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Synergistic effects of a cremophor EL drug delivery system and its U0126 cargo in an ex vivo model

Christensen, S. T. ; Grell, A. S. LU ; Johansson, S. E. LU ; Andersson, C. M. ; Edvinsson, L. LU and Haanes, K. A. (2019) In Drug delivery 26(1). p.680-688
Abstract

Neuroprotection has proven clinically unsuccessful in subarachnoid hemorrhage. We believe that this is because the major component in the early damage pathway, the vascular wall, has not been given the necessary focus. U0126 is a potent inhibitor of vascular phenotypical changes, exemplified by functional endothelin B (ETB) receptor upregulation. The current study aimed to determine the optimal dose of U0126 ex vivo and test the toxicology of this dose in vivo. To find the optimal dose and test a suitable in vivo delivery system, we applied an ex vivo model of blood flow cessation and investigated functional ETB receptor upregulation (using a specific agonist) as the primary endpoint. The secondary endpoint was depolarization-induced... (More)

Neuroprotection has proven clinically unsuccessful in subarachnoid hemorrhage. We believe that this is because the major component in the early damage pathway, the vascular wall, has not been given the necessary focus. U0126 is a potent inhibitor of vascular phenotypical changes, exemplified by functional endothelin B (ETB) receptor upregulation. The current study aimed to determine the optimal dose of U0126 ex vivo and test the toxicology of this dose in vivo. To find the optimal dose and test a suitable in vivo delivery system, we applied an ex vivo model of blood flow cessation and investigated functional ETB receptor upregulation (using a specific agonist) as the primary endpoint. The secondary endpoint was depolarization-induced contractility assessed by 60 mM K+ stimuli. Furthermore, an in vivo toxicology study was performed on the optimal selected doses. U0126 (10 µM) had a strong effect on the prevention of functional ETB receptor contractility, combined with minimal effect on the depolarization-induced contractility. When cremophor EL was chosen for drug delivery, it had an inhibitory and additive effect (combined with U0126) on the ETB receptor contractility. Hence, 10 µM U0126 in 0.5% cremophor EL seems to be a dose that will be close to the maximal inhibition observed ex vivo on basilar arteries, without exhibiting side effects in the toxicology studies. U0126 and cremophor EL are well tolerated at doses that have effect on ETB receptor upregulation. Cremophor EL has an additional positive effect, preventing functional ETB receptor upregulation, making it suitable as a drug delivery system.

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Please use this url to cite or link to this publication:
author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Basilar artery, cremophor EL, endothelin-1, MEK1/2, optimal dose, U0126
in
Drug delivery
volume
26
issue
1
pages
9 pages
publisher
Informa Healthcare
external identifiers
  • pmid:31274009
  • scopus:85069267265
ISSN
1071-7544
DOI
10.1080/10717544.2019.1636421
language
English
LU publication?
yes
id
657285ad-f651-4607-adca-3c38949c0189
date added to LUP
2019-07-29 10:08:38
date last changed
2020-07-08 05:01:04
@article{657285ad-f651-4607-adca-3c38949c0189,
  abstract     = {<p>Neuroprotection has proven clinically unsuccessful in subarachnoid hemorrhage. We believe that this is because the major component in the early damage pathway, the vascular wall, has not been given the necessary focus. U0126 is a potent inhibitor of vascular phenotypical changes, exemplified by functional endothelin B (ETB) receptor upregulation. The current study aimed to determine the optimal dose of U0126 ex vivo and test the toxicology of this dose in vivo. To find the optimal dose and test a suitable in vivo delivery system, we applied an ex vivo model of blood flow cessation and investigated functional ETB receptor upregulation (using a specific agonist) as the primary endpoint. The secondary endpoint was depolarization-induced contractility assessed by 60 mM K+ stimuli. Furthermore, an in vivo toxicology study was performed on the optimal selected doses. U0126 (10 µM) had a strong effect on the prevention of functional ETB receptor contractility, combined with minimal effect on the depolarization-induced contractility. When cremophor EL was chosen for drug delivery, it had an inhibitory and additive effect (combined with U0126) on the ETB receptor contractility. Hence, 10 µM U0126 in 0.5% cremophor EL seems to be a dose that will be close to the maximal inhibition observed ex vivo on basilar arteries, without exhibiting side effects in the toxicology studies. U0126 and cremophor EL are well tolerated at doses that have effect on ETB receptor upregulation. Cremophor EL has an additional positive effect, preventing functional ETB receptor upregulation, making it suitable as a drug delivery system.</p>},
  author       = {Christensen, S. T. and Grell, A. S. and Johansson, S. E. and Andersson, C. M. and Edvinsson, L. and Haanes, K. A.},
  issn         = {1071-7544},
  language     = {eng},
  month        = {07},
  number       = {1},
  pages        = {680--688},
  publisher    = {Informa Healthcare},
  series       = {Drug delivery},
  title        = {Synergistic effects of a cremophor EL drug delivery system and its U0126 cargo in an ex vivo model},
  url          = {http://dx.doi.org/10.1080/10717544.2019.1636421},
  doi          = {10.1080/10717544.2019.1636421},
  volume       = {26},
  year         = {2019},
}