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Arthritis Research and Therapy

, 11:R12

First Online: 26 January 2009Received: 13 September 2008Revised: 01 December 2008Accepted: 26 January 2009

Abstract

IntroductionGlucocorticoids are a mainstay of anti-inflammatory therapy, but significant adverse effects ultimately limit their utility. Previous efforts to design glucocorticoid structures with an increased therapeutic window have focused on dissociating anti-inflammatory transcriptional repression from adverse effects primarily driven by transcriptional activation. An alternative to this medicinal chemistry approach is a systems biology based strategy that seeks to amplify selectively the anti-inflammatory activity of very low dose glucocorticoid in immune cells without modulating alternative cellular networks that mediate glucocorticoid toxicity.

MethodsThe combination of prednisolone and the antithrombotic drug dipyridamole was profiled using in vitro and in vivo models of anti-inflammatory activity and glucocorticoid-induced adverse effects to demonstrate a dissociated activity profile.

ResultsThe combination synergistically suppresses release of proinflammatory mediators, including tumour necrosis factor-α, IL-6, chemokine C-C motif ligand 5 RANTES, matrix metalloproteinase-9, and others, from human peripheral blood mononuclear cells and mouse macrophages. In rat models of acute lipopolysaccharide-induced endotoxemia and delayed-type hypersensitivity, and in chronic models of collagen-induced and adjuvant-induced arthritis, the combination produced anti-inflammatory activity that required only a subtherapeutic dose of prednisolone. The immune-specific amplification of prednisolone anti-inflammatory activity by dipyridamole did not extend to glucocorticoid-mediated adverse effects, including corticosterone suppression or increased expression of tyrosine aminotransferase, in vivo after repeat dosing in rats. After 8 weeks of oral dosing in mice, treatment with the combination did not alter prednisolone-induced reduction in osteocalcin and mid-femur bone density, which are markers of steroid-induced osteoporosis. Additionally, amplification was not observed in the cellular network of corticotroph AtT-20-D16v-F2 cells in vitro, as measured by pro-opiomelanocortin expression and adrenocorticotropic hormone secretion.

ConclusionsThese data suggest that the multi-target mechanism of low-dose prednisolone and dipyridamole creates a dissociated activity profile with an increased therapeutic window through cellular network selective amplification of glucocorticoid-mediated anti-inflammatory signaling.

AbbreviationsACTHadrenocorticotropic hormone

CCL2monocyte chemotactic protein-1

CIcombination index

CIAcollagen-induced arthritis

CRFcorticotropin-releasing factor

CXCL2macrophage inflammatory protein-2

CXCL10interferon-gamma-inducible protein-10

DNFB2,4-dinitrofluorobenzene

DUSP1dual-specificity phosphatase-1

ELISAenzyme linked immunosorbent assay

FBSfetal bovine serum

GRglucocorticoid receptor

GREglucocorticoid response element

HPAhypothalamus-pituitary-adrenal

ILinterleukin

LPSlipopolysaccharide

PBMCperipheral blood mononuclear cell

PDEphosphodiesterase

POMCpro-opiomelanocortin

RArheumatoid arthritis

RT-PCRreverse transcription polymerase chain reaction

SEGRAselective glucocorticoid receptor agonist

TATtyrosine aminotransferase

TNFtumor necrosis factor.

Electronic supplementary materialThe online version of this article doi:10.1186-ar2602 contains supplementary material, which is available to authorized users.

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Autor: Grant R Zimmermann - William Avery - Alyce L Finelli - Melissa Farwell - Christopher C Fraser - Alexis A Borisy

Fuente: https://link.springer.com/



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