WO1998006426A1

WO1998006426A1 - Use of a plasminogen activator for the treatment of pulmonary disorders

Info

Publication number: WO1998006426A1
Application number: PCT/DK1997/000330
Authority: WO
Inventors: Jørgen Brodersen GRAM; Jøgen JESPERSEN
Original assignee: Gram Joergen Brodersen; Jespersen Joegen
Priority date: 1996-08-14
Filing date: 1997-08-14
Publication date: 1998-02-19
Also published as: AU3765897A

Abstract

A new 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 is disclosed. A device provided with a container containing a liquid solution of a plasminogen activator and means for nebulizing the liquid solution is also disclosed.

Description

USE OF A PLASMINOGEN ACTIVATOR FOR THE TREATMENT OF PULMONARY DISORDERS.

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. Despite comprehensive research during the last decade the mortality rate has remained high, reportedly above 50% (1,2) . Although a number of phar acologic regimes has been recommended, a recent review suggests a limited success in most approaches

(3) . Therefore, there is a need for a treatment, which adheres more specifically to the pathogenesis of pulmonary disorders .

Deposition of fibrin in the lungs plays a critical role in the evolution of several pulmonary disorders, including respiratory distress syndrome (RDS) , respira- tory distress syndrome-hyaline membrane disease (RDS- HMD) , adult respiratory distress syndrome (ARDS) , septic shock, and pneumonia. This is supported by a substantial amount of literature, which, however, did not have any impact on presently recommended treatment regimes of ARDS (3-5) . Under normal circumstances 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). In contrast, 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 . To ensure the complete removal of clotted blood, streptokinase was installated endoscopically in the lungs (16) . The hitherto suggested treatment regimes for pulmonary disorders caused by the presence of fibrin in the lungs, primarily in the alveoles, have not gained widespread acceptance due to a number of reasons .

The intravenous administration of urokinase, tissue plasminogen activator, and plasmin (13 and 15) is a non-specific systemic treatment which may activate fibrinolysis anywhere in the body, also in areas where fibrinolyse is not wanted. Furthermore, 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 .

The inhalation of an aerosol comprising heparin

(14) does not dissolve or remove the fibrin already present in the alveoles, only the formation of new fibrin is prevented due to the inhibition of thrombin.

The administration of 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.

Thus, 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.

The term "pulmonary administration" used herein means administration to one or both lungs. E.g., the aerosol may be administrated through the oral, intra- nasal or intratracheal route.

The term "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.

At present, 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. When a droplet is deposited on the lung tissue, it is presumed that the plasminogen activator comes into contact with the plasminogen and activates it to the active enzyme plasmin. The plasmin will digest the fibrin and thus clear the obstructed alveoles.

As the size of the droplets is of great importance for the area of deposition, the physician may design the droplet size to reach the target areas of the lungs. In most diseases related to the deposition of fibrin, the fibrin is deposited in the alveoles. Thus, the size of the droplets is designed to carry the droplets all the way through the bronchial tree before deposition. To reach the alveoles, the size of the droplets should preferably be in the range of 2-8 μm. If the droplets are to be deposited in the bronchial tree, the size should preferably be in the range of 10- 16 μm.

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.

It is preferred to use 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) .

Especially preferred are genuine plasminogen activators (e.g. t-PA and SCUPA), for which no immunological complications may be predicted. 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.

Whereas the administration of plasminogen activator as an aerosol to the lungs may provide for the destruction of the fibrin deposited within the lung, it might be beneficial to co-administrate 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. When 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 .

It may be desired to stop further deposition of fibrin. Therefore, one or more of the reactions involved in the formation of fibrin may be inhibited. It is preferred to obstruct the last step in the blood clotting cascade, which is the conversion of fibrinogen to fibrin. This step is catalized by thrombin which may be inhibited by a heparinoid, e.g. heparin, or a thrombin inhibitor, e.g. hirudin or antithrombin. Thus, in a preferred embodiment of the invention, 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

10,000-30,000 IU/24 h. 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 . Usually, 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 (FIO₂) 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. Thus, 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.

In the following, the present invention will be illustrated by means of an example, however, this example is not to be considered as limiting for the scope of protection.

EXAMPLE

A 27 year old woman was admitted to the intensive care unit from home. In attempt of suicide she had taken 2500 mg of Amitryptylin (Saroten^®) and 400 mg Estazolen (Doπvnamid^®) . At admittance she was confused, had a temperature of 38.3°C, a heart rate of 145 bpm and a marked widening of the QRS complexes . Biochemical measurements demonstrated an oxygen saturation of 0.89

(ref. 0.95-0.99), a p_a02 of 6.7 kP_a (ref. 9.2-15.0 kP_a) , P_aC0₂ of 3.9 kP_a (ref. 4.3-6.0 kP_a) , a white blood cell concentration of 18.3-109/1 (ref. 2.9- 10.4-10⁹/1), a blood platelet concentration of 134-10⁹/1 (ref. 160-340 • 10⁹/1) , and a serum creatinine kinase of 4,984 U/l (ref. 50-150 U/l) , while she had no evidence of deterioration of function of kidneys or liver. 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, Stockholm, 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 Tinzapaπn (Innohep^®) 3,500 anti X_a units once per day. Due to slight haemodynamic instability intravenous Dopamin (Dopmin^®) was administered continuously in a dose of 3.5 μg/kg/ mm, and because of deterioration of lung function controlled ventilation was on day 3 changed to pressure controlled ventilation with a PEEP of 8 cm H2O and a FIO2 of 0.6. The condition deteriorated further, and on day 5 PEEP had been increased to 12 cm H2O and FIO2 to 0.80. Now 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/cm⁵ - ² , while Cl (4.3 (lm/m²) and PVRI (324 dyn sec/cmS-m²) were significantly increased. At that time 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. In the following days the dose was increased to 12 ng/kg/min, but despite a short improvement with this treatment and changing to prone position the condition of the patient deteriorated with e.g. increasing FIO2 (0.85) and increasing PVRI (465 dyn- s • /cm⁵m²) .

On day 9 it was concluded that the patient did not respond favourably to synthetic prostacyclin and the prognosis of the patient was considered to be poor. It was decided to stop treatment with synthetic prostacyclin and start inhalation of 30 mg nebulized rt-PA (Actilyse^®) through the respirator system and 20 mg intravenous rt-PA, both regimens given simultaneously over 2 hours. The treatment was followed by continuous inhalation of nebulized heparin (Heparin Leo^®) in a dose of 15,000 IU/24h.

Five hours after treatment with rt-PA there was a sudden increase in P_aθ2 of 12.9 to 26.6 kP_a, while P_aC02 showed a transient decrease. It was now possible to rapidly reduce FIO2 from 0.85 to 0.40 and still keep the same P_aθ2 and P_aC02 as before start of treatment with rt-PA and heparin. No other radical therapeutical changes or interventions were made during the last period up to this sudden improvement. The condition remained stable and 2 days later the chest roent- genogram showed less intensive infiltration of the lungs. Inhalation with heparin was continued for 13 days, the patient was extubated after 22 days, and on day 32 she was discharged from the ICU in a stable condition to the medical ward. No episodes of bleeding were observed.

References

1. Suchyta MR, Clemmer TP, Elliote LG, Orane JF jr., Weaver LK. The adult respiratory distress syndrome: a report of survival and modifying fac- tors. Chest 1992; 101: 1074-9.

2. Steinberg KP, McHugh LG, Hudson LD . Causes of mortality in patients with the adult respiratory distress syndrome (ARDS) : an update. Am Rev Respir Dis 1993; 147/Suppl A347. Abstr. 3. Kollef M, Shuster DP. The acute respiratory distress syndrome. N Engl J Med 1995; 323: 27-37. 4. Ricou B. A broader view of ARDS. In: Vincent J-L, ed. 1996 Yearbook of Intensive Care and Emergency. Berlin: Springer, 1996: 375-88. 5. Puybasset L, Rouby JJ. Pharmacologic approach of hypoxemia in ARDS patients. In: Vincent J-L, ed. 1996 Yearbook of Intensive Care and Emergency. Berlin: Springer, 1996: 434-65.

6. Bartozzi P, Aastedt B, Zenzius L, Lynch K, Le- Maire F, Zapol W, Chapman H. Depressed bronchoalveolar activity in patients with adult respiratory distress syndrome. N Engl J Med 1990; 323: 890-7.

7. Idell S, James KK, Levin EG, Schwartz BS , Macanda N, Maunder RJ, Martin TR, McLarty J, Fair DS .

Local abnormalities in coagulation and fibrinolytic pathways predispose to alveolar fibrin deposition in the adult respiratory distress syndrome. J Clin Invest 1989; 84: 695-705. 8. Idell S, Peters J, James KK, Fair DS, Coalson JJ. Local abnormalities of coagulation and fibrinolytic pathways that promote alveolar fibrin deposition in the lungs of Baboons with diffuse alveolar damage. J Clin Invest 1989; 84: 181-93. 9. Idell S, Koenig KB, Fair DS, Martin TR, McLarty J, Mauder RJ. Serial abnormalities of fibrin turnover in evolving adult respiratory distress syndrome, am J Physiol 1991; 261: 1240-8. 5 10. Malik AB, Johnson A, Tahamont MV. Mechanism of lung vascular injury after intravascular coagulation. NY Acad Sci 1982; 384: 213-34. 11. Saldeen T. Fibrin derived peptides and pulmonary injury. NY Acad Sci 1982; 384: 319-31.

10 12. Johnson A, Carcia-Szabo R, Kaplan JE, Malik AB . Fibrin degradation products increase lung trans- vascular fluid filtration after thrombin- induced pulmonary microembolism. Thromb Res 1985; 37: 543-54.

15 13. Hardaway RM, Williams CH, Marvste M, Farias M, Tseng A, Pinon I, Yanez D, Martinez M, Navar J. Prevention of adult respiratory distress syndrome with plasminogen activator in pigs. Crit Care Med 1990; 18: 1413-8.

20 14. Jaques LB, Mahadoo J, Kavanagh LW. Intrapulmonary heparin. A new procedure for anticoagulant therapy. Lancet 1976; 2: 1157-61.

15. Ambrus JL and Ambrus CM. Changes in the fibrino- lysin system in the infantile and adult respira-

25 tory distress syndrome (ARDS) caused by trauma and/or septic shock in patients and in experimental animals. Journal of Medicin 1990; 21: 67- 84.

16. Harke H. Fibrinolysetherapie bei chirurgisch 30 behandelten Intensivpatienten . Klin Wochenschr

1991; 69: 150-156.

17. Astrup T. Tissue activators of plasminogen. Fed Proc 1966; 25: 42-51. 18. Ranby M. Studies of the kinetics of plasminogen activator by tissue plasminogen activator. Bio- chim Biophys Acta 1982; 704: 461-9.

19. Gurewich V. Fibrinolytic properties of single- chain urokinase plasminogen activator and how they complement those of tissue plasminogen activator. In: Harber E, Braunwald E (eds) Thrombolysis Basic contributions and clinical progress. Mosby Year Book, St. Louis 1991; 51-60.

Claims

P A T E N T C L A I M S

1. 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.

2. Use according to claim 1, wherein the fibrin is present in the alveoles.

3. Use according to claim 1 or 2 , wherein a pharmaceutical composition comprising a plasminogen activator is co-administrated intravenously.

4. Use according to any of the preceding claims, wherein the plasminogen activator is 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.

5. Use according to claim 4, wherein the plasminogen activator is SCUPA or rt-PA.

6. Use according to any of the preceding claims, wherein a heparinoid is administrated simultaneously or subsequent to the administration of a plasminogen activator.

7. Use according to claim 6, wherein the heparinoid is heparin.

8. Use according to any of the claims 1 to 6 , wherein a thrombin inhibitor is administrated simulta- neously or subsequent to the administration of a plasminogen activator.

9. Use according to claim 8, wherein the thrombin inhibitor is hirudin or antithrombin.

10. Use according to any of the receding claims, wherein the pharmaceutical composition is administrated orally as an aerosol.

11. Use according to claim 1 wherein the pulmonary disorder is respiratory distress syndrome (RDS) , respiratory distress syndrome-hyaline membrane disease (RDS-HMD) , adult respiratory distress syndrome (ARDS) , septic shock, or pneumonia.

12. 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.

13. A device according to claim 12, wherein the plasminogen activator is 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.

14. A device according to claim 12 or 13, wherein the pharmaceutical composition in addition comprises a heparinoid and/or a thrombin inhibitor.

15. A method for the treatment of pulmonary dis- orders caused by or related to the presence of fibrin, wherein an aerosol comprising a plasminogen activator is administrated to the lungs.

16. A method according to claim 15, wherein the plasminogen activator is 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.

17. A method according to claim 15, wherein a pharmaceutical composition comprising a plasminogen activator is co-administrated intravenously.

18. A method according to claim 15, wherein a heparinoid or a thrombin inhibitor is administrated simultaneously or subsequent to the administration of a plasminogen activator.

19. A method according to claim 15, wherein the pulmonary disorder is respiratory distress syndrome (RDS) , respiratory distress syndrome-hyaline membrane disease (RDS-HMD) , adult respiratory distress syndrome (ARDS) , septic shock, or pneumonia.