CHRONIC INFLAMMATION AND TRANSPLANTATION
Embodiments of the present invention feature methods for treating inflammatory disease and transplantation characterized in that it includes: (i) the incubation of organs with one or more Bryostatin-1 derivatives under conditions which permits vascular exposure to these compounds prior to or immediately following organ ‘harvesting’, and (ii) intravenous, transdermal, intraperitoneal, intra-alveolar instillation of Bryostatin-1 in vivo during active disease, or during periods of disease remission and (iii) prophylactic administration of Bryostatin-1 to limit the development of GVHD.
1 . A method of treating or preventing chronic inflammatory disease or transplantation injury, comprising the steps of administering an effective amount of Bryostatin-1, Bryostatin-1 analog or a pharmaceutically acceptable salt thereof to reduce or prevent induced neutrophil transendothelial migration.
2 . The method of claim 1 wherein said effective amount of Bryostatin-1, Bryostatin analog or pharmaceutically acceptable salt thereof is 10 −7 M per 50 to 90 kg of individual being treated.
3 . The method of claim 1 wherein said effective amount of Bryostatin-1, Bryostatin analog or pharmaceutically acceptable salt thereof is 500 micrograms for 50 to 90 kg of individual being treated.
4 . The method of claim 1 wherein said effective amount Bryostatin-1, Bryostatin-1 analog or a pharmaceutically acceptable salt thereof is held in a dosage form.
5 . The method of claim 4 wherein said dosage form is an oral dosage form.
6 . The method of claim 5 wherein said oral dosage form is a solid oral dosage form.
7 . The method of claim 4 wherein said effective amount of Bryostatin-1, Bryostatin-1 analog or a pharmaceutically acceptable salt thereof is dispersed or dissolved in a saturated polyalkylene glycol glyceride.
8 . The method of claim 7 wherein said polyalkylene glycol glyceride is a mixture of polyalkylene esters of one or more eight carbons to eighteen carbons saturated fatty acids with glycerol.
9 . The method of claim 8 wherein said polyalkylene glycol is a polyethylene glycol having a molecular weight of 1000 to 2000.
10 . The method of claim 9 wherein said polyalkylene glycol is a polyethylene glycol having a molecular weight of 1400 to 1600.
11 . The method of claim 5 wherein said Bryostatin-1, Bryostatin-1 analog or pharmaceutically acceptable salt thereof is present in said oral dosage form in an amount of 1 to 30% by weight.
12 . The method of claim 11 wherein said Bryostatin-1, Bryostatin-1 analog or pharmaceutically acceptable salt thereof is present in said oral dosage form in an amount of 10 to 20% by weight.
13 . The method of claim 11 wherein said Bryostatin-1, Bryostatin-1 analog or pharmaceutically acceptable salt thereof is present in said oral dosage form in an amount of 2 to 25% by weight.
14 . The method of claim 2 wherein said dosage form is a pharmaceutical parenteral formulation.
15 . The method of claim 14 wherein said pharmaceutical formulation comprises polyalkylene glycol glyceride.
16 . The method of claim 15 wherein said polyalkylene glycol glyceride is a mixture of polyalkylene esters of one or more eight carbons to eighteen carbons saturated fatty acids with glycerol.
17 . The method of claim 15 wherein said polyalkylene glycol is a polyethylene glycol having a molecular weight of 1000 to 2000.
18 . The method of claim 17 wherein said polyalkylene glycol is a polyethylene glycol having a molecular weight of 1400 to 1600.
19 . The method of claim 14 wherein said Bryostatin-1, Bryostatin-1 analog or pharmaceutically acceptable salt thereof is present in said pharmaceutical formulation in an amount of 1 to 30% by weight.
20 . The method of claim 19 wherein said Bryostatin-1, Bryostatin-1 analog or pharmaceutically acceptable salt thereof is present in said pharmaceutical formulation in an amount of 10 to 20% by weight.
21 . The method of claim 19 wherein said Bryostatin-1, Bryostatin-1 analog or pharmaceutically acceptable salt thereof is present in said pharmaceutical parenteral formulation in an amount of 2 to 25% by weight.
22 . The method of claim 14 wherein said-1, Bryostatin-1 analog or pharmaceutically acceptable salt thereof is present in said pharmaceutical parenteral formulation as a dispersion in water having a concentration of 0.5 to 70% by weight.
23 . The method of claim 1 wherein said chronic inflammatory disease or transplantation injury is in humans.
24 . The method of claim 23 wherein said chronic inflammatory disease or transplantation injury is leukocyte mediated tissue injury.
25 . The method of claim 23 wherein said chronic inflammatory disease or transplantation injury is mammalian ischemic, transplantation and leukocyte mediated injury and diseases.
26 . A dosage form for treating chronic inflammatory disease or transplantation injury comprising an effective amount of Bryostatin-1, Bryostatin-1 analog or a pharmaceutically acceptable salt thereof to reduce or prevent induced neutrophil transendothelial migration.
27 . The dosage form of claim 26 wherein said dosage form is a solid oral dosage form.
28 . The dosage form of claim 26 wherein said effective amount of Bryostatin-1, Bryostatin-1 analog or a pharmaceutically acceptable salt thereof is dispersed or dissolved in a saturated polyalkylene glycol glyceride.
29 . The dosage form of claim 28 wherein said polyalkylene glycol glyceride is a mixture of polyalkylene esters of one or more eight carbons to eighteen carbons saturated fatty acids with glycerol.
30 . The dosage form of claim 29 wherein said polyalkylene glycol is a polyethylene glycol having a molecular weight of 1000 to 2000.
31 . The dosage form of claim 30 wherein said polyalkylene glycol is a polyethylene glycol having a molecular weight of 1400 to 1600.
32 . The dosage form of claim 31 wherein said Bryostatin-1, Bryostatin-1 analog or pharmaceutically acceptable salt thereof is present in said oral dosage form in an amount of 1 to 30% by weight.
33 . The dosage form of claim 32 wherein said Bryostatin-1, Bryostatin-1 analog or pharmaceutically acceptable salt thereof is present in said oral dosage form in an amount of 10 to 20% by weight.
34 . The dosage form of claim 27 wherein said Bryostatin-1, Bryostatin-1 analog or pharmaceutically acceptable salt thereof is present in said oral dosage form in an amount of 2 to 25% by weight.
35 . The dosage form of claim 26 wherein said dosage form is a pharmaceutical parenteral formulation.
36 . The dosage form of claim 35 wherein said pharmaceutical parenteral formulation comprises polyalkylene glycol glyceride.
37 . The dosage form of claim 36 wherein said polyalkylene glycol glyceride is a mixture of polyalkylene esters of one or more eight carbons to eighteen carbons saturated fatty acids with glycerol.
38 . The dosage form of claim 37 wherein said polyalkylene glycol is a polyethylene glycol having a molecular weight of 1000 to 2000.
39 . The dosage form of claim 38 wherein said polyalkylene glycol is a polyethylene glycol having a molecular weight of 1400 to 1600.
40 . The dosage form of claim 26 wherein said Bryostatin-1, Bryostatin-1 analog or pharmaceutically acceptable salt thereof is present in said pharmaceutical formulation in an amount of 1 to 30% by weight.
41 . The dosage form of claim 40 wherein said Bryostatin-1, Bryostatin-1 analog or pharmaceutically acceptable salt thereof is present in said pharmaceutical formulation in an amount of 10 to 20% by weight.
42 . The dosage form of claim 26 wherein said Bryostatin-1, Bryostatin-1 analog or pharmaceutically acceptable salt thereof is present in said pharmaceutical parenteral formulation in an amount of 2 to 25% by weight.
43 . The dosage form of claim 26 wherein said Bryostatin-1, Bryostatin-1 analog or pharmaceutically acceptable salt thereof is present in said pharmaceutical parenteral formulation as a dispersion in water having a concentration of 0.5 to 70% by weight.