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Details for Patent: 6,013,619

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Details for Patent: 6,013,619

Title: Pulmonary surfactants and therapeutic uses, including pulmonary lavage
Abstract:The present invention discloses useful surfactant molecules including polypeptides, proteins, and a variety of other organic molecules, as well as methods of making and using same. Surfactant compositions, including liposomal surfactant compositions, are also disclosed. Use of the surfactant molecules of the present invention in pulmonary lavage procedures for a variety of therapeutic applications is also disclosed, including the treatment of respiratory distress syndrome; the removal of inflammatory exudate from inflamed lung tissues; and the treament of meconium aspiration syndrome in infants.
Inventor(s): Cochrane; Charles G. (La Jolla, CA), Revak; Susan D. (San Diego, CA)
Assignee: The Scripps Research Institute (La Jolla, CA)
Filing Date:Apr 28, 1997
Application Number:08/848,580
Claims:1. A method for pulmonary lavage of a mammal comprising:

a) applying gas positive end-expiratory pressure (PEEP) with a ventilator into a lung section of said mammal at a pressure of from about 4 to 16 cm water;

b) instilling a lavage composition containing dilute surfactant in a pharmaceutically acceptable aqueous medium into said lung; and

c) removing pulmonary fluid from said lung using short intervals of tracheo-bronchial suction at a negative pressure of about 20 to 100 mm mercury.

2. The method of claim 1 wherein said ventilator PEEP is applied for a preselected time period prior to instilling step (b).

3. The method of claim 2 wherein said time period is up to about 30 minutes.

4. The method of claim 1 wherein said ventilator PEEP is applied continuously during steps (b) and (c).

5. The method of claim 1 wherein said ventilator PEEP is applied for a preselected time period after removing step (c).

6. The method of claim 5 wherein said time period is up to about 24 hours.

7. The method of claim 6 wherein said time period is from about 0.5 to 6 hours.

8. The method of claim 1 wherein said ventilator PEEP is administered for up to about 30 minutes prior to instillation step (b), continuously throughout steps (b) and (c), and for up to about 24 hours after the completion of step (c).

9. The method of claim 1 wherein said mammal is a newborn infant and wherein said ventilator PEEP levels are 4-15 cm water.

10. The method of claim 9 wherein said ventilator PEEP levels are 6-9 cm water.

11. The method of claim 9 wherein said ventilator PEEP levels are 8 cm water.

12. The method of claim 1 wherein said mammal is an adult, a juvenile or infant.

13. The method of claim 12 wherein said ventilator PEEP levels are 6-12 cm water.

14. The method of claim 12 wherein said ventilator PEEP levels are 8-10 cm water.

15. The method of claim 1 wherein said gas contains 21 to 100% oxygen.

16. The method of claim 15 wherein said gas contains 50 to 100% oxygen.

17. The method of claim 1 wherein said dilute surfactant is present in said composition at 0.1-50 mg per ml.

18. The method of claim 17 wherein said dilute surfactant is present in said composition at 0.5-20 mg per ml.

19. The method of claim 17 wherein said dilute surfactant is present in said composition at 2-10 mg per ml.

20. The method of claim 1 wherein said lavage composition is instilled in a volume of 4-60 ml per kilogram.

21. The method of claim 20 wherein said lavage composition is instilled in a volume of 8-30 ml per kilogram per lung section.

22. The method of claim 1 wherein said removing step interval is about 2 to 120 seconds.

23. The method of claim 22 wherein said removing step interval is about 5 to 20 seconds.

24. The method of claim 1 wherein said instilling and removing steps are repeated in sequence 1 to 5 times.

25. The method of claim 1 wherein said composition is instilled in a first and second series, wherein said first series comprises from 1 to 3 cycles of steps (b) and (c) using dilute surfactant in said composition at 0.1 to 10 mg per ml, and wherein said second series comprises from 1 to 5 cycles of steps (b) and (c) using dilute surfactant in said composition at 10 to 50 mg per ml.

26. The method of claim 1 further comprising after step (c):

(d) instilling a composition containing surfactant in a pharmaceutically acceptable aqueous medium into said lung, wherein said surfactant is present in said composition at 15 to 100 milligrams per ml of composition and wherein from 10 to 300 mg of surfactant is instilled per kilogram.

27. The method of claim 1 wherein said lavage is conducted to treat respiratory distress syndrome (RDS) in said mammal.

28. The method of claim 27 wherein said RDS is caused by meconium aspiration.

29. The method of claim 27 wherein said RDS is associated with pulmonary inflammation.

30. The method of claim 27 wherein said RDS is associated with pulmonary infection.

31. The method of claim 27 wherein said RDS is associated with acute hypoxemia.

32. The method of claim 27 wherein said RDS is associated with persistant fetal circulation.

33. The method of claim 27 wherein said RDS is associated with congenital diaphramatic hernia.

34. The method of claim 27 wherein said RDS is associated with sepsis, pulmonary trauma, cranial or body trauma, pancreatitis, aspiration of gastric contents, heated vapor inhalation, noxious vapor inhalation, pneumonia or multiple transfusions.

35. The method of claim 1 wherein said mammal is a human.

36. The method of claim 1 wherein said lavage composition contains a natural pulmonary surfactant isolated from a mammal, or fragment thereof.

37. The method of claim 36 wherein said mammal is selected from the group consisting of bovine, porcine and human.

38. The method of claim 36 wherein said natural pulmonary surfactant is selected from the group consisting of surfactant proteins SP-B and SP-C.

39. The method of claim 36 wherein said natural pulmonary surfactant is substantially isolated human pulmonary surfactant (SP) protein.

40. The method of claim 1 wherein said lavage composition comprises one or more phospholipids and is polypeptide-free.

41. The method of claim 1 wherein said surfactant is a synthetic pulmonary surfactant.

42. The method of claim 41 wherein said synthetic pulmonary surfactant comprises one or more phospholipids and a polypeptide, said polypeptide, when admixed with said phospholipid, forms a synthetic pulmonary surfactant having a surfactant activity greater than the surfactant activity of the phospholipid alone.

43. The method of claim 41 wherein said synthetic pulmonary surfactant comprises one or more pharmaceutically acceptable phospholipids admixed with a polypeptide comprising at least 10 amino acid residues and no more than about 60 amino acid residues, said polypeptide including a sequence having alternating hydrophobic and hydrophilic amino acid residue regions represented by the formula (Z.sub.a U.sub.b).sub.c Z.sub.d, wherein:

Z is a hydrophilic amino acid residue independently selected from the group consisting of R, D, E and K;

U is a hydrophobic amino acid residue independently selected from the group consisting of V, I, L, C and F;

a has an average value of about 1 to about 5;

b has an average value of about 3 to about 20;

c is 1 to 10; and

d is 0 to 3.

44. The method of claim 43, wherein said polypeptide has an amino acid residue sequence represented by the formula:

KLLLLKLLLLKLLLLKLLLLK.

45. The method of claim 43 wherein said polypeptide has an amino acid residue sequence selected from the group consisting of:

KLLLLKLLLLKLLLLKLLLLK,

KLLLLLLLLKLLLLLLLLKLL, and

KKLLLLLLLKKLLLLLLLKKL.

46. The method of claim 41 wherein said synthetic pulmonary surfactant comprises one or more pharmaceutically acceptable phospholipids admixed with a polypeptide having an amino acid residue sequence selected from the group consisting of:

DLLLLDLLLLDLLLLDLLLLD,

RLLLLRLLLLRLLLLRLLLLR,

RLLLLLLLLRLLLLLLLLRLL,

RRLLLLLLLRRLLLLLLLRRL,

RLLLLCLLLRLLLLCLLLR,

RLLLLCLLLRLLLLCLLLRLL, and

RLLLLCLLLRLLLLCLLLRLLLLCLLLR.

47. The method of claim 41 wherein said synthetic pulmonary surfactant comprises:

a) a polypeptide comprising at least 10 amino acid residues and no more than about 60 amino acid residues and constituted by alternating groupings of charged amino acid residues and uncharged amino acid residues, and

b) one or more pharmaceutically acceptable phospholipids, wherein said polypeptide is present in an amount sufficient to increase the surfactant activity of the composition above that of said phospholipid.

48. The method of claim 42, wherein said phospholipid is present in a polypeptide: phospholipid weight ratio in the range of about 1:7 to about 1:1,000.

49. The method of claim 42, wherein said phospholipid is selected from the group consisting of:

1,2-dipalmitoyl-sn-glycero-3-phosphocholine (dipalmitoylphosphatidylcholine, DPPC);

phosphatidyl glycerol (PG); and

an admixture of DPPC and PG in a weight ratio of about 3:1.

50. The method of claim 42, further comprising palmitic acid.

51. The method of claim 42 wherein said polypeptide comprises at least 10 amino acid residues and no more than about 60 amino acid residues and constituted by alternating groupings of charged amino acid residues and uncharged amino acid residues.

52. The method of claim 51 wherein said alternating groupings of amino acid residues represented by the formula (Z.sub.a J.sub.b).sub.c Z.sub.d, wherein:

Z is an amino acid residue independently selected from the group consisting of R, D, E, and K;

J is an .alpha.-aminoaliphatic carboxylic acid;

a has an average value of about 1 to about 5;

b has an average value of about 3 to about 20;

c is 1 to 10; and

d is 0 to 3.

53. The method of claim 51 wherein said alternating groupings of amino acids residue regions represented by the formula (B.sub.a U.sub.b).sub.c B.sub.d, wherein:

B is an amino acid residue independently selected from the group consisting of H, 5-hydroxylysine, 4-hydroxyproline, and 3-hydroxyproline;

U is an amino acid residue independently selected from the group consisting of V, I, L, C, Y, and F;

a has an average value of about 1 to about 5;

b has an average value of about 3 to about 20;

c is 1 to 10; and

d is 0 to 3.

54. The method of claim 51 wherein said alternating groupings of amino acid residues represented by the formula (B.sub.a J.sub.b).sub.c B.sub.d, wherein:

B is an amino acid residue independently selected from the group consisting of H, 5-hydroxylysine, 4-hydroxyproline, and 3-hydroxyproline;

J is an .alpha.-aminoaliphatic carboxylic acid;

a has an average value of about 1 to about 5;

b has an average value of about 3 to about 20;

c is 1 to 10; and

d is 0 to 3.

55. The method of claim 54 wherein said J is an .alpha.-aminoaliphatic carboxylic acid having four to six carbons, inclusive.

56. The method of claim 54 wherein said J is selected from the group consisting of .alpha.-aminobutanoic acid, .alpha.-aminopentanoic acid, .alpha.-amino-2-methylpropanoic acid, and .alpha.-aminohexanoic acid.

57. The method of claim 42 wherein said polypeptide comprises at least 10 amino acid residues and no more than about 60 amino acid residues and constituted by alternating groupings of charged amino acid residues and uncharged amino acid residues as represented by the formula {(Charged).sub.a (Uncharged).sub.b }.sub.c (Charged).sub.d, wherein:

a has an average value of about 1 to about 5;

b has an average value of about 3 to about 20;

c is 1 to 10; and

d is 0 to 3.
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