WO2015051695A1 - Utilisation d'une composition pharmaceutique dans la fabrication de médicaments pour le traitement d'une sepsie et d'une lésion pulmonaire inflammatoire - Google Patents

Utilisation d'une composition pharmaceutique dans la fabrication de médicaments pour le traitement d'une sepsie et d'une lésion pulmonaire inflammatoire Download PDF

Info

Publication number
WO2015051695A1
WO2015051695A1 PCT/CN2014/087043 CN2014087043W WO2015051695A1 WO 2015051695 A1 WO2015051695 A1 WO 2015051695A1 CN 2014087043 W CN2014087043 W CN 2014087043W WO 2015051695 A1 WO2015051695 A1 WO 2015051695A1
Authority
WO
WIPO (PCT)
Prior art keywords
sepsis
borneol
edaravone
composition
group
Prior art date
Application number
PCT/CN2014/087043
Other languages
English (en)
Chinese (zh)
Inventor
张正平
杨士豹
华垚
陈荣
王鹏
龚兆龙
Original Assignee
烟台益诺依生物医药科技有限公司
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 烟台益诺依生物医药科技有限公司 filed Critical 烟台益诺依生物医药科技有限公司
Publication of WO2015051695A1 publication Critical patent/WO2015051695A1/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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/4152—1,2-Diazoles having oxo groups directly attached to the heterocyclic ring, e.g. antipyrine, phenylbutazone, sulfinpyrazone
    • 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
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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

Definitions

  • the present invention belongs to the field of pharmaceuticals and relates to the use of 3-methyl-1-phenyl-2-pyrazol-5-one and borneol compositions for the treatment of related diseases caused by endotoxemia caused by various causes.
  • Sepsis is a common complication after severe trauma (burn), shock, and major surgery. It can be further developed into septic shock and multiple organ dysfunction syndrome (MODS).
  • MODS septic shock and multiple organ dysfunction syndrome
  • the incidence of sepsis is high, with more than 18 million cases of severe sepsis every year in the world, and 750,000 cases of sepsis in the United States each year, and this number is rising at a rate of 1.5% to 8.0% per year.
  • the condition of sepsis is dangerous and the mortality rate is high. About 14,000 people die every day from the world, and about 215,000 people die each year in the United States. According to foreign epidemiological surveys, the mortality rate of sepsis has exceeded that of myocardial infarction, which has become the main cause of death of non-cardiac people in the intensive care unit. In recent years, despite advances in anti-infective therapy and organ function support technologies, the mortality rate of sepsis is still as high as 30% to 70% (J. Clin. Invest. 2003,
  • ALI acute lung injury
  • ARDS acute respiratory distress syndrome
  • DVT deep vein thrombosis
  • DIC metabolic acidosis
  • MODS multiple organ dysfunction syndrome
  • the underlying pathogenesis of sepsis is unclear, involving complex systemic inflammatory network effects, genetic polymorphisms, immune dysfunction, coagulopathy, tissue damage, and host abnormal responses to different infectious pathogenic microorganisms and their toxins. In terms of the system, it is closely related to the multi-system and multi-organ pathophysiological changes. The pathogenesis of sepsis still needs to be further clarified.
  • Sepsis can be caused by infection in any part, clinically common in pneumonia, peritonitis, cholangitis, urinary tract infection, cellulitis, meningitis, abscess and so on.
  • the most common pathogens of sepsis and septic shock are Gram-negative bacteria (mainly including Escherichia coli, Klebsiella and Pseudomonas aeruginosa).
  • Gram-positive bacteria such as staphylococcus, streptococcus
  • the basic treatment needs to use antibiotics to control the source of infection.
  • Oxidative stress during sepsis is reflected by lipid peroxidation and anti-oxidation in plasma.
  • Oxidative damage may be an important cause of cell damage, organ dysfunction, and death.
  • the oxidant causes the cells to produce lipid peroxides, and a large amount of oxygen radicals act on the lipids to raise the lipid peroxides, resulting in tissue damage.
  • Oxygen free radicals cause mitochondrial swelling, mitochondrial dysfunction, lipid peroxidation, inhibition of respiration, and depletion of mitochondrial antioxidants.
  • Long-term exposure to NO in oxidative damage leads to cell damage. This damage occurs in a paracrine or autocrine form, thereby inhibiting cell respiration, resulting in uneven blood flow distribution, increased intestinal permeability, and peroxide.
  • ischemia-reperfusion leads to the production of intestinal superoxide dismutase, which leads to an increase in the level of oxygen free radicals, and a large amount of peroxide is produced from nitric oxide.
  • Increased nitric oxide production means intestinal damage, intestinal dysfunction, and bacterial translocation.
  • Innate immune cells (including monocytes, macrophages, neutrophils, NK cells, etc.) recognize the Pathogen Associated Molecular Pattern (PAMP) by the indicated Pattern Recognition Receptor (PRR).
  • PAMP Pathogen Associated Molecular Pattern
  • PRR Pattern Recognition Receptor
  • the lamina limbal growth factor and mucosa contain a large number of immune cells, including T lymphocytes, B lymphocytes, macrophages, mast cells, and neutrophils. In the case of sepsis, these cells release a large number of cytokines, including IL-1 ⁇ , IL-4, IL-6, IL-10, IFN- ⁇ , and TNF- ⁇ .
  • IFN- ⁇ and TNF- ⁇ can increase the permeability of intestinal mucosal epithelial cells under pathological conditions. IFN- ⁇ secreted by intraepithelial lymphocytes is an important factor in the loss of intestinal mucosal function caused by complete parenteral nutrition. IFN- ⁇ leads to an increase in the expression of iNOS, especially when combined with TNF- ⁇ and IL-1 ⁇ . It is currently believed that cytokines increase iNOS resulting in increased permeability of the intestinal mucosa.
  • ROS reactive oxygen species
  • the borneol is divided into synthetic borneol and natural borneol.
  • Synthetic borneol contains isoborne brain, which has toxic side effects on the human body; natural borneol does not contain isoborneol.
  • Natural borneol belongs to the class of bicyclic monoterpenoids, which can be processed from crystalline crystals of the genus Dryobalanopsaromatica Gaertn.f. resin of the Dipterocarpaceae plant (traditional medicine, 2006, 15(9): 57).
  • Natural borneol belongs to the class of bicyclic monoterpenoids, which can be processed from crystalline crystals of the genus Dryobalanopsaromatica Gaertn.f. resin of the Dipterocarpaceae plant (traditional medicine, 2006, 15(9): 57).
  • the volatile oils of plants Valeriana officinalis, Matricaria chamomilla, Lavandulaofficinalis, and the like (Biochem Pharmacol. 2005, 69
  • Natural borneol has a strong anti-inflammatory effect, possibly by inhibiting the transcription factor NF- ⁇ B activation, inhibiting the expression of inflammatory proteins (iNOS and COX-2) and inflammatory cytokines (TNF- ⁇ , IL-1 ⁇ , etc. Release, and thus the role of cytoprotection (Neuroscience. 2011, 176: 408-19; West China Pharmaceutical Journal 2006, 21 (6): 523-526). Natural borneol can penetrate the blood-brain barrier, protect against cerebral infarction area and ischemia-induced inflammatory response, and improve energy metabolism, thereby reducing ischemic brain damage (West China Pharmaceutical Journal 2005, 20 (4): 323-325 Journal of Xinxiang Medical College 2006, 23(1): 23-25).
  • natural borneol can also improve blood coagulation and antithrombotic activity in rats (Am J Chin Med. 2008; 36(4): 719-27). In addition, natural borneol also enhances the inhibitory amino acid GABA receptor activity (Biochem Pharmacol. 2005, 69(7): 1101-11).
  • the structure of natural borneol is as follows:
  • the 3-methyl-1-phenyl-2-pyrazolin-5-one and natural borneol mass ratio 4:1 compositions have been tested in clinical trials for the treatment of ischemic stroke. Preclinical animal experiments show that the mass ratio of the two can reduce the area of cerebral infarction in a synergistic ratio of 4:1 to 1:1 (patent CN 101848711 B).
  • a combination of 3-methyl-1-phenyl-2-pyrazolin-5-one and natural borneol is selected to exert a mechanism for scavenging free radicals and inhibiting inflammation, and synergistic resistance Excessive inflammatory response during the onset of sepsis, reducing tissue damage, thereby reducing sepsis mortality.
  • An object of the present invention is to provide a pharmaceutical composition for the preparation of a medicament for treating a disease associated with endotoxemia, which comprises 3-methyl-1-phenyl-2-pyrazoline- 5-ketone or a pharmaceutically acceptable salt thereof and borneol, and further, the combination of the drugs can synergistically increase the efficacy of a disease associated with endotoxemia.
  • the borneol of the present invention comprises natural borneol.
  • SIRS systemic inflammatory response syndrome
  • sepsis sepsis
  • severe sepsis sepsis shock
  • sepsis-related diffuse intravascular Coagulation DIC
  • ALI acute lung injury
  • ARDS acute respiratory distress syndrome
  • MOFS multiple organ failure syndrome
  • septic brain injury septic brain injury, and other causes of inflammatory lung injury, including but not limited to bacteria Pneumonia.
  • the above composition is used for the preparation of a treatment for sepsis, severe sepsis, septic shock, and septic brain injury and inflammatory lung injury.
  • Patent Document CN200510009561.1 discloses: tail vein administration of edaravone 1.5, 3, 6 mg/kg can significantly improve LPS-induced pus Symptomatic indicators of toxic rats, including animal survival rate.
  • the present inventors have found that a combination of 3-methyl-1-phenyl-2-pyrazolin-5-one and natural borneol has a clear therapeutic effect in the treatment of sepsis, than 3-methyl-1-phenyl-2.
  • -Pyrazolin-5-one alone is more effective, especially in reducing Mortality, reduction of inflammatory factors production, improvement of tissue damage, etc. have obvious superiority, can significantly increase survival rate and median survival, reduce excessive inflammatory response in sepsis, thereby reducing organ damage.
  • the weight ratio of 3-methyl-1-phenyl-2-pyrazolin-5-one to natural borneol is from 10:1 to 1:10, and the preferred weight ratio is from 4:1 to 1:4.
  • a further preferred weight ratio is from 4:1 to 2:1, more preferably 10:1, 4:1, 2:1, 1:2, 1:4 or 1:10.
  • the present invention provides suitable routes of administration and frequency of administration of a combination of 3-methyl-1-phenyl-2-pyrazolin-5-one and natural borneol. Because the patient's inflammatory response is excessive, the condition is critical, and the mortality rate is high, it is best to administer it by intravenous injection, and it is better to administer the drug twice a day for two consecutive days.
  • Figure 2-A Effect of different doses of edaravone on the survival rate of CLP model rats.
  • Fig. 5 Pathological changes of lung tissue (400X) at 6h, 12h and 24h after LPS modeling and drug treatment.
  • Figure 6-A shows the effect of multiple doses of drugs (6 and 24 h after modeling) on the pathology of LPS-induced lung injury.
  • Figure 6-B shows the effect of multiple doses of drugs (6 and 24 h after modeling) on pathological scores of LPS-induced lung injury.
  • Figure 7-A shows the effect of drugs on LPS-induced serum inflammatory factor TNF- ⁇
  • Figure 7-B shows the effect of drugs on LPS-induced serum inflammatory factor IL-6 in mice
  • Figure 7 shows the effect of drugs on LPS-induced MPO activity in lung tissue of mice.
  • Figure 8-A shows the effect of drugs on white blood cell counts in lung tissue lavage fluid of LPS-induced model mice.
  • Figure 8-B shows the effect of drugs on inflammatory factor TNF- ⁇ in lung tissue lavage fluid of LPS-induced mouse models.
  • Figure 8-C shows the effect of drugs on inflammatory factor IL-6 in lung tissue lavage fluid of LPS-induced model mice.
  • Figure 9-A shows the effect of composition (4:1) on secretion of KC (keratinocyte growth factor) by MLE-12 cells.
  • mice weighing 25-30 g were depilated on the abdomen one day before the experiment.
  • the cecum was punctured 3 times with a 16-gauge needle and a small amount of intestinal contents was extruded.
  • the cecum was also placed in the abdominal cavity, and the abdominal wall incision was sutured layer by layer.
  • mice After the operation, the penicillin eye ointment was applied to prevent infection, and the wound was bandaged. The mice recovered their activity capacity about 20 minutes after the operation was completed. Before CLP surgery, the mice were lively and active, the fur was smooth and radiant, the lips and front and rear claws were ruddy, the eating and drinking were active, and the bowel movements were normal. After CLP surgery, the mice showed impotence, vertical hair, lips, and front and rear claws were red. Reduced eating and drinking, loose stools, congestion in the eyes, fever and fever; mice died within 8-30 hours after surgery. At autopsy, multiple organ abnormalities were found and pathological damage occurred. These indicate that the model is successful.
  • mice male, 64, were randomly divided into sham operation group, sepsis model group, edaravone treatment group (single iv, 6 mg/kg) and composition (4:1) treatment group ( Single iv, 7.5 mg/kg).
  • composition (4:1) represents edaravone 3 mg/kg + natural borneol 0.75 mg/kg.
  • Edaravone injection specification 5mL: 10mg (including edaravone 10mg), produced by Nanjing Xiansheng Dongyuan Pharmaceutical Co., Ltd.; composition (4:1) injection, the specification is 5mL: 12.5mg (including Edaravone 10 mg and natural borneol 2.5 mg were dissolved in 8% 1,2,-propanediol aqueous solution). Both were diluted with physiological saline to the desired concentration before use. The tail vein was slowly bolused ( ⁇ 5 min) 30 minutes after CLP modeling.
  • the composition (4:1) can reduce animal mortality and prolong sepsis.
  • Example 4 Effect of multiple doses of composition (4:1) on survival rate of CLP model rats
  • Eighty SD rats were randomly divided into sham operation group, CLP model group, edaravone treatment group (3mg/kg) and composition (4:1) treatment group (3.75mg/kg, including edaravone). 3 mg/kg and natural borneol 0.75 mg/kg).
  • the administration was diluted with physiological saline to a dose of 10 mL/kg.
  • 30 minutes after CLP modeling the tail vein was injected, followed by tail vein administration once every 12 hours, twice daily (BID, once every 12 hours). Rat deaths were recorded every 4 hours after CLP administration.
  • Edarabi's new patent document CN200510009561.1 discloses that a single tail vein administration of edaravone at 1.5, 3, and 6 mg/kg can significantly improve the survival rate of LPS-induced sepsis rats.
  • the present study found that edaravone 1.5 and 3 mg/kg (BID) treatment can significantly improve the survival rate of animals, but the high dose of edaravone 6 mg/kg (BID) did not improve the survival rate of the animals, but increased after 24 hours. Animal mortality (see Figure 2-A).
  • composition (4:1) 3.75mg/kg (BID) treatment effect was significantly better than the edaravone best treatment group (3mg/kg, BID), which not only improved the median survival of the animals, but also improved the severe pus Survival rate of toxic animals (see Figure 2-B and Table 2). This indicates that natural borneol in the composition can increase the efficacy of edaravone in the treatment of sepsis.
  • Example 5 Effect of composition (4:1) administration on plasma inflammatory factors in septic rats
  • the graph data in Figure 3 is represented as mean ⁇ SD; the results of t-test analysis are expressed as: &&&&, p ⁇ 0.0001, compared with sham surgery; ****, p ⁇ 0.0001, compared with CLP model group; # #,p ⁇ 0.01,###, p ⁇ 0.001, compared with the edaravone 3 mg/kg group.
  • TNF- ⁇ (2h) and IL-6 (6h) were significantly elevated in rat plasma after CLP surgery.
  • the levels of TNF- ⁇ and IL-6 in the plasma of the edaravone group were significantly decreased, while the levels of TNF- ⁇ and IL-6 in the plasma of the composition (4:1) group were lower than those of the edaravone group.
  • Example 6 Protective effect of composition on cognitive impairment in septic rats
  • the inhibitory avoidance test includes learning training and memory testing.
  • the detection device is a 50 ⁇ 25 ⁇ 25 cm box, and the bottom is composed of stainless steel bars of the same diameter (1 mm in diameter), each spaced 1 cm apart, and a platform of 7 cm wide and 2.5 cm high.
  • the rats were placed on a platform and the latency of their limbs all falling onto the grid was recorded. Once the animal falls to the grid, it will be subjected to a 2 second 0.4 mA electric shock and then placed back into the squirrel cage. After 24 hours of training and training experiments, a memory test was performed. In addition to no foot shock, the test procedure is consistent with the training time, and the latency (maximum 180 seconds) falling on the grid is used as a detection index for inhibitory avoidance memory.
  • Example 7 Effect of different ratios on survival rate in septic rats
  • compositions including edaravone: natural borneol mass ratios of 10:1, 4:1, 2:1, 1:2, 1:4 and 1:10, respectively, are shown in Table 4.
  • the solvent of the composition was physiological saline containing 8% 1,2-propanediol.
  • the above composition was diluted with physiological saline to the administration volume before administration.
  • composition was first dissolved with 1,2-propanediol and then diluted with pre-warmed physiological saline.
  • 108 SD rats were randomly divided into sham operation group, CLP model group, composition (10:1) treatment group (3.3 mg/kg), composition (4:1) treatment group (3.75 mg/kg), combination. (2:1) treatment group (4.5 mg/kg), composition (1:2) treatment group (9 mg/kg), composition (1:4) treatment group (15 mg/kg) and composition (10: 1) Treatment group (33 mg/kg).
  • the doses of each group were edaravone 3 mg/kg and natural borneol were 0.3 mg/kg, 0.75 mg/kg, 1.5 mg/kg, 6 mg/kg, 12 mg/kg and 30 mg/kg, respectively.
  • the mode of administration is tail vein injection, which is administered twice a day (BID, once every 12 hours).
  • CLP was performed in the late sepsis 30 min after the severe sepsis model, followed by tail vein administration once every 12 h (BID); the death of the rats was recorded every 4 h after CLP administration.
  • the compositions (4:1 to 1:4) were paired with animals in the different ratio combinations designed. Both survival and median survival rates improved. From the animal survival rate (Fig. 4), it was found that the natural borneol composition in the composition showed two stages: the lower dose of natural borneol increased the edaravone to increase the survival rate of the animal, but the high dose of natural borneol did not use the animal later. Survival, high doses of natural borneol (12, 30 mg / kg, BID) multiple doses may be toxic to severe sepsis animals.
  • Example 8 Effect of replicating mouse acute lung injury (ALI) model and composition on lung injury
  • mice Healthy male C57BL/6 mice, 7-8 weeks, weighing 20-23 g. Eighty-five C57 male mice were randomly assigned to each group of 5-6, and the penis intravenous injection of the composition (4:1) immediately after instillation of LPS 1 mg/kg (12.5 mg/kg, containing edaravone 10 mg) /kg and natural borneol 2.5mg/kg), edaravone (10mg/kg), natural borneol (2.5mg/kg), dexamethasone (5mg/kg) and normal saline, etc., normal control airway Instilled saline. The animals were sacrificed in three batches at 6h, 12h, and 24h after LPS instillation.
  • BALF bronchoalveolar lavage fluid
  • the ALI mice generally observed that the airway instilled into the LPS model mice had a bit of bleeding spots and edema on the surface of the lung tissue, while the physiological control group showed no abnormal changes in the lung appearance. Histopathological sections showed a large amount of neutrophil accumulation in the lumen of the airway and in the lumen of the lumen. A large amount of neutrophil infiltration and erythrocyte exudation were observed in the interstitial space of the lung. There was protein edema in the alveoli, and the edge of the alveolar space was light. A transparent film is formed. LPS induced inflammatory infiltration of lung tissue increased with time, and tissue inflammatory cell infiltration at 24h resulted in structural damage.
  • mice Male Bal/c mice weighing 20-22 g. Twenty randomly divided into groups, each group of 4-7, after pentobarbital sodium anesthesia, surgical incision tracheal instillation into LPS (10 ⁇ L / 50 ⁇ L) suture, respectively, in the tail vein injection of edara 0.5h and 6.5h after modeling Feng (6mg/kg), composition 4:1 (7.5mg/kg, edaravone 6mg/kg, natural borneol 1.5mg/kg) or intraperitoneal injection of dexamethasone DEX (5mg/kg) 3h after modeling The model group was injected with a vehicle control in the tail vein. 24 hours after model establishment, lung tissue was fixed in 10% formalin, and conventional paraffin sections were taken and HE stained.
  • Normal lung tissue consists of alveolar, intrapulmonary bronchial branches, blood vessels and interstitial. The structure is clear. There is no inflammatory exudate in the alveolar cavity and bronchial cavity. There is no inflammatory cell infiltration in the bronchus and blood vessels in the lung. Most mice have alveolar walls. Mild congestion.
  • Alveolar wall 7 mice had mild or moderate venous inflammatory cell infiltration in the alveolar wall.
  • the inflammatory cell types were mainly neutrophils and mononuclear macrophages, and a few (3) had mild or slight bleeding locally. In the heavier lesions, the surrounding alveolar cavity is enlarged and is emphysema.
  • Intrapulmonary bronchus and perivascular tissue the space around the perivascular tissue of the lung is significantly widened, with irritated red edema fluid (perivascular edema) and infiltration of inflammatory cells of the same type, with varying degrees of severity, mostly mild or mild. 1 moderate.
  • Alveolar wall 4 mice with mild hyperemia, mild or moderate inflammatory cell infiltration, inflammatory cell type same as before, 3 local minor hemorrhage, 3 mild or mild emphysema.
  • Intrapulmonary bronchus and perivascular tissue 2 perivascular tissues have a very small amount of inflammatory cells infiltrated with the same type, and 1 has mild edema.
  • Composition (4:1) group (4) the degree of cell infiltration of lung tissue inflammation was reduced compared with the model group
  • Alveolar wall 4 mice with mild hyperemia, mild or moderate inflammatory cell infiltration, inflammatory cell type same as before, 1 local minor bleeding.
  • Intrapulmonary bronchus and perivascular tissue 2 perivascular tissues have a very small amount of inflammatory cell infiltration of the same type, and mild edema.
  • Alveolar wall 5 mice with mild hyperemia, mild or moderate inflammatory cell infiltration, inflammatory cell type same as before, and 1 mild emphysema.
  • Intrapulmonary bronchus and perivascular tissue There were a small or very small amount of inflammatory cells infiltrating into the perivascular tissue of the two lungs, one of which was mildly edematous.
  • the lesions were recorded as 0.5 (slight), 1 (mild), 2 (moderate), 3 (severe), and no lesions were 0 (negative), and all scores were added. Calculate the average score for each animal in each group.
  • the lung tissue damage scores of the drug groups were shown in Figure 6-B. Both edaravone and the composition (4:1) were able to reduce LPS-induced lung injury.
  • Example 10 Effect of a single intravenous injection composition on serum inflammatory factors
  • mice Male Bal/c mice weighing 20-22 g. Twenty-four randomized groups, 6 in each group, were anesthetized with sodium pentobarbital, and the trachea was instilled into LPS (10 ⁇ L/50 ⁇ L). The edaravone (6 mg/kg) was injected into the tail vein 0.5 h after modeling. The composition was 4:1 (7.5 mg/kg, wherein edaravone 6 mg/kg, natural borneol 1.5 mg/kg) or intraperitoneal injection of dexamethasone DEX (5 mg/kg), and the model group was injected with a vehicle control in the tail vein.
  • LPS 10 ⁇ L/50 ⁇ L
  • the composition was 4:1 (7.5 mg/kg, wherein edaravone 6 mg/kg, natural borneol 1.5 mg/kg) or intraperitoneal injection of dexamethasone DEX (5 mg/kg), and the model group was injected with a vehicle control in the tail vein.
  • composition 4:1 significantly reduced the levels of inflammatory factors TNF- ⁇ and IL-6 in the serum at the early (2 h) induction of LPS, and its effect was due to the edaravone group.
  • Example 11 Effect of multiple intravenous injections on MPO activity in lung tissue
  • mice Male Bal/c mice weighing 20-22 g. Thirty randomized groups of 6 rats in each group were anesthetized with sodium pentobarbital, and the trachea was instilled into LPS (10 ⁇ L/50 ⁇ L). The edaravone was injected into the tail vein at 0.5 h and 6.5 h after modeling. 6mg/kg), composition 4:1 (7.5mg/kg, edaravone 6mg/kg, natural borneol 1.5mg/kg) or intraperitoneal injection of dexamethasone DEX (5mg/kg) 3h after modeling, model A vehicle control was injected into the tail vein.
  • LPS 10 ⁇ L/50 ⁇ L
  • the edaravone was injected into the tail vein at 0.5 h and 6.5 h after modeling. 6mg/kg), composition 4:1 (7.5mg/kg, edaravone 6mg/kg, natural borneol 1.5mg/kg) or intraperitoneal injection of dex
  • mice 24 hours after modeling, mice were anesthetized with pentobarbital sodium, the thoracic cavity was opened, the left atrial appendage was cut, and normal saline was injected through the right ventricle to perfuse the blood in the pulmonary circulation until the lungs turned white.
  • the lung tissue was taken out, wrapped in weighing paper, and frozen at -20 °C.
  • the MPO activity of lung tissue of each group was detected according to the myeloperoxidase (MPO) test kit (Nanjing built).
  • MPO myeloperoxidase
  • MPO activity in lung tissue of mice was significantly increased after LPS modeling
  • the high, edaravone and composition (4:1) administration groups significantly reduced MPO activity, and the composition (4:1) group had lower MPO activity levels than the edaravone group.
  • Example 12 Effect of multiple intravenous injections on inflammatory cells and inflammatory factors in lung tissue lavage fluid
  • mice Male Bal/c mice weighing 20-22 g. Twenty-four randomized groups, 6 rats in each group, were anesthetized with sodium pentobarbital, and the trachea was instilled into LPS (10 ⁇ L/50 ⁇ L). The edaravone was injected into the tail vein at 0.5 h and 6.5 h after modeling. 6mg/kg), composition 4:1 (7.5mg/kg, edaravone 6mg/kg, natural borneol 1.5mg/kg) or intraperitoneal injection of dexamethasone DEX (5mg/kg) 3h after modeling, model A vehicle control was injected into the tail vein.
  • LPS 10 ⁇ L/50 ⁇ L
  • the edaravone was injected into the tail vein at 0.5 h and 6.5 h after modeling. 6mg/kg), composition 4:1 (7.5mg/kg, edaravone 6mg/kg, natural borneol 1.5mg/kg) or intraperitoneal injection of de
  • the cell pellet was resuspended in 0.5 ml of PBS, and then added with 0.5 ml of white blood cell staining solution, uniformly stained, fixed for staining, and counted for blood cells.
  • the contents of TNF- ⁇ and IL-6 in the supernatant of alveolar lavage fluid were determined according to the ELISA (Essay) instructions.
  • the number of white blood cells in the alveolar lavage fluid increased after LPS modeling, and the administration group significantly reduced the number of white blood cells, and the composition (4:1) group was significantly better than the edaravone group.
  • the composition (4:1) significantly reduced the inflammatory factor content and was significantly better than the edaravone group.
  • Example 13 Effect of composition on the function of mouse epithelial cells (MLE-12)
  • Lung epithelial cells are also important cells of the lung defense barrier, the priming cells of the pulmonary inflammatory response.
  • an LPS-induced mouse lung epithelial cell line (MLE-12) was used to make an inflammatory model. 2 ⁇ 10 5 cell/ml MLE-12 cells were resuspended in complete medium (Gibco RPMI-1640 medium + 4% FBS), and then inoculated into 48-well plates. After 24 hours of culture, the compositions were pre-incubated separately (4: 1), edaravone, natural borneol (final concentration of 1 mM) for 15 min, and then LPS (final concentration 1 ⁇ g / mL) induced cells.
  • KC keratinocyte growth factor
  • the composition (4:1) significantly inhibited the release of KC from LPS-stimulated mouse lung epithelial cells, suggesting an improvement in the initial inflammatory response to LPS-induced acute lung injury. . Edaravone only had a certain effect in the early stage, and the inhibition disappeared after 12h; while the effect of natural borneol on KC began to appear after 9h. This suggests that the composition (4:1) combines the effects of both on KC and exerts a function of inhibiting KC release from 0 to 24 hours after administration.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Rheumatology (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Pain & Pain Management (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pulmonology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

La présente invention concerne une utilisation d'une composition pharmaceutique dans la fabrication d'un médicament destiné au traitement de maladies associées provoquées par une endotoxémie. La composition pharmaceutique comprend la 3-méthyl-1-phényl-2-pyrazolin-5-one ou un sel associé pharmaceutiquement acceptable et du bornéol. Les maladies comprennent, sans caractère limitatif, le syndrome de réponse inflammatoire systémique, la sepsie, la sepsie grave, le choc septique, la coagulation intravasculaire disséminée associée à la sepsie, les lésions pulmonaires aiguës, le syndrome de détresse respiratoire aiguë, le syndrome de défaillance multiviscérale, les lésions cérébrales septiques et les lésions pulmonaires inflammatoires provoquées par d'autres causes, notamment mais non exclusivement la pneumonie bactérienne.
PCT/CN2014/087043 2013-10-12 2014-09-22 Utilisation d'une composition pharmaceutique dans la fabrication de médicaments pour le traitement d'une sepsie et d'une lésion pulmonaire inflammatoire WO2015051695A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201310474253.8 2013-10-12
CN201310474253.8A CN104546832A (zh) 2013-10-12 2013-10-12 一种药物组合物在制备治疗脓毒症药物中应用

Publications (1)

Publication Number Publication Date
WO2015051695A1 true WO2015051695A1 (fr) 2015-04-16

Family

ID=52812516

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2014/087043 WO2015051695A1 (fr) 2013-10-12 2014-09-22 Utilisation d'une composition pharmaceutique dans la fabrication de médicaments pour le traitement d'une sepsie et d'une lésion pulmonaire inflammatoire

Country Status (2)

Country Link
CN (1) CN104546832A (fr)
WO (1) WO2015051695A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112891362A (zh) * 2021-03-01 2021-06-04 天津红日药业股份有限公司 一种用于治疗脓毒症的药物组合物及其应用
CN114748493A (zh) * 2022-05-17 2022-07-15 安徽医科大学 一种王不留行黄酮苷在制备治疗脓毒症的药物中的应用
US20220233503A1 (en) * 2016-05-20 2022-07-28 Institut Pasteur Methods of treating sepsis with synaptic vesicle 2a and/or 2b binding chemical entities

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107613976B (zh) * 2015-06-10 2021-07-06 江苏先声药业有限公司 一种组合物在制备治疗肌萎缩性侧索硬化症药物中的应用
CN112957356A (zh) * 2015-11-06 2021-06-15 先声药业有限公司 一种药物组合物在制备肾功能衰竭药物中的应用
CN106668006B (zh) * 2015-11-06 2021-02-05 先声药业有限公司 3-甲基-1-苯基-2-吡唑啉-5-酮和（+）2-莰醇的组合物的应用

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1954812A (zh) * 2005-10-28 2007-05-02 江苏先声药物研究有限公司 依达拉奉的新用途

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1954812A (zh) * 2005-10-28 2007-05-02 江苏先声药物研究有限公司 依达拉奉的新用途

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
LIANG, KE; ZENG, NAN ET AL.: "The Effect of aromatic resuscitation drugs on Lethal Hit of lipopolysaccharide in D-galactosamine sensibilized mice", PHARMACOLOGY AND CLINICS OF CHINESE MATERIA MEDICA, vol. 27, no. 1, 31 December 2011 (2011-12-31), pages 58 - 60 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20220233503A1 (en) * 2016-05-20 2022-07-28 Institut Pasteur Methods of treating sepsis with synaptic vesicle 2a and/or 2b binding chemical entities
CN112891362A (zh) * 2021-03-01 2021-06-04 天津红日药业股份有限公司 一种用于治疗脓毒症的药物组合物及其应用
CN114748493A (zh) * 2022-05-17 2022-07-15 安徽医科大学 一种王不留行黄酮苷在制备治疗脓毒症的药物中的应用
CN114748493B (zh) * 2022-05-17 2023-05-30 安徽医科大学 一种王不留行黄酮苷在制备治疗脓毒症的药物中的应用

Also Published As

Publication number Publication date
CN104546832A (zh) 2015-04-29

Similar Documents

Publication Publication Date Title
WO2015051695A1 (fr) Utilisation d'une composition pharmaceutique dans la fabrication de médicaments pour le traitement d'une sepsie et d'une lésion pulmonaire inflammatoire
EP1519750A2 (fr) Utilisation d'agents oxygenants pour accroitre la reponse d'un hote aux infections
Wang et al. Intestinal ischemic reperfusion injury: Recommended rats model and comprehensive review for protective strategies
CA2778371C (fr) Composition de soin externe pour la peau comprenant un sel et du sucre en tant que principes actifs pour prevenir et traiter la vaginose et utilisation de cette composition
KR102007280B1 (ko) 글루타릴 히스타민의 기도 질환 치료 용도
ITMI20130075A1 (it) Combinazione orale per la prevenzione e il trattamento di patologie vescicali, pelviche e dell¿apparato uro-genitale
CN106163542A (zh) 用于促进皮肤溃疡和伤口愈合的组合物
JP2018503637A (ja) ビフェニル誘導体及びその使用
CN111973631A (zh) 牙髓间充质干细胞在制备阿尔茨海默病治疗药物中的用途
ES2783879T3 (es) Dimetilaminomiqueliolida para su uso en el tratamiento de fibrosis pulmonar
US11224633B2 (en) Kit for treating sepsis and/or any systemic (SIRS) or damaging cellular hyperinflammation
WO2022028375A1 (fr) Utilisation thérapeutique d'une solution d'extrait de graisse acellulaire pour des maladies pulmonaires
Kocdor et al. The effects of pentoxifylline on bacterial translocation after intestinal obstruction
Maseda et al. Severe Mucor necrotizing fasciitis associated to dipyrone-induced agranulocytosis
EP3955947A1 (fr) Méthode et composition pour inverser et/ou inhiber l'athérosclérose
ES2273872T3 (es) Gatifloxacino como inhibidor de la produccion de citoquinas.
CN113244208B (zh) Hpa在制备治疗非酒精性脂肪性肝病药物中的应用
CN113473992A (zh) 用于治疗和预防中性粒细胞胞外陷阱相关并发症的化合物
CN112603917B (zh) 辣椒素酯的新用途
CN113274389B (zh) 氟非尼酮在制备治疗急性肺损伤药物中的应用
CN114366730B (zh) 没食子酸及包含其的药物组合物用于治疗细菌性前列腺炎的应用
TWI780460B (zh) 副乾酪乳桿菌gks6用於製備預防或治療腎功能異常組合物的用途
CN113694066B (zh) 三棱素c在制备治疗缺血性脑卒中的药物中的应用
US20230404969A1 (en) Compositions and method for effective management of peritonitis
Sheoran et al. Therapeutic Value of Earthworms to Achieve Sustainable Development Goal Number 3

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: 14852553

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: 14852553

Country of ref document: EP

Kind code of ref document: A1