WO2021219112A1 - Composé d'isovaléryl-spiramycine ou application d'une composition d'isovaléryl-spiramycine dans la préparation d'un médicament destiné au traitement d'une maladie septique - Google Patents

Composé d'isovaléryl-spiramycine ou application d'une composition d'isovaléryl-spiramycine dans la préparation d'un médicament destiné au traitement d'une maladie septique Download PDF

Info

Publication number
WO2021219112A1
WO2021219112A1 PCT/CN2021/091248 CN2021091248W WO2021219112A1 WO 2021219112 A1 WO2021219112 A1 WO 2021219112A1 CN 2021091248 W CN2021091248 W CN 2021091248W WO 2021219112 A1 WO2021219112 A1 WO 2021219112A1
Authority
WO
WIPO (PCT)
Prior art keywords
isovalerylspiramycin
cells
derivatives
sepsis
add
Prior art date
Application number
PCT/CN2021/091248
Other languages
English (en)
Chinese (zh)
Inventor
姜恩鸿
夏明钰
王恒
赵小峰
Original Assignee
沈阳福洋医药科技有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 沈阳福洋医药科技有限公司 filed Critical 沈阳福洋医药科技有限公司
Publication of WO2021219112A1 publication Critical patent/WO2021219112A1/fr

Links

Images

Classifications

    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses

Definitions

  • the invention belongs to the field of medicinal chemistry. Specifically, it relates to the application of isovalerylspiramycin compounds or their compositions in the preparation of drugs for treating sepsis diseases.
  • Sepsis and the multiple organ dysfunction syndrome caused by it is currently one of the most common causes of death in clinically critically ill patients.
  • the fatality rate of patients with sepsis is more than 20%, and after the disease progresses to the septic shock stage, the patients die The rate can rise to 40% to 70%. Therefore, the treatment of sepsis has always been a severe challenge facing the intensive care unit.
  • sepsis can induce septic shock and MODS, which are often induced by infection, severe trauma, burns, major surgery and other factors.
  • Sepsis is a pathological process in which inflammation activation and immunosuppression coexist. Its development stage is systemic inflammatory response syndrome-sepsis-septic shock-multiple organ failure. The patient has a long hospital stay, poor prognosis, and high mortality. .
  • Plasma fibrinogen (Fg) is activated and converted into fibrin, and Fg is mostly reduced.
  • the change of Fg in common infectious diseases is often slightly increased or unchanged [ 1].
  • PKT platelet count
  • PT prothrombin time
  • APTT thromboplastin time
  • Fg fibrinogen
  • Severe sepsis is an acute and critical illness in which various infections cause systemic inflammatory reactions. It is often complicated by acute coagulation dysfunction and acute renal failure, which greatly increases the difficulty of treatment and faces life-threatening patients. Therefore, severe sepsis has a very high death rate. Rate.
  • the pathophysiological cause of sepsis is that the pathogen enters the blood, causing the inflammatory cells in the blood vessel to proliferate and activate, secrete inflammatory mediators, and produce a large number of immunologically active factors. It can also destroy the vascular endothelial cells, initiate the endogenous blood coagulation pathway, and cause diffuseness. Intravascular coagulation, coagulation-anticoagulation system balance is disturbed, but coagulation-related factors can further promote inflammatory cells to further secrete inflammatory factors, leading to such a cycle and rapid deterioration of the disease.
  • Carrimycin also known as Bitespiramycin and Shengjimycin, was developed by the Institute of Biotechnology of the Chinese Academy of Medical Sciences in cooperation with the applicant.
  • the 4′′-O-isovaleryltransferase gene (4′′-O-isovaleryltransferase gene) was cloned into Streptomyces spiramyceticus, and the spiramycin 4′′-OH was acylated and the isovaleryl group was added at the 4′′ position.
  • the total content of the main active ingredient isovalerylspiramycin (I+II+III) in climycin is not less than 60%, and the total content of acylated spiramycin is not less than 80%. It is a kind of pharmacy. Accepted pharmaceutical composition.
  • the central structure is a 16-membered lactone ring, which is connected with one molecule of folofamine, one molecule of mycosaminoglycan and one molecule of mycaminophen.
  • the difference in the structure of the mycine is that the group attached to the 4" position of mycylmycose is an isovaleryl group instead of a hydroxyl group.
  • the chemical structure, as shown in formula (1), contains more than ten components.
  • the finished product of climycin The composition standard is that the proportion of isovalerylspiramycin III ⁇ 30%, the total proportion of isovaleryl spiramycin I, II, and III ⁇ 60%, the proportion of total acylated spiramycin ⁇ 80%, and other unknown components The sum of ⁇ 5%.
  • the technical problem to be solved by the present invention is to overcome the shortcomings of the prior art and provide an application of isovalerylspiramycin compound or its composition in preparing medicines for treating sepsis.
  • the first object of the present invention is to provide the use of isovalerylspiramycin compounds or their compositions in the preparation of drugs for the treatment of sepsis.
  • septic diseases include systemic inflammatory response, sepsis, severe sepsis, septic shock, organ dysfunction or organ failure caused by infection emergency damage.
  • the sepsis disease is induced by coronavirus disease.
  • the sepsis disease is induced by the SARS-COV-2 virus, which means that it includes viral sepsis, especially COVID-19-related sepsis.
  • the isovalerylspiramycin compound is selected from isovalerylspiramycin I or its derivatives, isovalerylspiramycin II or its derivatives, isovalerylspiramycin III or its derivatives Things.
  • the isovalerylspiramycin composition is selected from isovalerylspiramycin I or its derivatives, isovalerylspiramycin II or its derivatives, isovalerylspiramycin III or its derivatives A combination of at least two of the derivatives, or colimycin;
  • the isovalerylspiramycin-based composition further includes a medically acceptable carrier.
  • the dosage of the drug is 10-1500 mg/kg, preferably 50-1000 mg/kg, more preferably 100-500 mg/kg.
  • the main recognized pathogenesis of sepsis includes:
  • TNF-a tumor necrosis factor
  • IL-1 interleukin-1
  • IL-6 interferon- ⁇
  • TNF-a is the most important pro-inflammatory cytokine in the early stage of inflammation. It plays an important role in the immune defense response and is also a key mediator of endotoxin damage.
  • the role of IL-1 in sepsis is similar to that of TNF-c. It is expressed through IL-1 ⁇ and initiates an inflammatory response together with TNF-a.
  • IL-6 is an inflammatory mediator produced under the action of IL-1, which can promote the proliferation of T lymphocytes together with TNF-a.
  • the level of IL-6 in plasma can be used as a predictor of the severity of sepsis.
  • a large number of studies have confirmed that the synthesis of pro-inflammatory cytokines in sepsis is closely related to the mitogen-activated protein kinase (MAPK) pathway, which plays a role by activating a variety of downstream transcription factors and protein molecules.
  • MAPK mitogen-activated protein kinase
  • HMGB1 The advanced cytokine high mobility group box-1 protein B1 (HMGB1), as one of the important late inflammatory mediators, can interact with transcription factors, nucleosomes and histones, and participate in transcription regulation, DNA replication, Cell life activities such as cell differentiation. HMGB1 can bind to TLR4, activate nuclear factor (NF)-KB and MAPK and other signal transduction pathways, further promote the production of TNF-a, IL-1, IL-6 and other mediators by cells, and aggravate tissue inflammation and damage.
  • NF nuclear factor
  • the body secretes a large number of inflammatory mediators in the early stage of sepsis, and then undergoes an immunosuppressive stage during the course of the disease, which is mainly manifested by the anergy of T lymphocyte clones and the negative regulation of immunosuppressive cells (such as Treg), etc. .
  • the interaction between coagulation dysfunction and inflammation has become a key link in the development and prognosis of sepsis.
  • the process includes the activation of the coagulation system, the inhibition of physiological anticoagulation mechanisms, and the inhibition of the fibrinolytic pathway.
  • Isovalerylspiramycin I or its derivatives, isovalerylspiramycin II or its derivatives, isovalerylspiramycin III or its derivatives, or colimycin can inhibit PI3K/AKT/m-
  • the TOR signal pathway reduces the level of m-TORC1, thereby inhibiting the protein synthesis of the inflammatory factor NF-KB in its nucleus.
  • the inflammatory factors such as IL-4, IL-6, TNF-a are also significantly reduced to achieve anti-inflammatory effects. .
  • the second object of the present invention is a combination product for the treatment of septic diseases, including isovalerylspiramycin I or its derivatives, isovalerylspiramycin II or its derivatives, and isovalerylspiramycin III Or at least one of its derivatives, or colimycin as the first active ingredient of the drug, further comprising a second active ingredient of the drug, and the second active ingredient of the drug is selected from related drugs for the treatment of sepsis;
  • the first active medicament ingredient and the second active medicament ingredient are separate preparations, or they are compounded into one preparation.
  • the second active ingredient of the drug includes, but is not limited to, antibiotics, statins, lipid A antagonists, recombinant human bactericidal protein, recombinant human lactoferrin, superantigen antagonists, corticosteroids, recombinant human activated protein C and the like.
  • the present invention has the following beneficial effects compared with the prior art:
  • the isovalerylspiramycin compound or its composition has a good therapeutic effect in the treatment of sepsis, and has important social and economic benefits.
  • Figure 1 is the effect of ISP I and LPS on the viability of BV2 cells;
  • A is the effect of ISP I on the viability of BV2 cells, and
  • B is the effect of LPS on the viability of BV2 cells;
  • Figure 2 shows the effect of ISP I and LPS on NO production in BV2 cells.
  • Figure 3 shows the effect of ISP I and LPS on IL-6 in BV2 cells.
  • Fig. 4 is the evaluation result of climycin on the ability of macrophages to phagocytize chicken red blood cells, A is the control group, B is the climycin group, and C is the itraconazole group;
  • FIG. 5 shows the first batch of C57BL/6 mice by intragastric administration for three consecutive days, 50mg/kg, to construct an abdominal inflammation model, and the detection results of abdominal neutrophils (Gr-1 and CD11b double positive cells);
  • Figure 6 shows the first batch of C57BL/6 mice by intragastric administration for seven days, 50mg/kg, to construct an abdominal cavity inflammation model, and the detection results of abdominal neutrophils (Gr-1 and CD11b double positive cells);
  • FIG 7 shows the second batch of C57BL/6 mice by intragastric administration for three consecutive days, 50mg/kg, to construct an abdominal cavity inflammation model, and the detection results of abdominal neutrophils (Gr-1 and CD11b double positive cells);
  • Figure 8 shows the second batch of C57BL/6 mice by intragastric administration for three consecutive days, 50mg/kg, to construct an abdominal inflammation model, and the detection results of the ratio of CD4+ and CD8+ cells in the peripheral blood;
  • Figure 9 is a histogram of the ratio of CD4+/CD3+ and CD8+/CD3+ cells in peripheral blood in Figure 8;
  • Figure 10 shows the second batch of C57BL/6 mice by intragastric administration at 50 mg/kg for three consecutive days to construct a model of abdominal inflammation, and the detection results of the proportion of CD3+ cells in the peripheral blood;
  • Figure 11 is a bar graph of the proportion of CD3+ cells in peripheral blood in Figure 10;
  • A is that RAW cells are treated with drugs for 1 hour, and then they are induced to differentiate into M1 type, and the level of TNF- ⁇ is detected;
  • B is that RAW cells are treated with drugs for 1 hour, and then they are induced to differentiate into M1 type to detect iNOS. Level;
  • C means that RAW cells are treated with drugs for 1 hour, and then they are induced to differentiate into M2 type, and the level of Arg-1 is detected;
  • A is the first addition of cytokines to induce RAW cells to differentiate into M1 macrophages, and corresponding drugs are added to detect the expression of TNF- ⁇ ;
  • B is the first addition of cytokines to induce RAW cells to differentiate into M1 macrophages , And then add the corresponding drugs to detect the expression of iNOS;
  • C is to add cytokines to induce the differentiation of RAW cells into M2 macrophages, and then add the corresponding drugs to detect the expression of Arg-1;
  • A is the first addition of cytokines to induce RAW cells to differentiate into M2 macrophages, and the corresponding drugs are added to detect the expression of TNF- ⁇ ;
  • B is the first addition of cytokines to induce RAW cells to differentiate into M2 macrophages , And then add the corresponding drugs to detect the expression of iNOS;
  • C is to add cytokines to induce the differentiation of RAW cells into M2 macrophages, and then add the corresponding drugs to detect the expression of Arg-1;
  • Figure 15 is the diachronic change curve of inflammatory cytokine IL- ⁇ (FAS) (mean line graph ⁇ SE thorn);
  • Figure 16 is the diachronic change curve of inflammatory cytokine IL-4 (FAS) (mean line graph ⁇ SE thorn);
  • Figure 17 is the diachronic change curve of inflammatory cytokine IL- ⁇ (PPS) (mean line graph ⁇ SE thorn);
  • Figure 18 is the diachronic change curve (PPS) of the inflammatory cytokine IL-4 (mean line graph ⁇ SE spike).
  • the main drug and auxiliary materials are respectively passed through a 100 mesh sieve, and the prescription amount isovalerylspiramycin I or isovalerylspiramycin II or isovalerylspiramycin III, microcrystalline cellulose and 1/2
  • the prescription amount of sodium starch glycolate is mixed uniformly, then 5% povidone K 30 aqueous solution is added to make soft material, granulated with 18 mesh sieve, wet granules are dried at 60°C under ventilation conditions for 2 hours; after drying, the granules are granulated with 18 mesh sieve , Then add 1/2 prescription amount of sodium starch glycolate and magnesium stearate and mix them uniformly, then press tablets with a dimple die with a diameter of 11mm to obtain a tablet-containing core with a tablet weight of 350mg and a hardness of 6.5kg.
  • Preparation of coating solution Weigh the required Opadry II (white), add the required amount of water in the mixing container, add it in portions, after all is added, reduce the stirring speed to make the vortex disappear, and continue to stir 30min, ready.
  • Preparation of film-coated tablets put the tablet core in the coating pan and determine the coating conditions.
  • the host speed is 20r/min
  • the inlet air temperature is 40°C
  • the outlet air temperature is 30°C
  • the spray pressure is 0.02Mpa
  • the spray flow rate is 1ml. /min for coating, after constant spraying for 1.5h, until the surface of the tablets is smooth and uniform in color, which meets the film coating inspection standard as qualified.
  • the weight gain of the coating is about 5%.
  • Example 2 Isovalerylspiramycin I or Isovalerylspiramycin II or Isovalerylspiramycin III Tablets (calculated as 10,000 tablets)
  • Preparation process Weigh an appropriate amount of starch, dilute it to 15% concentration, heat it to a paste, and make an adhesive; main ingredient isovalerylspiramycin I or isovalerylspiramycin II or isovalerylspiramycin III , Auxiliary materials starch, low-substituted hydroxypropyl cellulose, sodium carboxymethyl starch, magnesium stearate, respectively, through a 100 mesh sieve, according to the prescription amount, weigh the required main materials and auxiliary materials; isovalerylspiramycin I, starch ⁇ After mixing the low-substituted hydroxypropyl cellulose thoroughly, use starch paste with 15% starch concentration to make soft material, granulate with 14-mesh sieve, dry at 50-60°C, control moisture within 3-5%, 14-mesh sieve Whole granules, add sodium carboxymethyl starch and magnesium stearate to mix, determine the particle content; calculate the tablet weight according to the particle content, press the tablet ( ⁇ 9mm shallow concave punch
  • Preparation process weigh the main material isovalerylspiramycin I or isovalerylspiramycin II or isovalerylspiramycin III, and the auxiliary material medicinal starch according to the amount of the process formula, then put it into the mixer and mix thoroughly 1.5-2 hours; the data obtained by sampling and testing the content should be basically consistent with the theoretical data (the weight of each capsule is about 0.105g), and the qualified medical No.
  • 3 capsules and the mixed raw materials to be filled shall be fully automatic capsules Machine operation requirements, respectively fill in the loader for filling, the filled capsules are tested for difference (within ⁇ 10%, ⁇ 0.3g), the dissolution rate meets the requirements, and the capsules that meet the requirements after the test are put into the polishing machine Add liquid paraffin and light it for 15-20 minutes, and then take it out for inspection of the finished product packaging box.
  • Example 4 isovalerylspiramycin I or isovalerylspiramycin II or isovalerylspiramycin III dry syrup (calculated by 10,000 bags)
  • Citric acid (0.5%) 15g
  • the total weight is about 5000g
  • Preparation process isovalerylspiramycin I or isovalerylspiramycin II or isovalerylspiramycin III original powder, citric acid and sucrose are respectively crushed into particles by a high-speed jet mill, 85% passing through 300 mesh, 15% Pass through 180 meshes, then weigh the pulverized fine powder according to the prescription amount and mix it thoroughly for 1-1.5 hours, measure its content, calculate the filling quantity (theoretical filling quantity is 500mg per bag), and then put the mixture into the bagging machine , Pack the aluminum foil paper, divide it according to the operation requirements of the packing machine, the difference of the packing quantity is within ⁇ 5%, after packing, carry out the inspection and pass the outer packaging.
  • Example 5 isovalerylspiramycin I or isovalerylspiramycin II or isovalerylspiramycin III granules (calculated by 10,000 bags)
  • Preparation process isovalerylspiramycin I or isovalerylspiramycin II or isovalerylspiramycin III original powder, powdered sugar, and dextrin through a 120-mesh sieve, and weigh the isovalerylspiramycin according to the prescription amount I. Mix the powdered sugar and dextrin evenly. Use 5% PVP-K 30 mortar to make the above-mentioned materials into soft material. The rocking granule is granulated and dried at 70°C.
  • mice were purchased from Experimental Animal Center of Jiangsu University, mouse IL-1 ⁇ ELISA kit (Invitrogen (88-7013-88)), mouse IL-4 ELISA kit (Invitrogen (88-7044-88) )), other experimental instruments and reagents are the existing conventional instruments and reagents.
  • mice Grouping of mice and administration
  • Calinomycin dissolving method, add 0.48ml polyethylene glycol 400 to clalimycin several times, then add 2.4 ⁇ l Tween 80, shake and mix well, then add 1.92ml distilled water (add 200 ⁇ l each time and shake and mix well. ), respectively formulated to concentrations of 1.44mg/ml, 2.88mg/ml, and 5.76mg/ml.
  • Azithromycin first dissolve it with a small amount of absolute ethanol, then add water to make the content of absolute ethanol 10%, and prepare it to a concentration of 1.82mg/ml.
  • mice male, 18-20g in size, 144 mice, after adaptive feeding in the laboratory, the mice weighed about 24g, and they were randomly divided into 6 groups: normal group, model group, and low group (30mg/kg), Kezhong group (60mg/kg), Kegao group (120mg/kg), azithromycin (37.9mg/kg) group.
  • Each component has 8 time points: 0h, 0.5h, 2.5h, 4.5h, 12h, 24h, 48h and 72h. 3 mice at each time point.
  • the mice in the normal group were given no administration or bacteria, and the model group was given no administration of bacteria.
  • Climycin and azithromycin were both administered intragastrically (500 ⁇ l). The same volume of solvent. After the administration, the mice were killed in batches at different time points.
  • Model establishment The concentration of Staphylococcus aureus is determined in the in vitro experiment report. After the concentration is measured, it is resuspended in physiological saline to make the concentration 3 ⁇ 108 CFU/ml, and injected into the tail vein at 24g/100 ⁇ l injection. The administration started one hour after the injection.
  • the mouse eyeballs were taken blood and sacrificed.
  • the tissues and organs were taken and weighed with an electronic balance. Weigh 50mg of each tissue and add it to a 1.5ml EP tube, then add 1ml of pre-cooled PBS, add magnetic beads and homogenize with a homogenizer. Pulp (300Hz, 30s). After standing on ice for 30 minutes, centrifuge at 4°C (10000g, 10min) with a centrifuge, and take the supernatant as the test sample.
  • Reagent preparation pH7.35 PBS, Tween 20, prepare a PBS solution containing 0.05% Tween 20 as a washing solution. (If crystals form in the buffer concentrate, heat it gently until completely dissolved).
  • Capture antibody Dilute the capture antibody (250x) 1:250 in coating buffer (1x).
  • 3.5 xELISA/ELISPOT diluent dilute the concentrated diluent (5x) 1:5 in deionized water.
  • Standard Recombinant mouse il-1 ⁇ standard, dissolved in distilled water, and the volume of distilled water added is on the label of the standard vial Specify.
  • Test results The effects of climycin on IL-4 factor and IL-1 ⁇ in various tissues and organs of mice are shown in Table 1 and Table 2, respectively.
  • Climycin has anti-inflammatory effects. Climycin has a significant effect on reducing IL4 factor in lung, kidney, liver and spleen, and its role is more significant in liver and spleen; Climycin is in small intestine , Lung, spleen, liver and kidney all have a significant effect on reducing IL-1 ⁇ factor, especially in the small intestine and lung.
  • ISP I isovalerylspiramycin I
  • mice microglia BV2 cells were purchased from the National Laboratory Cell Resource Sharing Platform (Beijing)
  • Isovalerylspiramycin I (Shenyang Tonglian Group Co., Ltd.), lipopolysaccharide (LPS055: B5L6529), trypsin, penicillin, streptomycin, dimethyl sulfoxide (DMSO), methyl thiazole blue (MTT) are all Purchased from Sigma Chemical (St. Louis, MO, USA), DMEM medium was purchased from Gibco Chemical (Grand Island, NY, USA), special grade fetal bovine serum was purchased from South America Lonsera, NO detection kit (Biyuntian Biotechnology Company), ELISA detection Kit (Shanghai Aibixin Biotechnology Company).
  • the instruments used in this test example can all be conventional instruments in the prior art.
  • BV2 cells were cultured in DMEM medium containing 10% FBS and placed in an incubator at 37°C and 5% CO 2. When the cells are cultured to a density of about 90%, they can be passaged and follow-up experiments.
  • MTT Tetramethylazolium Salt
  • succinate dehydrogenase and cytochrome c are present in the mitochondria of living cells.
  • the tetrazolium ring of MTT splits to produce blue-purple formazan crystals, DMSO Or the triple solution can dissolve the crystal, and detect the absorbance at the wavelength of 492nm/630nm, which can be used to detect the activity of the cells.
  • BV2 cells were seeded in a 96-well plate with a density of 1.6 ⁇ 10 5 cell/ml, 100 ⁇ l/well, with six replicate wells in each group, and normal culture for 24 hours before adding medicine. In addition to the negative control group, different concentrations of ISP I were added, and the culture was continued until the specified time. Aspirate and discard the culture solution, add sterile PBS to wash once, aspirate and discard PBS, add 100 ⁇ l of the prepared MTT to each well, and continue to incubate for 4 hours.
  • Inhibitoryratio(%) (A 630 , control-A 630, control )/(A 630 , control-A 630, blank ) ⁇ 100
  • BV2 cells were seeded in a 24-well plate at a rate of 1 ⁇ 10 5 /well, and cultured in DMEM medium containing 10% FBS. The culture was continued for 24 hours, and the cells were replaced with serum-free medium and cultured for 6 hours.
  • ISP I ISP I with final concentrations of 20 ⁇ M, 10 ⁇ M, and 5 ⁇ M to the corresponding wells for pretreatment.
  • LPS LPS with a final concentration of 10 ⁇ g/ml to the corresponding wells for induction treatment. After placing 5% CO 2 in a 37°C incubator for 24 hours, the supernatant was taken and stored at -20°C for NO detection.
  • the determination of NO was carried out in accordance with the instructions, the absorbance was measured at 540nm, and the corresponding NO content was calculated using the standard curve.
  • ISP I inhibits the production of NO induced by LPS
  • ISP I inhibit LPS-induced IL-6 production
  • the detection of IL-6 levels in the cell supernatant when different concentrations of LPS acted on the cells showed that 0.01-10 ⁇ g/ml LPS can induce IL-6 production.
  • the ELISA method detected the effect of ISP I on the production of IL-6 in the cell supernatant, and the results showed that 5 ⁇ M and 10 ⁇ M ISP I can significantly inhibit the production of IL-6 induced by LPS.
  • the concentration of LPS was 0.01 ⁇ g/ml, 0.1 ⁇ g/ml, 1 ⁇ g/ml and 10 ⁇ g/ml, and the amount of IL-6 produced by the cells increased.
  • Isovalerylspiramycin I (ISP I), the main active ingredient of climycin, can inhibit the production of inflammatory cytokines IL-6 and NO induced by LSP.
  • Calinomycin enhances the ability of macrophages to engulf chicken red blood cells to a certain extent.
  • the test of the influence of clerisomycin on immune cells showed that: clerisomycin can significantly promote the increase of total T cells (CD3 positive cells) in mice, including both CD4 and CD8 positive cells.
  • the transdifferentiation study of cleritromycin on differentiated macrophages showed that cleritromycin can significantly increase the expression levels of TNF-a and iNos in M2 macrophages, and it is significantly stronger than TNF- induced by LPS+INF-
  • the expression levels of a and iNos are better than itraconazole, and can significantly inhibit the expression level of Arg-1 in M2 macrophages.
  • OBJECTIVE To detect whether clinomycin can enhance the function of macrophages in normal mice.
  • the main detection index is the phagocytosis of macrophages.
  • itraconazole In view of the fact that there is no standard reagent in immunological research, itraconazole has the effect of promoting the polarization of macrophages and enhancing the phagocytosis of macrophages. Therefore, itraconazole was selected as a positive control in the experiment.
  • Reagents physiological saline, 6% chicken red blood cells, methanol, acetone, Giemsa staining solution, etc.; consumables: 1ml syringe, ordinary glass slide, gauze, petri dish, etc.
  • mice strain: Balb/c, age: 8-12, source: Chengdu Dashuo Experimental Animal Co., Ltd., quantity: 2 mice in each group.
  • the phagocytic percentage calculation formula is the number of phagocytic macrophages/total number of macrophages ⁇ 100%
  • the phagocytic macrophages can phagocytize chicken red blood cells (with megakaryocytes) or the chicken red blood cells that accumulate more around.
  • A is the control group
  • B is the climycin group
  • C is the itraconazole group.
  • the colimycin group (Keli) and itraconazole group (Yiqu) have a certain degree of enhancement in the ability of macrophages to phagocytize chicken red blood cells; however, the colimycin group and the itraconazole group There was no statistically significant difference between itraconazole groups.
  • the purpose of the experiment to detect whether climycin can enhance the inflammatory chemotaxis and migration ability of mouse neutrophils, mainly by constructing a mouse abdominal inflammation model, flow cytometric detection of the proportion of abdominal neutrophils, and the detection indicators are CD11b and Gr-1.
  • itraconazole was used as a positive control.
  • Reagents sterile PBS, fMLP, sterile HBSS, Gr-1-APC flow cytometry antibody, CD11b-FITC flow cytometry antibody, etc.; consumables: straws, rubber bands, scissors, tweezers, 1ml syringes, 15ml centrifuge tubes, flow tubes, etc. .
  • mice Strain: C57BL/6 mice, age: 8-12, source: Chengdu Dashuo Experimental Animal Co., Ltd., quantity: the first batch of administration for three days, each group of 3 mice, administration for 7 days each Each group has 4 mice. The second batch of repeated experiments was administered with 7 mice in each group for three days.
  • Figure 5-7 shows the peritoneal inflammation model of mice with different administration time and different batches, and the ratio of neutrophils (Gr-1 and CD11b double positive cells) was detected by flow cytometry.
  • Figure 5 shows the first batch of C57BL/6 mice by intragastric administration for three consecutive days, 50mg/kg, to construct an abdominal cavity inflammation model, and the detection results of peritoneal neutrophils (Gr-1 and CD11b double positive cells);
  • Figure 6 shows the first batch of C57BL/ 6 mice were gavaged continuously for seven days, 50mg/kg, the abdominal cavity inflammation model was constructed, and the test results of peritoneal neutrophils (Gr-1 and CD11b double positive cells);
  • Figure 7 shows the second batch of C57BL/6 mice by gavage for three consecutive days, 50mg /kg, construct the abdominal cavity inflammation model, and the test results of abdominal neutrophils (Gr-1 and CD11b double positive cells).
  • Figure 8-11 shows the detection of T lymphocytes in peripheral blood after the establishment of a mouse abdominal inflammation model three days after administration. Flow cytometry was used to detect the proportion of CD3+, CD4+ and CD8+ cells.
  • Calinomycin and itraconazole can significantly promote the migration of neutrophils to inflammation sites in mice, and the results are especially obvious in individual mice. Compared with the results of three days and seven days, there is no discovery that continuous medication for seven days can To further strengthen the effect. Climycin and itraconazole can significantly promote the increase of total T cells (CD3 positive cells) in mice, in which both CD4 and CD8 positive cells increase, but itraconazole performs better.
  • Macrophages can be divided into two categories: Classically activated macrophages (M1), which are characterized by increased expression of the major histocompatibility complex MHC class II, and nitric oxide (NO) Increased, reactive oxygen species and pro-inflammatory cytokines, such as tumor necrosis factor (Tumornecrosisfactor, TNF), interleukin-1 (IL-1) and interleukin-6 (IL-6), etc. increased.
  • TNF tumor necrosis factor
  • IL-1 interleukin-1
  • IL-6 interleukin-6
  • interleukin-4 IL-4
  • IL-10 interleukin-10
  • arginase Arginase, Arg
  • the purpose of this experiment is to detect whether clalimycin affects the differentiation of macrophages, and then to explore the potential immunomodulatory effects of clalimycin.
  • Reagents RAW246.7 cell line, 1640 medium, FBS, RNA extraction kit, reverse transcription kit, SYBR fluorescence quantitative kit.
  • Cytokines IL-4, INF- ⁇ , LPS; Consumables: Consumables related to cell culture.
  • Option 1 Explore whether the drug will promote or inhibit the polarization process of RAW246.7 cells.
  • Option 2 Explore whether the drug has an effect on polarized cells.
  • Climycin and itraconazole are prepared as a 10mM mother solution with DMSO for storage.
  • Option 1 Explore whether cleritromycin can promote or inhibit the differentiation of RAW246.7 cells
  • Figure 12A shows that RAW cells are treated with drugs for 1 hour, and then they are induced to differentiate into M1 type, and the level of TNF- ⁇ is detected.
  • NC RAW cells, do not do any treatment
  • PC1 RAW cells plus LPS+INF- ⁇ , induce RAW cells to differentiate into M1 macrophages
  • Keli RAW cells first add colimycin, then add LPS+INF- ⁇
  • Yiqu RAW cells are added with itraconazole first, then LPS+INF- ⁇
  • *P ⁇ 0.05, **P ⁇ 0.01, ***P ⁇ 0.001 are statistically tested.
  • Figure 12B shows that RAW cells are treated with drugs for 1 hour, and then they are induced to differentiate into M1 type, and the level of iNOS is detected;
  • Figure 12C shows that RAW cells are treated with drugs for 1 hour, and then they are induced to differentiate into M2 type, and the level of Arg-1 is detected.
  • NC RAW cells, without any treatment
  • PC2 RAW cells with IL-4, induce Differentiation of RAW cells into M2 type macrophages
  • Keli RAW cells first add colimycin, then IL-4
  • Yiqu RAW cells first add itraconazole, then IL-4
  • perform statistics Scientific test *P ⁇ 0.05, **P ⁇ 0.01, ***P ⁇ 0.001.
  • Climycin can increase the expression of TNF- ⁇ and iNos, and inhibit the expression of Arg-1. It is suggested that climycin may promote the differentiation and function of M1 macrophages.
  • Figure 13A First add cytokines to induce RAW cells to differentiate into M1 macrophages, then add corresponding drugs to detect the expression of TNF- ⁇
  • Figure 13B First add cytokines to induce RAW cells to differentiate into M1 type macrophages, then add corresponding drugs to detect the expression of iNOS
  • Figure 13A First add cytokines to induce RAW cells to differentiate into M2 macrophages, then add corresponding drugs to detect the expression of Arg-1
  • NC RAW cells, without any treatment
  • PC1 RAW cells plus LPS+INF- ⁇
  • PC2 RAW cells plus IL-4, induce RAW cells differentiate into M2 type macrophages
  • Keli (RAW cells first add LPS+INF- ⁇ to induce RAW cells to differentiate into M1 type macrophages, then add colimycin); Yiqu (RAW cells first add LPS +INF- ⁇ , induce RAW cells to differentiate into M1 type macrophages, plus itraconazole); and statistically tested, *P ⁇ 0.05, **P ⁇ 0.01, ***P ⁇ 0.001.
  • Option 2 B to explore whether climycin has a transdifferentiation effect on differentiated macrophages
  • Figure 14A First add cytokines to induce RAW cells to differentiate into M2 type macrophages, then add corresponding drugs to detect the expression of TNF- ⁇
  • Figure 14B First add cytokines to induce RAW cells to differentiate into M2 type macrophages, then add corresponding drugs to detect the expression of iNOS
  • Figure 14C First add cytokines to induce RAW cells to differentiate into M2 type macrophages, then add corresponding drugs to detect the expression of Arg-1
  • Figure 14A-14C NC (RAW cells, without any treatment); PC1 (RAW cells plus IL-4, induce RAW cells to differentiate into M2 macrophages); PC2 (RAW cells plus IL-4, induce RAW cells Differentiate into M2 type macrophages); Keli ((RAW cells first add IL-4, induce RAW cells to differentiate into M2 type macrophages, then add colimycin); Yiqu (RAW cells first add IL-4, induce RAW cells were differentiated into M2 type macrophages, plus itraconazole); and statistical tests were performed, *P ⁇ 0.05, **P ⁇ 0.01, ***P ⁇ 0.001.
  • Climycin can significantly increase the expression levels of TNF- ⁇ and iNos in M2 macrophages, and it is significantly stronger than the expression levels of TNF- ⁇ and iNos induced by LPS+INF- ⁇ , which is better than that of Itrax Conazole can significantly inhibit the expression level of Arg-1 in M2 macrophages.
  • Kunming mice half male and half male, weighing 18-22 g, were purchased from Chengdu Dashuo Experimental Animal Co., Ltd. (SPF grade). Feeding conditions: 25°C, humidity 60%. The breeding conditions are SPF-level, and the research process follows the guidelines for the breeding, management and use of laboratory animals.
  • Carbapenem-resistant Klebsiella pneumoniae group Weigh 0.24g of the drug, add 2.4ml Tween 80 and 2.4ml absolute ethanol to dissolve the drug, add distilled water to a total volume of 20ml, at this time the concentration is 12mg/ml . Take 14mL of the medicinal solution and add distilled water to a total volume of 20ml. At this time, the concentration is 8.4mg/ml, which is 70% of the original concentration. By analogy, take 14mL of high-concentration drug solution, add distilled water to a total volume of 20ml, dose interval 1:0.7, a total of 5 groups.
  • Carbapenem-resistant Acinetobacter baumannii group Weigh 0.45g of the drug, add 4.5ml Tween 80 and 4.5ml absolute ethanol to dissolve the drug, add distilled water to a total volume of 30ml, at this time the concentration is 15mg/ml . Take 24mL of the medicinal solution and add distilled water to a total volume of 30ml. At this time, the concentration is 12mg/ml, which is 80% of the original concentration. By analogy, take 24mL of high-concentration medicinal solution, add distilled water to a total volume of 30ml, dose interval 1:0.8, a total of 6 groups.
  • 1Bacterial inoculation Add 3ml LB medium into the centrifuge tube, take out the plate from 4°C, pick 2-3 colonies with an inoculating loop to inoculate the LB medium, and cultivate at 37°C.
  • MLD determination Take healthy Kunming mice, weighing 18-22g, and randomly divide them into several groups, each with 5 mice, both male and female.
  • the bacterial solution was diluted with 5% high-active dry yeast to different concentrations, injected intraperitoneally, 0.5 mL each, observed 7 days after infection, recorded the number of deaths of the mice, and the lowest bacterial count that caused 100% death of the mice was used as MLD.
  • the amount is used as the amount of infectious bacteria in the in vivo protection test.
  • 3Determination of drug dose range Take healthy Kunming mice, weighing 18-22g, and randomly divide them into several groups, each with 5 mice, both male and female.
  • Carbapenem-resistant Klebsiella pneumoniae group healthy Kunming mice, weighing 18-22 g, were randomly divided into 6 groups, each with 10 animals, both male and female. Among the 6 groups, 5 groups are the administration group, and the 1 group is the solvent control group.
  • Carbapenem-resistant Acinetobacter baumannii group healthy Kunming mice weighing 18-22 g were randomly divided into 7 groups, each with 10 animals, both male and female. Among the 7 groups, 6 groups were the administration group, and the 1 group was the solvent control group.
  • mice Prepare 1MLD with 5% high-active dry yeast. All mice were injected intraperitoneally with 0.5mL. One hour after the mice were infected, they were gavage with different concentrations of drugs or solvents. The administration volume was 0.2mL/10g, and the observation was continued for 14 days. The number of deaths of the mice was recorded.
  • MLD results (the maximum lethal bacteria count is determined):
  • mice infected with carbapenem-resistant Klebsiella pneumoniae or carbapenem-resistant Acinetobacter baumannii with clinomycin protection is shown in Table 5:
  • Climycin has a good antibacterial effect on carbapenem-resistant Acinetobacter baumannii and carbapenem-resistant Klebsiella pneumoniae, and can significantly improve the survival rate of infected animals.
  • the diachronic change curve of inflammatory cytokine IL- ⁇ (mean line graph ⁇ SE spike) is shown in Figure 15; the diachronic change curve of inflammatory cytokine IL-4 (FAS) ) (Mean line graph ⁇ SE burr) as shown in Figure 16.
  • the diachronic change curve of inflammatory cytokine IL- ⁇ (mean line graph ⁇ SE spike) is shown in Figure 17; the diachronic change curve of inflammatory cytokine IL-4 (PPS) ) (Mean line graph ⁇ SE burr) as shown in Figure 18.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Communicable Diseases (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Oncology (AREA)
  • Virology (AREA)
  • Molecular Biology (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un composé d'isovaléryl-spiramycine ou une application d'une composition d'isovaléryl-spiramycine dans la préparation d'un médicament destiné au traitement d'une maladie septique. Le composé d'isovaléryl-spiramycine selon l'invention est sélectionné parmi l'isovaléryl-spiramycine I ou un dérivé de celui-ci, l'isovaléryl-spiramycine II ou un dérivé de celui-ci, et l'isovaléryl-spiramycine III ou un dérivé de celui-ci. La composition d'isovaléryl-spiramycine selon l'invention est sélectionnée parmi une combinaison d'au moins deux éléments parmi l'isovaléryl-spiramycine I ou un dérivé de celui-ci, l'isovaléryl-spiramycine II ou un dérivé de celui-ci, et l'isovaléryl-spiramycine III ou un dérivé de celui-ci, et la carrimycine. Le composé d'isovaléryl-spiramycine ou la composition d'isovaléryl-spiramycine selon l'invention présente un bon effet thérapeutique dans le traitement du sepsis, et présente des avantages économiques et sociaux importants.
PCT/CN2021/091248 2020-04-30 2021-04-30 Composé d'isovaléryl-spiramycine ou application d'une composition d'isovaléryl-spiramycine dans la préparation d'un médicament destiné au traitement d'une maladie septique WO2021219112A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
CN202010363407 2020-04-30
CN202010363407.6 2020-04-30
CN202010363428 2020-04-30
CN202010363428.8 2020-04-30

Publications (1)

Publication Number Publication Date
WO2021219112A1 true WO2021219112A1 (fr) 2021-11-04

Family

ID=78243038

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2021/091248 WO2021219112A1 (fr) 2020-04-30 2021-04-30 Composé d'isovaléryl-spiramycine ou application d'une composition d'isovaléryl-spiramycine dans la préparation d'un médicament destiné au traitement d'une maladie septique

Country Status (2)

Country Link
CN (1) CN113577087A (fr)
WO (1) WO2021219112A1 (fr)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105497053A (zh) * 2015-12-31 2016-04-20 沈阳同联集团有限公司 可利霉素在抗结核分枝杆菌感染中的应用
CN110051845A (zh) * 2018-01-19 2019-07-26 沈阳福洋医药科技有限公司 一种mTOR抑制剂、药物组合物及其应用

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DK2578596T3 (en) * 2010-05-25 2017-07-17 Shenyang Fuyang Pharmaceutical Tech Co Ltd LEVOCARRIMYCIN, PHARMACEUTICAL COMPOSITIONS, METHODS OF PRODUCTION AND APPLICATIONS THEREOF
CN110051680B (zh) * 2018-01-19 2022-02-18 沈阳福洋医药科技有限公司 一种用于预防和/或治疗阿尔茨海默病的药物、组合产品及其应用

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105497053A (zh) * 2015-12-31 2016-04-20 沈阳同联集团有限公司 可利霉素在抗结核分枝杆菌感染中的应用
CN110051845A (zh) * 2018-01-19 2019-07-26 沈阳福洋医药科技有限公司 一种mTOR抑制剂、药物组合物及其应用

Non-Patent Citations (7)

* Cited by examiner, † Cited by third party
Title
DU XINXIN, GULIFIER TAIER, WANG YI, YU XIANGYOU: "Study on the Clinical Diagnosis and Treatment of COVID-19 and Associated Sepsis", JOURNAL OF CLINICAL INTERNAL MEDICINE, vol. 37, no. 3, 31 March 2020 (2020-03-31), pages 206 - 208, XP055862751, ISSN: 1001-9057, DOI: 10.3969/j.issn.1001-9057.2020.03.021 *
HUANG, CHAO: "[Innovation Made in Shenyang": Effective Drug for COVID-19, Carrimycin, is Expected to be Promoted Globally with an Annual Production of up to 100 Million Tablets]", SHENYANG DAILY, 28 March 2020 (2020-03-28), CN, pages 1 - 2, XP009531671 *
SHANG, ZHIWEN: "Innovation Made in Shenyang! Ministry of Science and Technology: Carrimycin is Effective in Treating COVID-19", SHENYANG DAILY, 27 March 2020 (2020-03-27), CN, pages A01 - 2, XP009531670 *
WANG HUI, ZHEN GAO, YUEJIA LIN, NI WAN, BIN CHEN, YANQING WANG, HUI ZHANG, XING ZHANG: "Implications of Previous Studies on Viral Respiratory Infections for Anti-COVID-19 Drug Development", CHINESE JOURNAL OF MODERN APPLIED PHARMACY, CHINESE PHARMACEUTICAL ASSOCIATION, CN, vol. 37, no. 5, 31 March 2020 (2020-03-31), CN , pages 513 - 524, XP055862760, ISSN: 1007-7693, DOI: 10.13748/j.cnki.issn1007-7693.2020.05.001 *
YU ZHONGKAI, ZHANG ZONGWANG, KAN XIANGDONG: "Research Progress of Sepsis", CHINESE JOURNAL HYGIENE RESCUE, vol. 5, no. 2, 30 April 2019 (2019-04-30), pages 118 - 121, XP055862744, ISSN: 2095-9133, DOI: 10.3877/cma.j.issn.2095-9133.2019.02.010 *
ZHOU HONG, LI XIAOLI , LI BIN: "Pay attention to 2019 coronavirus disease (COVID-19) induced sepsis immunosuppression", DI-SAN JUNYI DAXUE XUEBAO // ACTA ACADEMIAE MEDICINAE MILITARIS TERTIAE, DI-3 JUNYI DAXUE, CHONGQING, CN, vol. 42, no. 6, 1 January 2020 (2020-01-01), Chongqing, CN , pages 539 - 544, XP055852963, ISSN: 1000-5404, DOI: 10.16016/j.1000-5404.202002172 *
ZHUO NAO, SHI JIAXIN, LI XIAOMIN: "Advances in the Regulation of PI3K/AKT/mTOR Signalling on Autophagy In Sepsis", CHONGQING MEDICAL JOURNAL, CHONGQING YIXUE, CN, vol. 48, no. 11, 30 June 2019 (2019-06-30), CN , pages 1927 - 1929, XP055862753, ISSN: 1671-8348, DOI: 10.3969/j.issn.1671-8348.2019.11.033 *

Also Published As

Publication number Publication date
CN113577087A (zh) 2021-11-02

Similar Documents

Publication Publication Date Title
Fan et al. Effects of Astragalus polysaccharide liposome on lymphocyte proliferation in vitro and adjuvanticity in vivo
CN101836952B (zh) 一种氨溴索注射剂及其制备方法
WO2016183905A1 (fr) Composé d'icarisid, procédé de préparation de celui-ci, et application de celui-ci
WO2021219112A1 (fr) Composé d'isovaléryl-spiramycine ou application d'une composition d'isovaléryl-spiramycine dans la préparation d'un médicament destiné au traitement d'une maladie septique
CN113546089B (zh) 1-乙基-3，7-二甲基黄嘌呤在制备治疗肺炎药物中的应用
WO2021219113A1 (fr) Utilisation d'un composé d'isovaléryl-spiramycine ou d'une composition associée dans la préparation d'un médicament destiné au traitement des troubles immunitaires
CN108653322A (zh) 一种具有预防肿瘤转移的功能性保健品的组合物
CN113181166A (zh) 莪术烯醇在制备治疗抗肺癌药物中的应用、抗肺癌药物
CN115104735A (zh) 一种含有中药成份能提高机体免疫力的益生菌组合物
CN111568937A (zh) 片仔癀及其制剂在制备促进难愈性创面愈合的药物中的应用
WO2019141256A1 (fr) Utilisation de la carrimycine ou d'un principe actif de celle-ci
CN105708845B (zh) 一种苯丙素类化合物及其药学上可接受的盐在制备治疗炎症性疾病的药物中的应用
CN105663150B (zh) 一种苯丙素类化合物及其药学上可接受的盐在制备治疗炎症性疾病的药物中的应用
CN110882236A (zh) 一种抗肿瘤组合物、治疗癌症的药物制剂及其应用
CN110327284A (zh) 一种注射用头孢地嗪钠及其制备方法
WO2018196537A1 (fr) Composition pour prévenir et traiter un hémangiome ou un lymphome et son procédé de préparation et son utilisation
TWI813220B (zh) 包含副乾酪乳桿菌的組合物、及其經由細胞焦亡、細胞週期停滯而抑制鼻咽癌的用途
CN115040528B (zh) 地黄苷d的应用以及抗肿瘤转移药物
CN103301088A (zh) 一种鸡胚多糖胶囊制剂及其制备方法
CN113952350B (zh) 双氢青蒿素与绞股蓝皂苷-l在制备抗肿瘤药物中的应用
CN112138066B (zh) 龙葵或龙葵提取物在增加抗生素或抗肿瘤药物敏感性中的应用
CN117298086B (zh) 索法酮在制备预防和/或治疗nlrp3炎性小体介导的疾病的药物中的应用
CN114129705B (zh) 一种多肽在预防和治疗肺炎的药物中的应用
TW200423954A (en) Compositions containing an active fraction isolated from tannins and methods of use
WO2020228477A1 (fr) Médicament et produit combiné utilisés pour la prévention, le soulagement et/ou le traitement de la fibrose et utilisation correspondante

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 21795887

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 21795887

Country of ref document: EP

Kind code of ref document: A1