WO1999018982A1 - Facteur d'activation de cellules pulmonaires et son procede de preparation - Google Patents

Facteur d'activation de cellules pulmonaires et son procede de preparation Download PDF

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Publication number
WO1999018982A1
WO1999018982A1 PCT/CN1998/000215 CN9800215W WO9918982A1 WO 1999018982 A1 WO1999018982 A1 WO 1999018982A1 CN 9800215 W CN9800215 W CN 9800215W WO 9918982 A1 WO9918982 A1 WO 9918982A1
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WIPO (PCT)
Prior art keywords
lung
pneumocyclin
group
treatment
peaks
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Application number
PCT/CN1998/000215
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English (en)
Chinese (zh)
Inventor
Baihong Liu
Qunjun Du
Jianxin Pi
Original Assignee
Baihong Liu
Qunjun Du
Jianxin Pi
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 Baihong Liu, Qunjun Du, Jianxin Pi filed Critical Baihong Liu
Priority to AU94278/98A priority Critical patent/AU9427898A/en
Publication of WO1999018982A1 publication Critical patent/WO1999018982A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A61K35/42—Respiratory system, e.g. lungs, bronchi or lung cells

Definitions

  • the invention relates to a composition extracted from animal lungs for preventing and treating respiratory diseases.
  • the composition is formerly known as lung cell activin, referred to as pneumostimin, and its English name is Pulmonary Cell Active Fartor (PCAF).
  • PCAF Pulmonary Cell Active Fartor
  • bronchodilator drugs In the treatment of respiratory diseases such as asthma, the use of bronchodilator drugs alone is not comprehensive enough. For moderate and severe asthma, relying on regular use of bronchodilators (such as ⁇ 2 agonists) is even harmful because ⁇ 2 anti-inflammatory effects without excitement, pure symptomatic treatment can mask the development of inflammation, the AHR increased, and therefore must be combined with anti-inflammatory medication.
  • bronchodilators such as ⁇ 2 agonists
  • pure symptomatic treatment can mask the development of inflammation, the AHR increased, and therefore must be combined with anti-inflammatory medication.
  • anti-inflammatory drugs although asthma is relieved or preventive measures are temporarily controlled, most patients have recurrences of varying severity or interval length. This is mainly because antibiotics have no effect on lung tissue repair and regeneration, so The recurrence rate remains high, and drug withdrawal and disease appear. Experts generally believe that the efficacy of asthma patients is related to the susceptibility of macrophages to various drugs.
  • the present invention provides a substance capable of activating macrophages, the purpose of which is to regulate the immune function of the body and improve the indication of lung function.
  • a pneumocyclin characterized in that:
  • 1.2 is a composition containing the main components with a molecular weight of less than 20KDa: a polypeptide, a nucleic acid;
  • the aqueous solution of the composition has two peaks at 190400nm ultraviolet spectroscopic scanning, namely, 205 ⁇ 10nm, 260 ⁇ 10nm, and the valley between the two peaks is at 235 ⁇ 10nm;
  • lymphokines such as EL-1 and IL-2
  • Macromolecular protein test The sulphosalic acid method tests the protein as negative.
  • the aqueous solution of the composition is analyzed by high performance liquid chromatography, and has three or four main absorption peaks, and the relative area percentage of the main peaks is more than 40%.
  • Pulmonin can protect the lungs and bronchial tubes of animals and humans: It can repair the damage of lungs and bronchial tubes of animals and humans; promote the regeneration of human lung and bronchial tissue cells, thereby enhancing the efficacy of antibiotics; and can promote the growth of tissue cells in vitro.
  • Leptin can be extracted from the lung tissue of mammals and can prevent and treat respiratory diseases, especially prevent and treat chronic bronchitis, asthma, lung cancer, emphysema, tuberculosis, pneumonia, respiratory failure, bronchiectasis, lungs Respiratory diseases such as abscesses.
  • a method for preparing pneumocyclin which is characterized by-
  • the preparation method uses high-speed tissue masher, colloid mill and other mechanical and ultrasonic methods to break up the lung tissue.
  • the product added with distilled water after crushing can be repeatedly freeze-thawed.
  • an ultrafiltration method is used to extract the separated and clarified product, and the ultrafiltration molecular weight cuts off substances below 20KDa.
  • the labeled amount of the finished product in the preparation method uses the polypeptide content labeling method, the nucleic acid content labeling method and the biological activity unit labeling method.
  • pneumocontin supplements the lack of growth cytokines in asthma patients.
  • viscera is used to fill the viscera
  • Cytokines are ideal for supplementing cytokines in this organ of the human body, because it restores the integrity of the cytokine network, which is not possible with the prior art.
  • Pneumotensin can enhance the phagocytosis and secretion of macrophages in the lung. This is the most important defense and protection system in the lung. This promotes phagocytosis and eliminates allergens and inflammatory bacteria and viruses that cause lung diseases. Both controlled
  • type I allergies reduces the development of chronic airway inflammation and reduces the contraction and contraction of bronchial smooth muscle. Cramps.
  • Pulmonin is an extract of mammalian lung tissue cells. For example, fresh fetal lungs of newborn calves are washed, broken, and broken. Mechanical or ultrasonic methods such as high-speed tissue masher, colloid mill are used to break the lung tissue, and then Distilled water with a weight of 0.5-3.0 times the lung can be repeatedly frozen and thawed, and then separated and clarified; the separation method can be cloth filtration, screen filtration, filter paper filtration, filter bucket filtration, filter plate filtration; clarification by centrifugation, spin-drying, etc. method. The separated and clarified products are extracted. The ultrafiltration method and other physical and chemical methods are used for the extraction. Ultrafiltration has a molecular weight of less than 20KDa. Then sterilize and dispense; make pneumokinin into water needle or lyophilized powder needle.
  • the method of labeling the finished product uses the method of labeling polypeptide content, the method of labeling nucleic acid content, and the method of labeling biological activity units.
  • the obtained pneumocyclin has the following technical characteristics:
  • Macromolecular protein test The sulfosalic acid method tests the protein as negative.
  • the aqueous solution of the composition has two peaks at 190-400nm ultraviolet spectroscopic scanning, namely 205 ⁇ 10nm and 260 ⁇ 10nm, and the valley between the two peaks is at 235 ⁇ 10nm.
  • the aqueous solution of the composition was analyzed by high performance liquid chromatography, and there were three main absorption peaks, and the relative area percentages of the main peaks were above 40%.
  • This product performs general pharmacological tests on cats.
  • the tests show that pneumocyclin has no significant effect on the nervous system, cardiovascular system (heart rate, electrocardiogram, blood pressure, etc.) and respiratory system (frequency, depth, etc.) of animals.
  • Cholesterol enhances macrophage phagocytosis in bronchoalveolar lavage fluid from rats.
  • Pulvinin has the function of promoting IL-1 production in mice.
  • Pulvinin has the function of promoting IL-2 production in mice.
  • Pyrogen test The test was conducted strictly in accordance with Part 2 of the Pharmacopoeia of the People's Republic of China, and was qualified.
  • Abnormal toxicity test 0.5ml of this product was injected into the tail vein of mice.
  • Safety test Guinea pigs were intraperitoneally injected with 5ml of this product, healthy weight gain, and qualified.
  • Allergy test The test was carried out according to the cytochrome C solution allergy test method of Part Two of the Pharmacopoeia of the People's Republic of China, and it passed. A doubled attack test is also eligible.
  • Antihypertensive substances inspection conducted in strict accordance with Part 2 of the Pharmacopoeia of the People's Republic of China, and does not contain antihypertensive substances.
  • Acute toxicity test Two animals (mice, rats) were administered by three routes (i.e. intramuscular injection, intravenous injection, intraperitoneal injection), and proved to be more than 625 times the human dosage, without any toxic reaction, safe and reliable.
  • mice were used as experimental subjects and intramuscular injection was used to study the effect of pneumocyclin on chronic bronchitis in mice.
  • Prophylactic administration Intramuscular injection of pneumoviin at the beginning of exposure, two dose groups, namely the high and low dose groups, were administered 5 days a week for a total of 6 weeks.
  • Therapeutic administration 6 weeks after the animals were exposed to the virus, a bronchitis model was established and treated with pneumocyclin, which was also divided into a high-dose group and a low-dose group, 5 days a week for a total of 4 weeks. At this S0 2 concentration to maintain the amount of 100-200ppm.
  • Animals in the administration group had significantly improved indicators of weight gain, average number of coughs, and lung coefficients compared with the poisoned control group.
  • Pathological examination of the lung tissue with the optical microscope showed that the degree of inflammation of the lung tissue in the treatment group was milder. Transmission electron microscopy and scanning electron microscopy observations showed that the tracheal mucosal ciliary cells were less damaged in the treatment group.
  • mice living factor S0 2 inhalation due to bronchitis have better prevention and treatment. 1. Scanning electron microscope observation of trachea
  • the proportion of cilia in the visual field is large, and the trachea is lightly damaged. On the contrary, the damage is heavy, and the statistical results are shown in the table. As can be seen from the table, the average area of the cilia in the visual field was larger than that of the poisoning control group, either in the prophylactic or therapeutic group, and there was a statistical difference (P ⁇ 0.05), indicating that the cilia were damaged after treatment. Greatly reduced.
  • the lung tissue of each group of animals had different degrees of inflammation, as shown in Table 2. It can be seen from Table 2 that the inflammation of the lung tissue in the administration group was significantly lower than that in the poisoned control group. Scanning electron microscopy of trachea in experimental groups
  • Drugs Pulmonin, thymosin, sodium chloride injection.
  • IL-2 production Anticoagulant was added to each well of the culture plate, followed by TPA and PHA, and cultured for 24 hours. 20ul of supernatant was aspirated from each well for BL-2 activity measurement.
  • DL-2 responding cells induced by ConA C 57 BL / 6 mouse spleen was ground to prepare a cell suspension, A ConA was added, and cultured for 48 hours. The cells at the interface layer are layered to obtain EL-2 response cells (lymphocytes).
  • Blank control group 14 46.14 soil 9.42 ⁇ 0.001
  • Thymosin group 14 95.04 ⁇ 23.96 ⁇ 0.001
  • Pulmonin 1 group 14 114.51 + 21.09 ⁇ 0.001
  • Pulmonin 3 group 14 493.49 soil 63.42 ⁇ 0.001
  • Pulmonin can promote the production of interleukin II in mice (P ⁇ 0.001), that is, lung can improve the immune function of mice.
  • Incubation time add 0.5ml of lung macrophages to the wells of the reaction plate, 2 ° /.
  • Chicken red blood cells 0.5ml, HANK
  • Counting Count macrophages in units of 100 under an inverted microscope, and calculate the phagocytic rate and index of macrophages. 6. Results-Table 4 Rat red blood cell phagocytic rate and index of rat lung macrophages Group Phagocytic rate (%) P value Phagocytic index P value
  • Meat thymopeptide group 5.33 ⁇ 1.21 ⁇ 0.01 9.50 ⁇ 3.73 ⁇ 0.05 Pulmonin 1 group 12.00 + 1.41 ⁇ 0.001 17.83 ⁇ 2.32 ⁇ 0.001 Pneumocyclin 1 group 12.33 + 1.03 ⁇ 0.001 20.33 ⁇ 2.80 ⁇ 0.001 group Pulmonin 3 Group 13.17 + 1.33 ⁇ 0.001 26.33 ⁇ 4.89 ⁇ 0.001 Static blank control group 2.00 + 0.63 2.67 ⁇ 1.21
  • Pulse thymosin group 5.33 ⁇ 0.52 ⁇ 0.001 8.33 ⁇ 1.03 ⁇ 0.001 Pneumocyclin 1 group 10.33 ⁇ 0.52 ⁇ 0.001 16.83 + 2.04 ⁇ 0.001 Pneumocyclin 2 group 10.67 + 0.82 ⁇ 0.001 17.67 ⁇ 1.21 ⁇ 0.001 group Group 13.83 ⁇ 0.75 ⁇ 0.001 27.33 ⁇ 2.88 ⁇ 0.001
  • the P value in the table is the comparison value between each group and the blank control group.
  • Rat lung macrophages and phagocytosis rate increased with the increase in the dose of pneumocyclin, and the effect of the injection route was not significant.
  • Pulvin can promote the phagocytosis of rat lung macrophages, that is, lung can make macrophages In an activated state, the phagocytosis of foreign particles is enhanced. In inflammatory tissues, if the quality of activated alveolar macrophage selective secretions is strong and effective, it will play an important role in curbing the development of pneumonia, increasing the absorption of lesions and preventing tissue fibrosis, and improving the defense function of the lungs.
  • Phagocytosis is the most phagocytic cell in the body.
  • lymphokines It is an important effector cell in cellular immunity, and sensitized T cells release lymphokines to act on macrophages and enhance their killing ability.
  • Routine treatment group Routine treatment with anti-inflammatory and antipyretic; Oral antispasmodic.
  • Pneumovidin adjuvant treatment group On the basis of conventional treatment, give pneumocyclin 3mg (50kg) daily. Observation indicators:
  • Pulmonin has the effect of enhancing cellular immune function, and ⁇ cell function is affected in bronchial asthma. Pulmonin, as an immunomodulator, helps to improve ⁇ cell function.
  • Pulmonin can regulate the balance of cytokines in the body.
  • the imbalance between cytokines in bronchial asthma can promote the production of IL-2 and regulate the balance of cytokines in the body.
  • Pulmonin has the effect of enhancing the phagocytosis of macrophages. It can activate the phagocytosis of macrophages in bronchial asthma to enhance its membrane activity and increase lysosome and lysozyme content. Improves anti-inflammatory effects, and can reduce recurrent respiratory infections and induce asthma attacks.
  • pneumocyclin was used to assist in the treatment of 60 cases of bronchial asthma. Of the 50 cases who achieved clinical control and marked effect, 23 cases had been followed up continuously for more than 3 years and remained in a relatively stable state. It is stated that pneumocyclin has a certain effect on reducing and preventing respiratory infections and reducing the incentives for infection of asthma attacks.
  • Pulmonin is safe, has no local stimulating effect, does not produce allergic reactions, and has no systemic toxic and side effects. It is an ideal adjuvant treatment for bronchial asthma.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Cell Biology (AREA)
  • Physiology (AREA)
  • Pulmonology (AREA)
  • Engineering & Computer Science (AREA)
  • Biomedical Technology (AREA)
  • Biotechnology (AREA)
  • Developmental Biology & Embryology (AREA)
  • Immunology (AREA)
  • Virology (AREA)
  • Zoology (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un facteur d'activation de cellules pulmonaires (PCAF) extrait des poumons d'animaux et qui est une composition présentant une activité biologique utile dans la prévention et le traitement de maladies de l'appareil respiratoire. Le PCAF est une composition renfermant des polypeptides et des acides nucléiques en tant que composants principaux dont le poids moléculaire est inférieur à 20 Kda. La spectrométrie UV permet d'observer deux pics dans la solution aqueuse du PCAF. L'activité biologique de la composition est caractérisée en ce qu'elle peut stimuler des monocytes et le potentiel phagocytaire de macrophages in vivo et in vitro; elle peut également réguler la production de lymphokines telles les IL-1 et IL-2. L'invention concerne en outre une substance qui peut activer la fonction de macrophages de manière à réguler la fonction immunologique de l'organisme et à améliorer l'indice de la fonction pulmonaire.
PCT/CN1998/000215 1997-10-08 1998-10-08 Facteur d'activation de cellules pulmonaires et son procede de preparation WO1999018982A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU94278/98A AU9427898A (en) 1997-10-08 1998-10-08 Pulmonary cell active factor and methods for preparing the same

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN97119731A CN1194833A (zh) 1997-10-08 1997-10-08 肺活素
CN97119731.8 1997-10-08

Publications (1)

Publication Number Publication Date
WO1999018982A1 true WO1999018982A1 (fr) 1999-04-22

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AU (1) AU9427898A (fr)
WO (1) WO1999018982A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10955306B2 (en) 2019-04-22 2021-03-23 Allegro Microsystems, Llc Coil actuated pressure sensor and deformable substrate

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1992004907A1 (fr) * 1990-09-26 1992-04-02 Fred Possmayer Agents tensioactifs pulmonaires naturels et extraits lipidiques de ces agents
WO1994000131A1 (fr) * 1992-06-24 1994-01-06 Tokyo Tanabe Company Limited Agent prophylactique et agent curatif contre des maladies virales des voies respiratoires
CN1163571A (zh) * 1994-09-28 1997-10-29 比克·古尔顿·劳姆贝尔格化学公司 用于治疗irds和ards的含有至少一种糖皮质激素并混以一种肺表面活性剂的组合物

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1992004907A1 (fr) * 1990-09-26 1992-04-02 Fred Possmayer Agents tensioactifs pulmonaires naturels et extraits lipidiques de ces agents
WO1994000131A1 (fr) * 1992-06-24 1994-01-06 Tokyo Tanabe Company Limited Agent prophylactique et agent curatif contre des maladies virales des voies respiratoires
CN1163571A (zh) * 1994-09-28 1997-10-29 比克·古尔顿·劳姆贝尔格化学公司 用于治疗irds和ards的含有至少一种糖皮质激素并混以一种肺表面活性剂的组合物

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10955306B2 (en) 2019-04-22 2021-03-23 Allegro Microsystems, Llc Coil actuated pressure sensor and deformable substrate

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Publication number Publication date
CN1194833A (zh) 1998-10-07
AU9427898A (en) 1999-05-03

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