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WO1998006426A1 - Utilisation d'un activateur du plasminogene pour le traitement de troubles pulmonaires - Google Patents

Utilisation d'un activateur du plasminogene pour le traitement de troubles pulmonaires Download PDF

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Publication number
WO1998006426A1
WO1998006426A1 PCT/DK1997/000330 DK9700330W WO9806426A1 WO 1998006426 A1 WO1998006426 A1 WO 1998006426A1 DK 9700330 W DK9700330 W DK 9700330W WO 9806426 A1 WO9806426 A1 WO 9806426A1
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WO
WIPO (PCT)
Prior art keywords
plasminogen activator
use according
fibrin
administrated
pulmonary
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/DK1997/000330
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English (en)
Inventor
Jørgen Brodersen GRAM
Jøgen JESPERSEN
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Individual
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Individual
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Application filed by Individual filed Critical Individual
Priority to AU37658/97A priority Critical patent/AU3765897A/en
Publication of WO1998006426A1 publication Critical patent/WO1998006426A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • A61K38/46—Hydrolases (3)
    • A61K38/48—Hydrolases (3) acting on peptide bonds (3.4)
    • A61K38/49—Urokinase; Tissue plasminogen activator
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/164—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from bacteria
    • A61K38/166—Streptokinase

Definitions

  • the present invention relates to the use of a plasminogen activator for the treatment of pulmonary disorders .
  • Pulmonary disorders are often life-threatening conditions complicating a number of underlying predisposing disease states.
  • mortality rate has remained high, reportedly above 50% (1,2) .
  • phar acologic regimes has been recommended, a recent review suggests a limited success in most approaches
  • RDS respiratory distress syndrome
  • RDS- HMD respira- tory distress syndrome-hyaline membrane disease
  • ARDS adult respiratory distress syndrome
  • septic shock septic shock
  • ARDS septic shock
  • 3-5 a substantial amount of literature, which, however, did not have any impact on presently recommended treatment regimes of ARDS (3-5) .
  • the alveolar space is without obstructing fibrin, and studies on normal bronchoalveolar lavage have demonstrated considerable amounts of active plasminogen activators, primarily of the urokinase type (6,7).
  • bronchoalveolar lavage of ARDS patients is characterized by multiple haemostatic abnormalities, including increased concentrations of procoagulant factors, high concentration of fibrinolytic inhibitors and no or only traceable fibrinolytic activity (6-9) . It has been demonstrated that ARDS is associated with micro-vascular injury causing microvascular thrombosis and accumulation of a protein-rich fluid containing coagulation factors in the extravascular space (7-12). Because of an excessive inhibition of alveolar fibrinolysis in ARDS, this may ultimately lead to formation of alveolar fibrin.
  • Hardaway and co-workers have previously administrated intravenous urokinase and tissue plasminogen activator in order to prevent ARDS in pigs (13) .
  • Jaques and co-workers have reported on healthy human subjects' inhalation of a heparin aerosol from an ultrasonic nebulizer with mask (14) .
  • Ambrus and Ambrus treated infants who had developed severe RDS with human urokinase activated plasmin intravenously in a four hour infusion and human urokinase activated plasmin by aerosol (15) . Harke has reported the endoscopic removal of blood clottings in the bronchial system due to post bleeding following tonsillectomia .
  • streptokinase was installated endoscopically in the lungs (16) .
  • the intravenous administration of urokinase, tissue plasminogen activator, and plasmin is a non-specific systemic treatment which may activate fibrinolysis anywhere in the body, also in areas where fibrinolyse is not wanted.
  • the administrated thrombolytic agents will attack the thrombosis from the face of the lung pointing toward the body not from the lung side. Since it is believed that it is the presence of the fibrin in the alveolar space that is crucial for the prognosis it takes more time before the symptoms are alleviated due to the fact that digestion of the thrombosis happens from the blood side .
  • an aerosol comprising plasmin may be detrimental to the patient as plasmin is an active unspecific serine protease digesting not only fibrin but also other proteinous items in the lungs.
  • the present invention aims at suggesting a new method for the treatment of pulmonary disorders without the above drawbacks .
  • the new method provides for local and relatively quick treatment of a pulmonary disorder caused by or related to the presence of fibrin by the production of plasmin in si tu through the action of a plasminogen activator.
  • the present invention relates to the use of a plasminogen activator for the manufacture of a pharmaceutical composition for pulmonary administration as an aerosol for the treatment of pulmonary disorders caused by or related to the presence of fibrin.
  • pulmonary administration means administration to one or both lungs.
  • the aerosol may be administrated through the oral, intra- nasal or intratracheal route.
  • pulmonary disorder refers herein to any abnormality in the functioning of the lung, which is caused by or related to the presence of fibrin. Examples of such disorders are RDS, RDS-HMD, ARDS, septic shock, and pneumonia.
  • the plasminogen activator is believed to be carried by the droplets of the aerosol to the relevant sites of the lungs, where the droplets are deposited.
  • the size of the droplets determines the area of the lung, wherein they are predominately deposited.
  • the physician may design the droplet size to reach the target areas of the lungs.
  • the fibrin is deposited in the alveoles.
  • the size of the droplets is designed to carry the droplets all the way through the bronchial tree before deposition.
  • the size of the droplets should preferably be in the range of 2-8 ⁇ m. If the droplets are to be deposited in the bronchial tree, the size should preferably be in the range of 10- 16 ⁇ m.
  • plasminogen activator Any suitable plasminogen activator may be used.
  • Preferred plasminogen activators are selected among the group consisting of streptokinase, urokinase, tissue type plasminogen activator (t-PA) , recombinant tissue type plasminogen activator (rt-PA) , anisoylated plasminogen activator complex (APSAC) , single-chain urokinase plasminogen activator (SCUPA) , or combinations thereof.
  • a plasminogen activator which has fibrin affinity in order to be able to promote the conversion of plasminogen to plasmin.
  • the fibrin specific properties of the plasminogen activator leads to the formation of plasmin only in such areas wherein the plasmin is required. Thus, the potential detrimental effects of the presence of plasmin in areas not involved in the deposition of fibrin are avoided.
  • the affinity to fibrin also means that the generation of significant amounts of plasmin is slowed down when fibrin is digested.
  • a plasminogen activator requiring fibrin as a co-factor is i.a. rt-PA (17, 18).
  • Another plasminogen activator with fibrin specific properties is SCUPA (19) .
  • plasminogen activators e.g. t-PA and SCUPA
  • the non-genuine plasminogen activators may be regarded as non-self by the immunological system and a harmful immunological response may evolve in the lungs.
  • plasminogen activator as an aerosol to the lungs may provide for the destruction of the fibrin deposited within the lung
  • a pharmaceutical composition comprising a plasminogen activator intravenously.
  • the activation of plasmin in the blood will lead to the digestion of an obstructing micro-thrombosis in the blood vessels.
  • plasminogen activator is co-administrated intravenously, the thrombosis will be attacked not only from the lung side but also from the blood side.
  • the intravenously administrated plasminogen activator may be given in any appropriate amount, e.g. in an amount of 5-100 mg/dosage, preferably 10-40 mg/dosage .
  • thrombin which may be inhibited by a heparinoid, e.g. heparin, or a thrombin inhibitor, e.g. hirudin or antithrombin.
  • a heparinoid e.g. heparin or a thrombin inhibitor, e.g. hirudin or antithrombin is administrated simultaneously or subsequent to the plasminogen activator.
  • the agents for preventing further deposits of fibrin are preferably administrated as an aerosol, e.g. in an amount of 5,000-50,000 IU/24 h, preferably
  • the administration may take place as continuous inhaltion of the agent.
  • the pharmaceutical composition for pulmonary administration as an aerosol may be of the solid or the liquid type. If the pharmaceutical composition is of the solid type, the aerosol contains solid particles, which are administrated to the patient. If the pharmaceutical composition is of the liquid type, the plasminogen activator is typically dissolved in an aqueous medium, e.g. an isotonic solution.
  • the amount of administrated plasminogen activator depends on a number of factors, such as the severity of the disorder, the condition, file history, age, sex ect . of the patient.
  • the amount of plasminogen activator in a dosage may be in the range of 5-300 mg, preferably 10-60 mg .
  • a single administration should be sufficient, however, the treatment may be repeated or administrated continously, if desired.
  • the effect of the pulmonary administration of a plasminogen activator, as an aerosol, to a patient in need thereof is visible within hours.
  • the condition of the patient is rapidly improved, which is shown by the rapid decline in the demand for oxygen supply.
  • the case study reported in the following example shows that the demand for oxygen supply (FIO 2 ) declined from 0.85 to 0.40 within 5 hours.
  • the plasminogen activator containing solution may be nebulized according to any technique known in the art. If the patient is connected to a respirator, it may be convenient to nebulize the solution through the nebulizing means of the respirator. If the pulmonary disorder occurs in remote geographical areas or during war actions, the solution may be nebulized through a handy device.
  • the present invention also comprises a device for pulmonary administration of a pharmaceutical composition as an aerosol, wherein the device is provided with a container containing a liquid solution of a plasminogen activator and means for nebulizing the liquid solution.
  • Chest roentgenogram demonstrated bilateral infiltrations of the lungs, probably caused by aspiration. Due to respiratory insufficiency the patient was intubated and volume controlled ventilation was initi- ated with a Servo 900 C respirator (Siemens Elema, Sweden) applying a FIO2 of 0.4. The patient was treated with antibiotics, forced alkalinized diuresis, intravenous Acetylcystein (Muccocyst ® ) 600 mg per day, and as thrombo-prophylaxis subcutaneous Tinzapa ⁇ n (Innohep ® ) 3,500 anti X a units once per day.
  • Dopmin ® intravenous Dopamin
  • the chest roentgenogram showed diffuse bilateral infiltrations, pulmonary compliance was 27 ml/cm H2O, PCWP was 12 mm Hg, MPAP was 31 mm Hg, and SVRI was 1135 dyn sec/cm 5 - 2 , while Cl (4.3 (lm/m 2 ) and PVRI (324 dyn sec/cmS-m 2 ) were significantly increased.
  • the patient fulfilled the criterions of manifest ARDS and inhala- tion of nebulized synthetic prostacyclm (Flolan ® ) was started in a dose of 4 ng/kg/mm through the respirator system.
  • ARDS 25 tory distress syndrome

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Medicinal Chemistry (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Immunology (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Biomedical Technology (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

Cette invention se rapporte à une nouvelle utilisation d'un activateur du plasminogène pour la fabrication d'une composition pharmaceutique destinée à être administrée dans les poumons sous la forme d'un aérosol, en vue de traiter les troubles pulmonaires causés par la présence de fibrine ou associés à la présence de fibrine. Cette invention se rapporte également à un dispositif comportant un récipient renfermant une solution liquide d'un activateur de plasminogène et un moyen pour nébuliser la solution liquide.
PCT/DK1997/000330 1996-08-14 1997-08-14 Utilisation d'un activateur du plasminogene pour le traitement de troubles pulmonaires Ceased WO1998006426A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU37658/97A AU3765897A (en) 1996-08-14 1997-08-14 Use of a plasminogen activator for the treatment of pulmonary disorders

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DK0862/96 1996-08-14
DK86296 1996-08-14

Publications (1)

Publication Number Publication Date
WO1998006426A1 true WO1998006426A1 (fr) 1998-02-19

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PCT/DK1997/000330 Ceased WO1998006426A1 (fr) 1996-08-14 1997-08-14 Utilisation d'un activateur du plasminogene pour le traitement de troubles pulmonaires

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AU (1) AU3765897A (fr)
WO (1) WO1998006426A1 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105764488A (zh) * 2013-11-04 2016-07-13 得克萨斯州大学系统董事会 用于向受试者的气道施用酶的组合物和方法
WO2016179447A1 (fr) * 2015-05-06 2016-11-10 Board Of Regents, The University Of Texas System Compositions et procédés d'administration d'un enzyme dans les voies respiratoires d'un sujet
WO2021214320A1 (fr) 2020-04-23 2021-10-28 Previpharma Consulting Gmbh Plasminogène pour une utilisation dans le traitement et la prévention d'un dysfonctionnement pulmonaire
EP4094776A4 (fr) * 2020-02-11 2023-05-17 Talengen International Limited Procédé et médicament pour le traitement de la pneumonie virale

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4790305A (en) * 1986-06-23 1988-12-13 The Johns Hopkins University Medication delivery system
EP0363060A2 (fr) * 1988-10-04 1990-04-11 The Johns Hopkins University Inhalateur d'aérosols
WO1992018157A1 (fr) * 1991-04-16 1992-10-29 Boehringer Mannheim Gmbh Unite de conditionnement pharmaceutique contenant des activateurs de plasminogene destines a etre administres en plusieurs bols
WO1996014056A1 (fr) * 1994-11-04 1996-05-17 Alliance Pharmaceutical Corporation Utilisation de fluorocarbones liquides pour faciliter l'apport d'un medicament aux poumons

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4790305A (en) * 1986-06-23 1988-12-13 The Johns Hopkins University Medication delivery system
EP0363060A2 (fr) * 1988-10-04 1990-04-11 The Johns Hopkins University Inhalateur d'aérosols
WO1992018157A1 (fr) * 1991-04-16 1992-10-29 Boehringer Mannheim Gmbh Unite de conditionnement pharmaceutique contenant des activateurs de plasminogene destines a etre administres en plusieurs bols
WO1996014056A1 (fr) * 1994-11-04 1996-05-17 Alliance Pharmaceutical Corporation Utilisation de fluorocarbones liquides pour faciliter l'apport d'un medicament aux poumons

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
DIALOG INFORMATION SERVICES, File 73, Embase, Dialog Accession No. 332728, Embase Accession No. 75125664, CADE J.F. et al., "Resolution of Experimental Pulmonary Emboli with Heparin and Streptokinase in Different Dosage Regimens"; & J. CLIN. INVEST., (USA), 1974, 54/4 (782-791). *
FILE WPI, Derwent Accession No. 92-022762, CIRMEA MED. INST., "Treatment of Chronic Bronchitis-Involvesinhalation of Aerosol Contg. T-Activin and Urokinase in Addition to Usual Drug Therapy"; SU,A,1 629 063, 23-02-91, DW9203. *

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105764488A (zh) * 2013-11-04 2016-07-13 得克萨斯州大学系统董事会 用于向受试者的气道施用酶的组合物和方法
JP2016535782A (ja) * 2013-11-04 2016-11-17 ボード・オブ・リージエンツ，ザ・ユニバーシテイ・オブ・テキサス・システム 被験者の気道への酵素の投与のための組成物及び方法
EP3065705A4 (fr) * 2013-11-04 2017-10-18 Board of Regents, The University of Texas System Compositions et procédés d'administration d'un enzyme dans les voies respiratoires d'un sujet
US11033611B2 (en) 2013-11-04 2021-06-15 Board Of Regents, The University Of Texas System Compositions and methods for administration of an enzyme to a subject's airway
WO2016179447A1 (fr) * 2015-05-06 2016-11-10 Board Of Regents, The University Of Texas System Compositions et procédés d'administration d'un enzyme dans les voies respiratoires d'un sujet
EP4094776A4 (fr) * 2020-02-11 2023-05-17 Talengen International Limited Procédé et médicament pour le traitement de la pneumonie virale
WO2021214320A1 (fr) 2020-04-23 2021-10-28 Previpharma Consulting Gmbh Plasminogène pour une utilisation dans le traitement et la prévention d'un dysfonctionnement pulmonaire

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Publication number Publication date
AU3765897A (en) 1998-03-06

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