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R J Flower

Publications and source records attributed to R J Flower.

At least 19 recordsLinked to original sources
PubMed2003

Generation of innovative anti-inflammatory and anti-arthritic glucocorticoid derivatives that release NO: the nitro-steroids.

Addition to the prednisolone structure of a chemical moiety (linker+nitric ester) that releases NO species yielded a novel glucocorticoid (nitro-prednisolone or NCX-1015) with enhanced anti-inflammatory activities. Nitro-prednisolone was much more potent than prednisolone and the derivative devoid of the nitric ester in an acute peritonitis model (higher impact on neutrophil migration and soluble mediator generation) as well as in models of chronic inflammation (air-pouch granuloma and collagen II-induced arthritis). In the collagen II-induced arthritis model, NCX-1015 abrogated the plasma levels of a catabolite of cartilage and bone metabolism, indication of a disease modifying action. In an in vitro assay of bone resorption, NCX-1015 did not activate osteoclast activity, whereas prednisolone did. This lack of effect of NCX-1015 was chiefly due to NO. We propose that NCX-1015 is the prototype of a new class of glucocorticoids, the nitro-steroids, endowed with enhanced anti-inflammatory properties and reduced side effects. These and other experimental observations here reviewed may prompt the assessment of the clinical impact of the nitro-steroids on rheumatoid arthritis and inflammatory bowel disease.

Amino Acids↗
PubMed2003

Kinase-dependent regulation of the secretion of thyrotrophin and luteinizing hormone by glucocorticoids and annexin 1 peptides.

Our previous studies have identified a role for annexin 1 (ANXA1), a protein produced by the pituitary folliculostellate cells, as a paracrine/juxtacrine mediator of the acute regulatory effects of glucocorticoids on the release of adrenocorticotropic hormone and other pituitary hormones. In the present study, we focused on the secretion of thyroid stimulating hormone (TSH) and luteinizing hormone (LH) and used a battery of ANXA1-derived peptides to identify the key domains in the ANXA1 molecule that are critical to the inhibition of peptide release. In addition, as ANXA1 is a substrate for protein kinase C (PKC) and tyrosine kinase, we examined the roles of these kinases in the manifestation of the ANXA1-dependent inhibitory actions of dexamethasone on TSH and LH release. Dexamethasone suppressed the forskolin-induced release of TSH and LH from rat anterior pituitary tissue in vitro. Its effects were mimicked by human recombinant ANXA1 (hrANXA1) and a truncated protein, ANXA1(1-188). ANXA1(Ac2-26), also suppressed stimulated peptide release but it lacked both the potency and the efficacy of the parent protein. Shorter N-terminal ANXA1 sequences were without effect. The PKC inhibitor PKC(19-36) abolished the inhibitory actions of dexamethasone on the forskolin-evoked release of TSH and LH; it also attenuated the inhibitory actions of ANXA1(Ac2-26). Similar effects were produced by annexin 5 (ANXA5) which sequesters PKC in other systems. By contrast, the tyrosine kinase inhibitors, p60v-src (137-157) and genistein, had no effect on the secretion of TSH or LH alone or in the presence of forskolin and/or dexamethasone. Dexamethasone caused the translocation of a tyrosine-phosphorylated species of ANXA1 to the surface of pituitary cells. The total amount of ANXA1 exported from the cells in response to the steroid was unaffected by tyrosine kinase blockade. However, the degree of tyrosine-phosphorylation of the exported protein was markedly reduced by genistein. These results suggest that (i) the ANXA1-dependent inhibitory actions of dexamethasone on the release of TSH and LH require PKC and sequences in the N-terminal domain of ANXA1, but are independent of tyrosine kinase, and (ii) while dexamethasone induces the cellular exportation of a tyrosine-phosphorylated species of ANXA1, tyrosine phosphorylation per se is not critical to the steroid-induced passage of ANXA1 across the membrane.

Amino Acid Sequence↗
PubMed2002

The annexin-1 knockout mouse: what it tells us about the inflammatory response.

The 37kDa protein annexin 1 (Anx-1; lipocortin 1) is a glucocorticoid-regulated protein that has been implicated in the regulation of phagocytosis, cell signalling and proliferation, and postulated to be a mediator of glucocorticoids action in inflammation and in the control of anterior pituitary hormone release. Immuno-neutralisation or antisense strategies support this hypothesis as they can reverse the effect of glucocorticoids in several systems. We recently generated a line of mice lacking the Anx-1 gene noting that some tissues taken from such animals exhibited an increased expression of several proteins including COX-2 and cPLA2. In models of experimental inflammation, Anx-1(-/-) mice exhibit an exaggerated response and a partial or complete resistance to the anti-inflammatory effects of glucocorticoids. Several other anomalies were noted including abnormal leukocyte adhesion molecule expression, an increased spontaneous migratory behaviour of PMN in Anx-1(-/-) mice and a resistance in Anx-1(-/-) macrophages to glucocorticoid inhibition of superoxide generation. This paper reviews these and other data in the light of the development of the 'second messenger' hypothesis of glucocorticoid action.

Animals↗
PubMed2001

Analysis of the protection afforded by annexin 1 in ischaemia-reperfusion injury: focus on neutrophil recruitment.

Ischaemia-reperfusion injury underlies many of the most important cardiovascular diseases such as myocardial infarction, thrombotic stroke, embolic vascular occlusions and peripheral vascular insufficiency. Neutrophils feature prominently in this inflammatory component of post-ischaemic injury. Experimental therapies, shown to reduce neutrophil-mediated ischaemia-reperfusion injury include neutrophil depletion, direct inhibitors of neutrophil activators, antibodies against neutrophil adhesion molecules and the endothelial adhesion molecules. However, aside from these approaches, it is increasingly recognised that glucocorticoids are potent inhibitors of neutrophil-mediated injury. The anti-inflammatory actions of glucocorticoid include the activation of classical cytoplasmic receptors leading to changes in gene transcription as well as the induction of regulatory proteins, such as annexin 1. Annexin 1 is a potent inhibitor of neutrophil extravasation in vivo. Administration of the annexin 1 or peptides derived from its N-terminal domain, reduce neutrophil extravasation in models of acute inflammation. In addition, as reviewed by this article, annexin 1 protects against ischaemia-reperfusion in the heart and mesenteric microcirculation, as well as in multiple organ failure associated with splanchnic ischaemia-reperfusion. Such findings would suggest annexin 1 is a novel anti-inflammatory agent with a potential for the treatment of cardiovascular pathologies associated with neutrophil activation and recruitment.

Animals↗
PubMed2001

Neutrophil interaction with inflamed postcapillary venule endothelium alters annexin 1 expression.

Annexin 1 (ANX-A1) exerts antimigratory actions in several models of acute and chronic inflammation. This is related to its ability to mimic the effect of endogenous ANX-A1 that is externalized on neutrophil adhesion to the postcapillary endothelium. In the present study we monitored ANX-A1 expression and localization in intravascular and emigrated neutrophils, using a classical model of rat peritonitis. For this purpose, a pair of antibodies raised against the ANX-A1 N-terminus (ie, able to recognize intact ANX-A1) or the whole protein (ie, able to interact with all ANX-A1 isoforms) was used by immunofluorescence and immunocytochemistry analyses. The majority ( approximately 50%) of ANX-A1 on the plasma membrane of intravascular neutrophils was intact. Extravasation into the subendothelial matrix caused loss of this pool of intact protein (to approximately 6%), concomitant with an increase in total amount of the protein; only approximately 25% of the total protein was now recognized by the antibody raised against the N-terminus (ie, it was intact). In the cytoplasm of these cells, ANX-A1 was predominantly associated with large vacuoles, possibly endosomes. In situ hybridization confirmed de novo synthesis of ANX-A1 in the extravasated cells. In conclusion, biochemical pathways leading to the externalization, proteolysis, and synthesis of ANX-A1 are activated during the process of neutrophil extravasation.

Animals↗
PubMed2001

Opposing influences of glucocorticoids and interleukin-1beta on the secretion of growth hormone and ACTH in the rat in vivo: role of hypothalamic annexin 1.

1. This study exploited established immunoneutralization protocols and an N-terminal annexin 1 peptide (annexin 1(Ac2 - 26)) to advance our knowledge of the role of annexin 1 as a mediator of acute glucocorticoid action in the rat neuroendocrine system in vivo. 2. Rats were treated with corticosterone (500 microg kg(-1), i.p.) or annexin 1(Ac2 - 26) (0.1 - 10 ng rat(-1), i.c.v.) and 75 min later with interleukin 1beta (IL-1beta, 10 ng rat(-1), i.c.v. or 500 microg kg(-1), i.p). Blood was collected 1 h later for hormone immunoassay. Where appropriate, anti-annexin 1 polyclonal antiserum (pAb) was administered subcutaneously or centrally prior to the steroid challenge. 3. Corticosterone did not affect the resting plasma corticotrophin (ACTH) concentration but suppressed the hypersecretion of ACTH induced by IL-1beta (i.p. or i.c.v.). Its actions were quenched by anti-annexin 1 pAb (s.c. or i.c.v) and mimicked by annexin 1(Ac2 - 26). 4. By contrast, corticosterone provoked an increase in serum growth hormone (GH) which was ablated by central but not peripheral administration of anti-annexin 1 pAb. IL-1beta (i.c.v. or i.p.) did not affect basal GH but, when given centrally but not peripherally, it abolished the corticosterone-induced hypersecretion of GH. Annexin 1(Ac2 - 26) (i.c.v.) also produced an increase in serum GH which was prevented by central injection of IL-1beta. 5. The results support the hypothesis that the acute regulatory actions of glucocorticoids on hypothalamo-pituitary-adrenocortical function require annexin 1. They also provide novel evidence that the positive influence of the steroids on GH secretion evident within this timeframe is effected centrally via an annexin 1-dependent mechanism which is antagonized by IL-1beta.

Adrenocorticotropic Hormone↗
PubMed2001

Platelet tests in the prediction of myocardial infarction and ischaemic stroke: evidence from the Caerphilly Prospective Study.

A platelet test that is predictive of myocardial infarction (MI) and/or stroke would enable the targeting of anti-platelet drugs towards high-risk patients. The predictive power of several platelet tests for MI and for stroke was examined in 2000 older men in the Caerphilly Cohort Study of Heart Disease, Stroke and Cognitive Decline. The tests were: aggregation to adenosine diphosphate (ADP) in platelet-rich plasma (PRP); aggregation to ADP in whole blood measured using an impedance method and a test of platelet aggregation induced in whole blood by high-shear flow. Around 200 MIs and 100 ischaemic strokes occurred during a 10-year follow-up. Neither primary nor secondary aggregation in PRP was predictive of MI. However, the fifth of men in whom the primary response to ADP was least, showed the highest risk of a subsequent stroke [relative odds (RO) 1.64; 95% confidence interval (CI) 1.12-2.43]. Aggregation in whole blood was not predictive of MI but, again, the fifth of men with the least platelet response showed the highest stroke incidence (RO 1.79; 95% CI 1.06-3.00). Retention of platelets in the high-shear test was not predictive of either event.

Adenosine Diphosphate↗
PubMed2001

Neutrophil accumulation induced by bacterial lipopolysaccharide: effects of dexamethasone and annexin 1.

Annexin 1 (ANX-1) can reduce leucocyte migration in response to cytokines and chemokines in some rodent models of inflammation. However, its effectiveness against an inflammatory stimulus as strong as bacterial lipopolysaccharide (LPS) is unknown. Thus, we have examined whether ANX-1 can modulate LPS-induced neutrophil accumulation in the rat, as assessed by intravital microscopy and by myeloperoxidase (MPO) assay. The anti-inflammatory glucocorticoid, dexamethasone (DEX) was also studied for comparison. LPS superfusion induced adhesion of leucocytes to the endothelium and a subsequent increase in emigration from rat post-capillary venules over 2 h as assessed by intravital microscopy. Either ANX-1 or DEX was able to attenuate this adhesion and emigration of leucocytes. MPO activity in the lung, kidney and ileum was elevated after a 6-h exposure to LPS (intraperitoneal), indicating accumulation of neutrophils in these tissues. DEX attenuated the LPS-induced increase in MPO in the ileum but had no effect on MPO in the lungs or kidneys. This would suggest that the underlying mechanism by which neutrophils accumulate in the ileum, and more generally in the gastrointestinal compartment, is different from other vascular beds. ANX-1 had no effect on the LPS-induced increase in MPO activity in any of the tissues studied. Thus, from these data, ANX-1 appears to reduce leucocyte adhesion and emigration induced by a short-term (2 h), but not a longer (6 h) exposure to LPS.

Animals↗
PubMed2001

Annexin 1 peptides protect against experimental myocardial ischemia-reperfusion: analysis of their mechanism of action.

Myocardial reperfusion injury is associated with the infiltration of blood-borne polymorphonuclear leukocytes. We have previous described the protection afforded by annexin 1 (ANXA1) in an experimental model of rat myocardial ischemia-reperfusion (IR) injury. We examined the 1) amino acid region of ANXA1 that retained the protective effect in a model of rat heart IR; 2) changes in endogenous ANXA1 in relation to the IR induced damage and after pharmacological modulation; and 3) potential involvement of the formyl peptide receptor (FPR) in the protective action displayed by ANXA1 peptides. Administration of peptide Ac2-26 at 0, 30, and 60 min postreperfusion produced a significant protection against IR injury, and this was associated with reduced myeloperoxidase activity and IL-1beta levels in the infarcted heart. Western blotting and electron microscopy analyses showed that IR heart had increased ANXA1 expression in the injured tissue, associated mainly with the infiltrated leukocytes. Finally, an antagonist to the FPR receptor selectively inhibited the protective action of peptide ANXA1 and its derived peptides against IR injury. Altogether, these data provide further insight into the protective effect of ANXA1 and its mimetics and a rationale for a clinical use for drugs developed from this line of research.

Animals↗
PubMed2000

Increased apoptosis in U937 cells over-expressing lipocortin 1 (annexin I).

The potential involvement of endogenous lipocortin 1 in the process of cellular apoptosis, particularly in cells of the myelo-monocytic lineage, has been investigated. U937 cells were transfected either with an antisense or a sense DNA for lipocortin 1 and the stable clones 36.4AS clone (20-40% lower lipocortin 1 levels) and 15S (30% higher lipocortin 1 levels) were obtained. Cell apoptosis was induced by incubation with tumor necrosis factor-alpha: optimal responses were observed within a 24 h incubation period at a 5 ng/ml concentration. Apoptosis was assessed both morphologically, by annexin V binding and cell cycle analysis with propidium iodide. Whilst no consistent difference was seen between wild type cells and clone 36.4AS, a higher incidence of apoptosis (ranging from +30% to + 60%) was observed in the 15S clone. Release of arachidonic acid from loaded cells was promoted by 24 h incubation with the cytokine, and a higher degree of release was measured in the 15S clone. These data indicate that endogenous intracellular lipocortin 1 is involved in the promotion of apoptosis in cells of the myelo-monocytic derivation.

Annexin A1↗
PubMed2000

Annexin I is stored within gelatinase granules of human neutrophil and mobilized on the cell surface upon adhesion but not phagocytosis.

Annexin I, a member of the calcium- and phospholipid-binding annexin superfamily of proteins, is largely present in human neutrophils. To determine its exact intracellular distribution a combination of flow cytometry, confocal microscopy and electron microscopy analyses were performed on resting human neutrophils as well as on cells which had been activated. In resting neutrophils, annexin I was found to be present in small amounts in the nucleus, in the cytoplasm and partially also associated with the plasma membrane. The cytoplasmic pool of annexin I was predominant, and the protein was co-localized with gelatinase (marker of gelatinase granules), but not with human serum albumin or CD35 (markers of secretory vesicles), or with lysosomes. Electron microscopy showed the presence of annexin I inside the gelatinase granules. Neutrophil adhesion to monolayers of endothelial cells, but not phagocytosis of particles of opsonized zymosan, provoked an intense mobilization of annexin I, with a marked externalization on the outer leaflet of the plasma membrane. Remaining intracellular annexin I was also found in proximity of the plasma membrane. These results provide a novel mechanism for annexin I secretion from human neutrophils, which is via a degranulation event involving gelatinase granules.

Annexin A1↗
PubMed2000

An immunocytochemical and in situ hybridization analysis of annexin 1 expression in rat mast cells: modulation by inflammation and dexamethasone.

The presence and localization of the anti-inflammatory protein annexin 1 (also known as lipocortin 1) in perivenular rat mast cells was investigated here. Using the rat mesenteric microvascular bed and a combination of morphologic techniques ranging from immunofluorescence to electron microscopy analyses, we detected the presence of annexin 1 in discrete intracellular sites, both in the nucleus and in the cytoplasm. In resting mast cells, most of the protein pool (approximately 80% of the cytosolic portion) was localized to cytoplasmic granules. In agreement with other cell types, treatment of rats with dexamethasone (0.2 mg/kg, ip) increased annexin 1 expression in mast cells, inducing a remarkable appearance of clusters of protein immunoreactivity. This effect was most likely the result of de novo protein synthesis as determined by an increase in mRNA seen by in situ hybridization. Triggering an ongoing experimental inflammatory response (0.3 mg of carrageenin, ip) increased annexin 1 mRNA and protein levels. In conclusion, we report for the first time the localization of annexin 1 in connective tissue mast cells, and its susceptibility not only to glucocorticoid hormone treatment, but also to an experimental acute inflammatory response.

Animals↗
PubMed2000

Glucocorticoids act within minutes to inhibit recruitment of signalling factors to activated EGF receptors through a receptor-dependent, transcription-independent mechanism.

Recruitment to activated tyrosine kinase growth factor receptors of Grb2 and p21(ras) leads to downstream activation of the kinases Raf, MAPK/Erk kinase (Mek) and, subsequently, extracellular signal-regulated kinase (Erk). Activated Erk phosphorylates specific serine residues within cytosolic phospholipase A(2) (PLA(2)), promoting enzyme translocation to membranes and facilitating liberation of arachidonic acid (AA). In the A549 human adenocarcinoma cell line dexamethasone inhibited epidermal growth factor (EGF)-stimulated cytosolic PLA(2) (cPLA(2)) activation and AA release by blocking the recruitment of Grb2 to the activated EGF receptor (EGF-R) through a glucocorticoid receptor (GR)-dependent (RU486-sensitive), transcription-independent (actinomycin-insensitive), mechanism. The dexamethasone-induced block of Grb2 recruitment was parallelled by changes in phosphorylation status and subcellular localization of lipocortin 1 (LC1) and an increase in the amount of the tyrosine phosphoprotein co-localized with EGF-R. Like dexamethasone, peptides containing E-Q-E-Y-V from the N-terminal domain of LC1 also blocked ligand-induced association of Grb2, p21(ras) and Raf. Our results point to an unsuspected rapid effect of glucocorticoids, mediated by occupation of GR but not by changes in gene transcription, which is brought about by competition between LC1 and Grb2 leading to a failure of recruitment off signalling factors to EGF-R

Adaptor Proteins, Signal Transducing↗
PubMed2000

Investigation into the involvement of phospholipases A(2) and MAP kinases in modulation of AA release and cell growth in A549 cells.

1. We have investigated the contribution of specific PLA(2)s to eicosanoid release from A549 cells by using specific inhibitors of secretory PLA(2) (ONO-RS-82 and oleyloxyethylphosphocholine), cytosolic PLA(2) (AACOCF(3) and MAFP) and calcium-independent PLA(2) (HELSS, MAFP and PACOCF(3)). Similarly, by using specific inhibitors of p38 MAPK (SB 203580), ERK1/2 MAPK (Apigenin) and MEK1/2 (PD 98059) we have further evaluated potential pathways of AA release in this cell line. 2. ONO-RS-82 and oleyloxyethylphosphocholine had no significant effect on EGF or IL-1beta stimulated (3)H-AA or PGE(2) release or cell proliferation. AACOCF(3), HELSS, MAFP and PACOCF(3) significantly inhibited both EGF and IL-1beta stimulated (3)H-AA and PGE(2) release as well as cell proliferation. Apigenin and PD 98509 significantly inhibited both EGF and IL-1beta stimulated (3)H-AA and PGE(2) release and cell proliferation whereas, SB 203580 had no significant effect on EGF or IL-1beta stimulated (3)H-AA release, or cell proliferation but significantly suppressed EGF or IL-1beta stimulated PGE(2) release. 3. These results confirm that the liberation of AA release, generation of PGE(2) and cell proliferation is mediated largely through the actions of cPLA(2) whereas, sPLA(2) plays no significant role. We now also report a hitherto unsuspected contribution of iPLA(2) to this process and demonstrate that the stimulating action of EGF and IL-1beta in AA release and cell proliferation is mediated in part via a MEK and ERK-dependent pathway (but not through p38MAPK). We therefore propose that selective inhibitors of MEK and MAPK pathways may be useful in controlling AA release, eicosanoid production and cell proliferation.

Arachidonic Acid↗
PubMed2000

Evidence from immunoneutralization and antisense studies that the inhibitory actions of glucocorticoids on growth hormone release in vitro require annexin 1 (lipocortin 1).

1. Our previous studies have identified a role for annexin 1 as a mediator of glucocorticoid action in the neuroendocrine system. The present study centred on growth hormone (GH) and exploited antisense and immunoneutralization strategies to examine in vitro the potential role of annexin 1 in effecting the regulatory actions of glucocorticoids on the secretion of this pituitary hormone. 2. Rat anterior pituitary tissue responded in vitro to growth hormone releasing hormone, forskolin, 8-Bromo-cyclic adenosine 3'5'-monophosphate (8-Br-cyclic AMP) and an L-Ca(2+) channel opener (BAY K8644) with concentration-dependent increases GH release which were readily inhibited by corticosterone and dexamethasone. 3. The inhibitory actions of the steroids on GH release elicited by the above secretagogues were effectively reversed by an annexin 1 antisense oligodeoxynucleotide (ODN), but not by control (sense or scrambled) ODNs, as also were the glucocorticoid-induced increases in annexin 1. Similarly, a specific anti-annexin 1 monoclonal antibody quenched the corticosterone-induced suppression of secretagogue-evoked GH release while an isotype matched control antibody was without effect. 4. Transmission electron micrographs showed that the integrity and ultrastructural morphology of the pituitary cells were well preserved at the end of the incubation and unaffected by exposure to the ODNs, antibodies, steroids or secretagogues. 5. The results provide novel evidence for a role for annexin 1 as a mediator of the inhibitory actions of glucocorticoids on the secretion of GH by the anterior pituitary gland and suggest that its actions are effected at a point distal to the formation of cyclic AMP and Ca(2+) entry.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed2000

21-NO-prednisolone is a novel nitric oxide-releasing derivative of prednisolone with enhanced anti-inflammatory properties.

1. Anti-inflammatory effects of a novel derivative of the glucocorticoid prednisolone were investigated. NCX-1015 (prednisolone 21-[(4'-nitrooxymethyl)benzoate]) incubation in human platelet-rich plasma produced a time (0 - 60 min) and concentration (3 - 300 microM) dependent release of nitrite, that was mirrored by accumulation of cyclic guanosine monophosphate in the human platelets. Intraperitoneal injection of NCX-1015 to mice (up to 27.7 micromol kg(-1)) produced nitrite accumulation in the peritoneal cavity maximal at 60 min. 2. NCX-1015 dose-dependently induced the steroid sensitive cell surface marker CD163 in human peripheral blood mononuclear cells (PBMCs). NCX-1015 was more potent than prednisolone in inducing CD163. Similarly, lipopolysaccharide induced interleukin-1 beta release from these cells was inhibited by NCX-1015 with higher potency than prednisolone. 3. In the zymosan peritonitis model, NCX-1015 was more active than prednisolone in suppressing neutrophil extravasation (ED(50) of 5.5 and 25.8 micromol kg(-1), respectively), nitrite accumulation (ED(50) of 1.38 and 22.2 micromol kg(-1), respectively) and release of the chemokine KC (ED(50) of 5.5 and 27.7 micromol kg(-1), respectively) as determined at the 4 h time-point. No differences were measured for the levels of interleukin-1 beta or prostaglandin E(2). NCX-1015 administered orally was also found to be equally active. Co-administration of the nitric oxide donors NOC-18 ((z)-1-[(2-aminoethyl)-N-(2-aminoethyl)amino] diazen-1-ium-1, 2-diolate; 7.9 micromol kg(-1)) or sodium nitroprusside (13.8 micromol kg(-1)) with prednisolone resulted in an additive anti-migratory action. 4. In a chronic model of granulomatous tissue inflammation, administration of NCX-1015 (13.9 micromol kg(-1)) from day 1 (i.e. after induction of inflammation) was more effective than prednisolone in reducing the granuloma dry weight, and this was associated to a lower anti-angiogenic effect. 5. In conclusion we show that NCX-1015 is more potent than prednisolone in controlling several, though not all, parameters of acute and chronic inflammation, and propose that this effect may be due to a co-operation between the steroid moiety and nitric oxide or related species released in biological fluids. Whereas this aspect needs to be further clarified, we propose NCX-1015 as the first member of a novel class of anti-inflammatory compounds, the nitro-steroids.

Administration, Oral↗