hours, transferring film 80V 1 hour, half an hour closed by 5% milk, hatches primary antibodie for 4 DEG C and spends the night, TBST buffer (Tris-Buffered Saline and Tween 20) washes film 3 times, room temperature is hatched two and is resisted 1 hour, and TBST washes film 3 times, Odyssey Far Infrared Observation instrument is observed the nitric oxide synthetase iNOS protein expression level change etc. of inducing before and after drug effect.
4, Griess method detects NO burst size:
NO very easily forms NO in aqueous
2 -, in acid condition, NO
2 -with diazol sulfanilamide generation diazo reaction, generate diazonium compound, further with naphthylethenyl diamidogen generation coupling reaction, its production concentration and NO
2 -concentration has linear relationship, has maximum absorption band at 540-560nm place.Utilize this principle can detect the burst size of NO in cell conditioned medium.
the antiinflammatory effect of Application Example, 3-amino-2-hydroxy-4-phenylbutanoyl-valyl-isoleucine serial analogs
really:
The present embodiment is for Raw264.7 mouse macrophage, the impact that the inflammatory factor NO that comparative compound 1 ~ 6 is induced LPS expresses, comprises the burst size (Fig. 2) that LPS stimulates NO in the expression (Figure 1A and Figure 1B) of iNOS albumen in 24 hours later cell and cells and supernatant.
As shown in FIG. 1A and 1B for the protein expression level of iNOS in the Raw264.7 cell of LPS induction detects.By Raw264.7 cell with 3.5 × 10
5the density in/hole is inoculated in 12 orifice plates, by the RPMI-1640 overnight incubation containing 10% hyclone, compound 1 ~ 6 hatches 30 minutes in advance with the concentration of 0.2mg/ml, and matched group is equal-volume culture fluid (medium), stimulates induction 24 hours with the LPS of 0.1 μ g/ml.Collect supernatant, cell lysis carries out immunoblotting assay.Wherein, Figure 1A is twice immunoblot results of iNOS protein expression, and β-actin is contrast; Figure 1B is the quantitative analysis of iNOS protein expression, the Reinhoit Zahl of iNOS and β-actin is calculated with Image J software, get the result calculating mean value standard error of three independent experiments, comparative compound 1 ~ 6 result and LPS group, carry out significant difference analysis, wherein * * P<0.01.
Be illustrated in figure 2 Griess method and detect NO burst size in culture supernatant.Cell culture and stimulation induction are as described in Figure 1A and Figure 1B, and get culture supernatant, test kit detects the burst size of wherein NO.Get the result calculating mean value standard error of three independent experiments, comparative compound 1 ~ 6 and the result of LPS group, carry out significant difference analysis, wherein * P<0.05, * * P<0.01.
Found out by Figure 1A, Figure 1B, Fig. 2 testing result, the burst size of the inflammatory factor NO of the protein expression level in the Raw264.7 cell that 3-amino-2-hydroxy-4-phenylbutanoyl-valyl-isoleucine serial analogs (compound 1 ~ 6) is induced LPS and LPS induction all has the minimizing of about 50%.
Therefore, the invention provides 3-amino-2-hydroxy-4-phenylbutanoyl-valyl-isoleucine serial analogs and application thereof, namely its as active component for the preparation of the application in prevention and therapy inflammation disease and the pharmaceutical preparation caught relevant to inflammation.Thus, present invention also offers the pharmaceutical preparation for prevention and therapy inflammation disease, contain the active component and pharmaceutically acceptable carrier or excipient for the treatment of effective dose, described active component is acceptable salt on 3-amino-2-hydroxy-4-phenylbutanoyl-valyl-isoleucine serial analogs, its optical isomer or its materia medica.Further preferably, preferably, the dosage form of described pharmaceutical preparation comprises tablet, capsule, oral liquid, granule or injection (as lyophilized injectable powder).
Be described in detail specific embodiments of the invention above, but it is just as example, the present invention is not restricted to specific embodiment described above.To those skilled in the art, any equivalent modifications that the present invention is carried out and substituting also all among category of the present invention.Therefore, equalization conversion done without departing from the spirit and scope of the invention and amendment, all should contain within the scope of the invention.
Claims (4)
1. the compound meeting general formula (I) as active component for the preparation of the application in prevention and therapy inflammation disease and the pharmaceutical preparation caught relevant to inflammation;
Wherein, R1 is isopropyl or methyl-propyl, and R2 is isopropyl, methyl-propyl or 2-methyl-propyl, R3 be carboxyl or
Wherein, R
4be selected from: the C1-C4 alkyl of H, straight or branched, the C1-C4 hydroxyalkyl of straight or branched, the C1-C4 mercaptoalkyl of straight or branched, the C1-C4 alkyl carboxyl of straight or branched and C1-C4 alkylamidoalkyl.
2. application according to claim 1, it is characterized in that, described inflammation disease and catch relevant to inflammation comprise bacteriological infection, inflammation that uncomplicated cystitis, bronchitis, wound, Postoperative inflammatory reaction, unexpected injury, myocardial infarction, tuberculosis or sarcoidosis, sepsis, metastatic tumo(u)r, Active Rheumatoid Arthritis, seronegative spondylarthritis, immune vasculitis, polymyalgia rheumatica, segmental enteritis, dvt are formed.
3. one kind for prevention and therapy inflammation disease and the pharmaceutical preparation that catches relevant to inflammation, it is characterized in that, contain the active component and pharmaceutically acceptable carrier or excipient for the treatment of effective dose, described active component is acceptable salt on compound, its optical isomer or its materia medica described in claim 1.
4. pharmaceutical preparation according to claim 3, is characterized in that, the dosage form of described pharmaceutical preparation comprises tablet, capsule, oral liquid, granule or injection.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102198139A (en) * | 2010-03-26 | 2011-09-28 | 中国医学科学院医药生物技术研究所 | Pharmaceutical composition with antineoplastic effect, and application method thereof |
| CN102198150A (en) * | 2010-03-26 | 2011-09-28 | 中国医学科学院医药生物技术研究所 | Antitumor drug with double active components and application thereof |
| CN102631664A (en) * | 2011-01-28 | 2012-08-15 | 上海来益生物药物研究开发中心有限责任公司 | Application of 3-amino-2-hydroxy-4-phenyl-valyl-isoleucine |
| CN103588713A (en) * | 2013-06-07 | 2014-02-19 | 潍坊博创国际生物医药研究院 | Multi-target ubenimex prodrug derivative, as well as preparation method and application thereof |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102198139A (en) * | 2010-03-26 | 2011-09-28 | 中国医学科学院医药生物技术研究所 | Pharmaceutical composition with antineoplastic effect, and application method thereof |
| CN102198150A (en) * | 2010-03-26 | 2011-09-28 | 中国医学科学院医药生物技术研究所 | Antitumor drug with double active components and application thereof |
| CN102631664A (en) * | 2011-01-28 | 2012-08-15 | 上海来益生物药物研究开发中心有限责任公司 | Application of 3-amino-2-hydroxy-4-phenyl-valyl-isoleucine |
| CN103588713A (en) * | 2013-06-07 | 2014-02-19 | 潍坊博创国际生物医药研究院 | Multi-target ubenimex prodrug derivative, as well as preparation method and application thereof |
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