oxazolone and Edema

Cynaroside (CYN) is the predominant derivative of luteolin in aerial parts of Bidens tripartita which has been used in folk medicine as a diaphoretic, diuretic, antiseptic and anti-inflammatory agent. In our study, alginate (ALG), which is an anionic polymer with bioadhesive properties, was used as a CYN carrier, and multiple hydrogel formulations were created. Additionally, the present study evaluated the in vivo anti-inflammatory and anti-allergic activities of all preparations.. Novel gel formulations as topical carriers for CYN obtained from B. tripartita were developed and characterized. The bioadhesive properties of the designed preparations were also evaluated in an ex vivo model using the skin of hairless mice. In vitro CYN release from all formulations was examined and analysed by HPLC. Histopathological evaluation of mouse skin sections stained with H&E after carrageenan and oxazolone administration was also carried out. In addition, the influence of CYN on cell proliferation was examined by the PCNA staining method.. The results showed that 10 % CYN inhibited the release of anti-inflammatory mediators, and both tested concentrations, which included 5 % and 10 % (2 mg and 20 mg CYN per site, respectively), reduced oxazolone-induced ear swelling. Histopathological examination of the samples revealed a marked reduction in paw skin and ear tissue inflammation and in inflammatory infiltrates. The influence of CYN on cell proliferation was examined by the PCNA staining method, and the staining and distribution of PCNA-immunoreactive (PCNA-IR) cells were observed. After the application of the 5 % and 10 % hydrogels, the investigated samples showed decreased nuclear immunoreactivity to PCNA, which was similar to that of the control. Moreover, after application of the placebo formulation, fewer PCNA-IR cells were also observed.. The obtained data suggest that the topical application of CYN significantly reduces the number of T cells, mast cells and histiocytes in mouse skin with inflammation or atopic dermatitis.

Topics: Animals; Anti-Allergic Agents; Anti-Inflammatory Agents; Disease Models, Animal; Drug Compounding; Drug Liberation; Edema; Glucosides; Hydrogels; Luteolin; Male; Mice, Inbred C57BL; Oxazolone; Proliferating Cell Nuclear Antigen

Atopic dermatitis (AD) is a chronically relapsing inflammatory skin disease characterized by hyperproliferation and abnormal differentiation of the epidermis, and dermal infiltration of inflammatory cells. Appropriate animal models that recapitulate human AD and allow the analysis of disease processes in a reliable manner are essential to the study of AD. In this study, we established two AD models in rabbits by applying an allergen, Dermatophagoides farinae (Der f), or a hapten, oxazolone (OXZ). Application of the allergen or hapten induced a rapid onset and a chronically sustained AD-like skin lesion. The clinical symptoms, which include skin erythema, scaling, papula and edema, of AD-like rabbit skin were similar to those in human AD. Histological analysis showed that allergen- or hapten-treated rabbit skin showed increased epidermal thickening and inflammatory cell infiltration. Furthermore, PCNA and keratin 10 (K10) staining revealed excessive proliferation and insufficient differentiation of the epidermis in the rabbit AD-like skin. Western blot analysis showed decreased expression of thymic stromal lymphopoietin (TSLP), an AD cytokine, in the rabbit AD-like skin. Our results suggest that the allergen- or hapten-induced rabbit AD models have pathological features of human AD-like symptoms and will be useful for evaluating both pathogenic mechanisms and potential therapeutic agents for human AD.

Topics: Allergens; Animals; Cell Proliferation; Cytokines; Dermatitis, Atopic; Dermatophagoides farinae; Disease Models, Animal; Edema; Epidermis; Erythema; Female; Oxazolone; Rabbits; Thymic Stromal Lymphopoietin

To investigate the role of cannabinoid receptor-2 (CB2) in allergic inflammation in CB2 knockout (CB2-KO) mice.. The swelling reaction of the pinna to various stimuli was compared between CB2-KO and wild-type (WT) mice in terms of edema and acanthosis.. Ear swelling induced by repeated application of 2,4-dinitrofluorobenzene in CB2-KO mice was significantly decreased compared with that in WT mice. In an ovalbumin model, pinna edema was significantly suppressed in CB2-KO mice in comparison with that in WT mice. The contribution of CB2 to edema was investigated in a more extreme dermatitis model using oxazolone. Delayed-type hypersensitivity reactions in this model were also suppressed in CB2-KO mice. In each of these three different allergic dermatitis models, there was a significant decrease in edema and acanthosis in CB2-KO mice compared with WT mice.. These results clearly demonstrate that CB2 and its endogenous ligands participate not only in the acute, edematous phase of allergic dermatitis, but also in the chronic irreversible acanthosis reaction.

Topics: Animals; Dermatitis; Disease Models, Animal; Edema; Hypersensitivity, Delayed; Inflammation; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Ovalbumin; Oxazolone; Receptor, Cannabinoid, CB2

In contrast to the established role of blood vessel remodeling in inflammation, the biologic function of the lymphatic vasculature in acute inflammation has remained less explored. We studied 2 established models of acute cutaneous inflammation, namely, oxazolone-induced delayed-type hypersensitivity reactions and ultraviolet B irradiation, in keratin 14-vascular endothelial growth factor (VEGF)-C and keratin 14-VEGF-D transgenic mice. These mice have an expanded network of cutaneous lymphatic vessels. Transgenic delivery of the lymphangiogenic factors VEGF-C and the VEGFR-3 specific ligand mouse VEGF-D significantly limited acute skin inflammation in both experimental models, with a strong reduction of dermal edema. Expression of VEGFR-3 by lymphatic endothelium was strongly down-regulated at the mRNA and protein level in acutely inflamed skin, and no VEGFR-3 expression was detectable on inflamed blood vessels and dermal macrophages. There was no major change of the inflammatory cell infiltrate or the composition of the inflammatory cytokine milieu in the inflamed skin of VEGF-C or VEGF-D transgenic mice. However, the increased network of lymphatic vessels in these mice significantly enhanced lymphatic drainage from the ear skin. These results provide evidence that specific lymphatic vessel activation limits acute skin inflammation via promotion of lymph flow from the skin and reduction of edema formation.

Topics: Acute Disease; Adjuvants, Immunologic; Animals; Cytokines; Dermatitis; Disease Models, Animal; Edema; Humans; Hypersensitivity, Delayed; Keratin-14; Lymph; Lymphatic Vessels; Mice; Mice, Transgenic; Oxazolone; Vascular Endothelial Growth Factor C; Vascular Endothelial Growth Factor D; Vascular Endothelial Growth Factor Receptor-3

Chemokine receptor CCR4 is expressed by Th2 cells and is involved in the recruitment of inflammatory cells into the skin. We studied the effects of CCR4 deficiency in the murine model of oxazolone-induced contact hypersensitivity in CCR4-/- and wild-type (WT) mice. The inflammatory response in the skin at 24  hours post-elicitation was stronger in CCR4-/- mice compared with WT, evidenced by increased ear swelling and inflammatory cell infiltration. In addition, the mRNA expression levels of several cytokines, chemokines, chemokine receptors, and selectins in the skin of CCR4-/- mice were significantly elevated compared with WT mice. Time kinetic experiments during the sensitization and elicitation phases revealed that the number of CD3+CD4+ cells in CCR4-/- mice remained high longer during the sensitization phase and increased more rapidly during the elicitation phase compared with WT mice. These data demonstrate that the absence of CCR4 results in enhanced secondary immune response during allergic skin inflammation.

Topics: Adjuvants, Immunologic; Animals; CD3 Complex; CD4 Antigens; Dermatitis; Dermatitis, Contact; Disease Models, Animal; Edema; Interleukin-13; Mice; Mice, Mutant Strains; Oxazolone; Receptors, CCR4; T-Lymphocytes, Regulatory; Up-Regulation

We have studied scrovalentinoside, an iridoid with anti-inflammatory properties isolated from Scrophularia auriculata ssp. pseudoauriculata, as an anti-inflammatory agent in different experimental models of delayed-type hypersensitivity. We found that scrovalentinoside reduced the edema induced by oxazolone at 0.5 mg/ear and sheep red blood cells at 10 mg/kg. The observed effect occurred during the last phase or inflammatory response; during the earlier phase or induction of the delayed-type hypersensitivity reaction, no significant activity was noted. Thus, scrovalentinoside reduced both the edema and cell infiltration in vivo and reduced lymphocyte proliferation in vitro, affecting the cycle principally during the first 48 h. Whereas cells stimulated with phytohemagglutinin changed from the G(0)/G(1) phase to the S and G(2)/M phases, when these same cells were treated with scrovalentinoside (100 microM), they remained in the G(0)/G(1) phase. Finally, scrovalentinoside inhibited the production of the pro-inflammatory mediators' TNF-alpha, IFN-gamma, IL-1beta, IL-2, IL-4, LTB(4), and NO, but had no effect on the production of the anti-inflammatory cytokine IL-10.

Topics: Animals; Anti-Inflammatory Agents; Blotting, Western; Cell Cycle; Cell Proliferation; Disease Models, Animal; Edema; Female; Glycosides; Humans; Hypersensitivity, Delayed; Inflammation Mediators; Iridoid Glycosides; Iridoids; Macrophages; Mice; Oxazolone; Phytohemagglutinins; Plant Preparations; Plants, Medicinal; Rats; Receptors, Glucocorticoid; Scrophularia; T-Lymphocytes

Scropolioside A, an iridoid isolated from Scrophularia auriculata ssp. pseudoauriculata, showed anti-inflammatory properties against different experimental models of delayed-type hypersensitivity. This iridoid reduced the oedema induced by oxazolone by 79% (72 h) at 0.5 mg/ear while reducing that induced by sheep red blood cells by 47% (18 h), 45% (24 h) and 36% (48 h) at 10 mg/kg. In vivo it reduced both oedema formation and cell infiltration whereas in vitro it reduced the proliferation of activated T-lymphocytes (IC50 of 67.74 microM). Treatment with scropolioside A (100 microM) 18 and 24 h after phytohemagglutinin stimulation increased the number of cells arrested in the subG(0) phase whereas treatment 3 h after stimulation clearly increased the number of cells that passed to the S phase. Scropolioside A also inhibited the production of prostaglandin E2, leukotriene B4, nitric oxide, interleukin-1beta, interleukin-2, interleukin-4, tumour necrosis factor-alpha and interferon-gamma, but had no effect on the production of interleukin-10. Moreover, it modified the expression of both nitric oxide synthase-2 and cyclooxygenase-2, as well as the activation of nuclear factor-kappaB in RAW 264.7 macrophages.

Topics: Allergens; Animals; Anti-Inflammatory Agents; Apoptosis; Caspase 3; Cell Line; Cytokines; Dinoprostone; Ear; Edema; Erythrocytes; Female; Glucosides; Humans; Hypersensitivity, Delayed; Leukotriene B4; Lipopolysaccharides; Macrophages; Mice; Neutrophils; Oxazolone; Pancreatic Elastase; Pyrans; Sheep; T-Lymphocytes

The voltage-gated potassium channel Kv1.3 has been recently identified as a molecular target that allows for selective pharmacological suppression of effector memory T (T(EM)) cells without affecting the function of naïve and central memory T cells. We here investigated whether PAP-1, a small molecule Kv1.3 blocker (EC50=2 nM), could suppress allergic contact dermatitis (ACD). In a rat model of ACD, we first confirmed that the infiltrating cells in the elicitation phase are indeed CD8+ CD45RC- memory T cells with high Kv1.3 expression. In accordance with its selective effect on T(EM) cells, PAP-1 did not impair sensitization, but potently suppressed oxazolone-induced inflammation by inhibiting the infiltration of CD8+ T cells and reducing the production of the inflammatory cytokines IFN-gamma, IL-2, and IL-17 when administered intraperitoneally or orally during the elicitation phase. PAP-1 was equally effective when applied topically, demonstrating that it effectively penetrates skin. We further show that PAP-1 is not a sensitizer or an irritant and exhibits no toxicity in a 28-day toxicity study. Based on these results we propose that PAP-1 could potentially be developed into a drug for the topical treatment of inflammatory skin diseases such as psoriasis.

Topics: Adjuvants, Immunologic; Administration, Oral; Administration, Topical; Animals; CD8-Positive T-Lymphocytes; Dermatitis, Allergic Contact; Ear; Edema; Female; Furocoumarins; Immunologic Memory; Immunosuppressive Agents; Injections, Intraperitoneal; Injections, Intravenous; Interferon-gamma; Interleukin-17; Kv1.3 Potassium Channel; Leukocyte Common Antigens; Mice; Mice, Inbred BALB C; Oxazolone; Pancreatitis-Associated Proteins; Potassium Channel Blockers; Rats; Rats, Inbred Lew; Tumor Necrosis Factor-alpha

Animal testing causes ethical problems and in view of EU regulations (e.g. EU-Guideline (76/768/EEC, February 2003)) or REACH the development of reliable in vitro assays has become even more important. Up to now, we use the modified local lymph node assay (IMDS) for toxicological hazard identification of sensitizing and irritant properties of chemicals in accordance with OECD Guideline 429. In this study, we investigated whether analyses of cell signaling pathways can provide a methodology for the detection of sensitizing compounds in vitro. Murine and human skin explants as well as reconstituted skin models (epidermal model EST-1000 and full-thickness model AST-2000) were exposed to sensitizing (oxazolone and DNFB) or irritant compounds (SDS and TritonX-100). Phosphorylation of MAP-kinases (p38, ERK1/2 and JNK1/2), STAT1 and PLCgamma were determined by cytometric bead array (CBA). In skin explants, all three MAP-kinases were exclusively activated after exposure to sensitizing compounds. For the reconstituted skin models phosphorylations of p38 and JNK1/2 were obtained after stimulation with allergens, whereas treatments with irritant compounds led to ERK1/2 activation. Activation of PLCgamma and STAT1 were never detected. In conclusion, MAP-kinase activation provides a promising in vitro tool for the discrimination between sensitizers and irritants.

Topics: Allergens; Animals; Dinitrofluorobenzene; Dose-Response Relationship, Drug; Edema; Enzyme Activation; Extracellular Signal-Regulated MAP Kinases; Female; Humans; Irritants; JNK Mitogen-Activated Protein Kinases; Lymph Nodes; Membranes, Artificial; Mice; Mice, Hairless; Mice, Inbred C3H; Octoxynol; Oxazolone; p38 Mitogen-Activated Protein Kinases; Phospholipase C gamma; Phosphorylation; Signal Transduction; Skin; Skin Irritancy Tests; Sodium Dodecyl Sulfate; STAT1 Transcription Factor; Tissue Culture Techniques

A mixture of fatty acids obtained from sugar cane wax oil, the main components of which are palmitic, oleic, linoleic and linolenic acids, was evaluated topically in two experimental models of hypersensitivity: the ear swelling response to ovalbumin in sensitized mice (ED50 edema: 0.63 +/- 0.06 mg/ear, ED50 myeloperoxidase: 0.56 +/- 0.04 mg/ear, ED50 degranulated cells: 0.70 +/- 0,08 mg/ear) and oxazolone-induced contact hypersensitivity in mice (ED50 edema: 1.63 +/- 0.26 mg/ear, ED50 myeloperoxidase: 1.50 +/- 0.28 mg/ear, ED50 degranulated cells: 1.69 +/- 0.08 mg/ear). Also, the effect of this mixture was studied on the chemotaxis induced by fmlp (ED50: 25 +/- 3 microg/mL). The mixture showed anti-inflammatory activity in both in vivo models of allergy and in the chemotaxis test. Therefore, these results provide evidence about the potential usefulness of the mixture of fatty acids from sugar cane wax oil in cutaneous inflammatory and allergic disorders.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Dose-Response Relationship, Drug; Edema; Female; Hypersensitivity, Immediate; Mice; Mice, Inbred BALB C; Ovalbumin; Oxazolone; Phytotherapy; Plant Oils; Saccharum

Histamine H1 receptor antagonists have long been prescribed for atopic dermatitis as an adjuvant therapy with topical therapy by local applied steroids. Olopatadine is one of the second-generation histamine H1 receptor antagonists that are treated for allergic disorders. We investigated that the effect of olopatadine on oxazolone-induced chronic contact hypersensitivity response in BALB/c mice compared with other histamine H1 receptor antagonists loratadine, cetirizine and fexofenadine. The chronic contact hypersensitivity induced by repeated application of oxazolone was treated with olopatadine and other histamine H1 receptor antagonists at the effective doses on histamine-induced paw edema in mice. The effects of these drugs in the oxazolone-induced model were quantified by measurements of ear swelling, and levels of cytokines in the lesioned ear. Olopatadine significantly inhibited the ear swelling and the increased production of IL-4, IL-1beta, IL-6, GM-CSF and NGF in the lesioned ear. On the other hand, the other histamine H1 receptor antagonists did not significantly suppress the increase in ear thickness. Moreover, they did not affect the production of cytokines in the lesioned ear. These results indicate that olopatadine appears to exert additional biological effects besides its blockade of the histamine H1 receptor.

Topics: Animals; Cytokines; Dibenzoxepins; Drug Eruptions; Ear; Edema; Histamine; Histamine H1 Antagonists; Immunoglobulin E; Male; Mice; Mice, Inbred BALB C; Nerve Growth Factor; Olopatadine Hydrochloride; Oxazolone; Skin; Time Factors

Human semicarbazide-sensitive amine oxidase (SSAO) or vascular adhesion protein-1 (VAP-1) is a copper-containing amine oxidase (AOC3, EC 1.4.3.6) that has both enzymatic and adhesive function. SSAO catalyzes the oxidative deamination of primary amines, resulting in the formation of the corresponding aldehyde and release of hydrogen peroxide and ammonia. Membrane-bound SSAO is an inflammation-inducible endothelial cell adhesion molecule that mediates the interaction between leukocytes and activated endothelial cells in inflamed vessels. Both the direct adhesive and enzymatic functions seem to be involved in the adhesion cascade. LJP 1207 [N'-(2-phenyl-allyl)-hydrazine hydrochloride] is a potent (human SSAO IC(50) = 17 nM), selective, and orally available SSAO inhibitor that blocks both the enzymatic and adhesion functions of SSAO/VAP-1. In a mouse model of ulcerative colitis, LJP 1207 significantly reduces mortality, loss of body weight, and colonic cytokine levels. Quantitative histopathological assessment of colitis activity in this model showed a highly significant suppression of inflammation, injury, and ulceration scores in the animals treated with the SSAO/VAP-1 inhibitor. LJP 1207 also reduced serum levels of tumor necrosis factor-alpha and interleukin 6 in lipopolysaccharide (LPS)-challenged mice and prolonged survival post-LPS-induced endotoxemia. Therapeutic and prophylactic administration of LJP 1207 in the rat carrageenan footpad model also markedly inhibited swelling and inflammation. Overall, the data suggest that small molecule SSAO/VAP-1 inhibitors may provide clinical benefit in the treatment of acute and chronic inflammatory diseases.

Topics: Amine Oxidase (Copper-Containing); Animals; Anti-Inflammatory Agents; Carrageenan; Cell Adhesion; Cloning, Molecular; Colitis; Cyclooxygenase 2; Cytokines; Edema; Endothelial Cells; Endotoxemia; Female; Hydrazines; Inflammation; Male; Mice; Mice, Inbred Strains; Monoamine Oxidase Inhibitors; Oxazolone; Rats; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction

Exposure of skin to noxious environmental stimuli can cause allergic contact dermatitis (ACD), which is a major health risk. Epidemiological studies have determined that 40% of workers report that their jobs are very, or extremely, stressful, and the number of chemicals to which workers are exposed increases each year. We hypothesized that combined exposure to a workplace stressor and a sensitizing chemical would alter the time course and magnitude of the skin immune response. We assessed the mixed exposure of chemical and restraint stress using three potent skin sensitizers, 2,4 dinitrofluorbenzene (DNFB), dicyclohexylcarbodiimide (DCC), and oxazolone, (OXA) on the ear swelling response in stress-susceptible BALB/c mice. Quantitative analyses showed that the dose-response relationship for each chemical followed a cubic trend. Although stress did not alter the shape of the curve, application of restraint stress on day 1 or on day 6 diminished the ear swelling response to 0.1% DNFB. However, if the concentration of the challenge dose was increased to a more irritating concentration, 0.25% DNFB, ear swelling was enhanced. Restraint stress applied on day 6 also increased ear swelling in response to the highly irritating sensitizer DCC, but not to the low-irritancy chemical OXA. These data support the hypothesis that dose-response relationships exist for sensitization with chemical and that restraint stress modulation of the ear swelling response is both chemical specific and dependent on the irritancy potential of the chemical.

Topics: Acute Disease; Administration, Topical; Animals; Dermatitis, Allergic Contact; Dicyclohexylcarbodiimide; Dinitrofluorobenzene; Disease Models, Animal; Dose-Response Relationship, Immunologic; Ear, External; Edema; Irritants; Male; Mice; Mice, Inbred BALB C; Oxazolone; Restraint, Physical; Stress, Physiological

Repeated Ag exposure results in a shift in the time course of contact hypersensitivity (CH) from a typical delayed-type to an immediate-type response followed by a late phase reaction. Chronic CH responses are clinically relevant to human skin allergic diseases, such as atopic dermatitis, that are usually caused by repeated stimulation with environmental Ags. Chronic inflammatory responses result in part from infiltrating leukocytes. To determine the role of leukocyte adhesion molecules in chronic inflammation, chronic CH responses were assessed in mice lacking L-selectin, ICAM-1, or both adhesion molecules. Following repeated hapten sensitization for 24 days at 2-day intervals, wild-type littermates developed an immediate-type response at 30 min after elicitation, followed by a late phase reaction. By contrast, loss of ICAM-1, L-selectin, or both, eliminated the immediate-type response and inhibited the late phase reaction. Similar results were obtained when wild-type littermates repeatedly exposed to hapten for 22 days were treated with mAbs to L-selectin and/or ICAM-1 before the elicitation on day 24. The lack of an immediate-type response on day 24 paralleled a lack of mast cell accumulation after 30 min of elicitation and decreased serum IgE production. Repeated Ag exposure in wild-type littermates resulted in increased levels of serum L-selectin, a finding also observed in atopic dermatitis patients. The current study demonstrates that L-selectin and ICAM-1 cooperatively regulate the induction of the immediate-type response by mediating mast cell accumulation into inflammatory sites and suggests that L-selectin and ICAM-1 are potential therapeutic targets for regulating human allergic reactions.

Topics: Administration, Cutaneous; Animals; Antibodies, Monoclonal; Antigens; Cell Migration Inhibition; Cell Movement; Dermatitis, Contact; Down-Regulation; Edema; Hypersensitivity, Immediate; Immunoglobulin E; Injections, Intravenous; Intercellular Adhesion Molecule-1; L-Selectin; Mast Cells; Mice; Mice, Inbred C57BL; Mice, Knockout; Oxazolone

To determine whether macrophage migration inhibitory factor (MIF) is required for contact hypersensitivity (CHS) response, MIF-deficient (MIF KO) and wild-type (WT) mice were sensitized with trinitrochlorobenzene (TNCB) or oxazolone on their abdominal skin and challenged on the dorsum skin of one ear 5 days later. Significant ear swelling was observed in the WT mice, but this response was inhibited in the MIF KO mice (p<0.01 for MIF KO vs. WT mice in 24 h). In addition, lymph node cells from hapten-sensitized MIF KO mice showed a decreased capacity for transferring the CHS response. A topical application of TNCB (200 microg) caused a significant decline in epidermal Langerhans cell (LC) density (20.3%; p<0.01 compared with vehicle) 4 h after application in WT mice, but it failed to provoke a significant epidermal LC migration in MIF KO mice (7.4%). By mixed lymphocyte reaction, the T cell proliferative response to alloantigen was significantly decreased in the MIF KO mice compared with WT mice (p<0.005). Taken together, these results indicate that MIF is pivotal in the regulation of cutaneous immune responses and plays a central role in LC migration and T cell proliferation for the CHS response.

Topics: Administration, Topical; Adoptive Transfer; Animals; Chemotaxis, Leukocyte; Croton Oil; Dermatitis, Allergic Contact; Edema; Epidermis; Female; Haptens; Immune Sera; Immunoglobulin G; Irritants; Isoantigens; Langerhans Cells; Lymph Nodes; Lymphocyte Activation; Lymphocyte Culture Test, Mixed; Macrophage Migration-Inhibitory Factors; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Knockout; Oxazolone; Picryl Chloride; Rabbits; Specific Pathogen-Free Organisms

Angiogenesis and enhanced microvascular permeability are hallmarks of a large number of inflammatory diseases. Although up-regulation of proangiogenic factors such as vascular endothelial growth factor and interleukin-8 have been previously reported in inflamed tissue, the biologic role of endogenous inhibitors of angiogenesis in inflammation has remained unclear. To investigate the biologic role of the potent angiogenesis inhibitor thrombospondin-2 (TSP-2) in the control of cutaneous inflammation, delayed-type hypersensitivity reactions were elicited in the ear skin of wild-type and TSP-2-deficient mice by topical sensitization and challenge with oxazolone. Cutaneous TSP-2 expression was up-regulated in the inflamed skin of wild-type mice, predominantly in dermal fibroblasts and microvessels. Lack of TSP-2 resulted in a significantly enhanced inflammatory response with increased angiogenesis, edema formation, and inflammatory infiltration. Ear swelling and inflammation persisted for more than 2 weeks in TSP-2-deficient mice, as compared with 1 week in wild-type mice. Although baseline vascular permeability was unchanged, significantly enhanced microvascular leakage was found in the inflamed skin of TSP-2-deficient mice. Moreover, the fraction of rolling leukocytes was significantly increased in the untreated skin of TSP-2-deficient mice. These results reveal an important role of TSP-2 in limiting the extent and the duration of edema formation, angiogenesis, and inflammatory cell infiltration during acute and chronic inflammation.

Topics: Animals; Capillary Leak Syndrome; Capillary Permeability; Chemotaxis, Leukocyte; Dermatitis, Allergic Contact; Ear; Edema; Flow Cytometry; Image Processing, Computer-Assisted; Inflammation; Leukocyte Count; Male; Mice; Mice, Knockout; Neovascularization, Pathologic; Oxazolone; Thrombospondins

The topical anti-inflammatory activity of extracts from Cassia angustifolia, Rheum palmatum, Coptis chinensis, Phellodendron amurense and Scutellaria baicalensis, plants used in traditional East Asian medicine against different skin disorders, was studied. Though in different degree, all the extracts significantly inhibited the edema induced by 12-O-tetradecanoylphorbol-13-acetate (TPA), in both single or multiple application, oxazolone, and arachidonic acid (AA). None of the extracts inhibited in vitro the activity of phospholipase A(2) (PLA(2)) from Naja naja.

Topics: Administration, Topical; Animals; Anti-Inflammatory Agents; Drugs, Chinese Herbal; Edema; Female; Mice; Oxazolone; Phospholipases A; Plants, Medicinal; Polygonaceae; Rosales

To elucidate if the planar chiral paracyclophane moiety conveys pharmacological activity to arylacetic acid analogs in two animal models.. Female NMRI mice (6 mice/group); female Wistar rats (8 rats/group); thrombocytes from human blood.. The enantiomers of [2.2]paracyclophaneacetic acid were applied locally (10(-7) and 10(-6) mol/ear) and orally (10-100 mg/kg).. (a) Phorbol myristyl acetate model of acute inflammation of the inner auricle. (b) Oxazolone model of allergic contact dermatitis. (c) Carrageenan model of acute inflammation. (d) Inhibition of cyclooxygenase-1 and 12-lipoxygenase (in vitro).. (a) PMA model: pR-(-)-[2.2]paracyclophaneacetic acid (10(-6) mmol/ear): 58% inhibition after 24 h (p < 0.05). (b) Oxazolone model: pR-(-)-[2.2]paracyclophaneacetic acid (10(-6) mmol/ear): 42% inhibition after 24 h (p < 0.05). (c) Carrageenan model: pR-(-)-[2.2]paracyclophaneacetic acid (10 mg/kg): 31.4% inhibition (paw volume 0.48 +/- 0.13 ml). (d) Cyclooxygenase-1 and 12-lipoxygenase: no inhibition at concentrations up to 10 microM.. The easily accessible [2.2]paracyclophane moiety should find its use in medicinal chemistry as it is a pharmacophoric substituent with the interesting feature of planar chirality.

Topics: Acetates; Animals; Anti-Inflammatory Agents, Non-Steroidal; Carrageenan; Edema; Female; Humans; Inflammation; Mice; Molecular Conformation; Oxazolone; Polycyclic Compounds; Rats; Rats, Wistar; Stereoisomerism; Structure-Activity Relationship; Tetradecanoylphorbol Acetate

The anti-inflammatory and anti-allergic activity of perilla leaf extract was investigated. The oral administration of perilla leaf extract to mice inhibited two types of acute inflammatory models, arachidonic acid-induced ear edema and 12-o-tetradecanoylphorbol-13-acetate-induced ear edema. Oral administration of perilla leaf extract also inhibited the contact dermatitis model, oxazolone-induced ear edema, by affecting sensitization.

Topics: Administration, Oral; Animals; Anti-Allergic Agents; Anti-Inflammatory Agents; Arachidonic Acid; Dermatitis, Contact; Disease Models, Animal; Edema; Magnoliopsida; Male; Mice; Mice, Inbred ICR; Oxazolone; Plant Extracts; Tetradecanoylphorbol Acetate

The development of contact hypersensitivity (CHS) greatly depends on the allergenicity of the inducing agent. However, various cofactors are known to influence the outcome of the response as well. From this perspective, we have compared the effects of five different vehicles: acetone, ethanol, dimethyl formamide (DMF), dimethyl sulfoxide (DMSO), and a 4 to 1 mixture of acetone and olive oil (AOO) on the cellular and humoral immune responses to epicutaneously applied oxazolone in female BALB/c mice. A single application of 0.2% oxazolone dissolved in acetone or ethanol induced stronger proliferative responses and higher lymph node cell numbers than the other three vehicles. Moreover, both vehicles led to higher numbers of oxazolone-specific Ab forming cells in the draining lymph nodes of sensitized animals. When the IgG2a/IgG1 ratios were determined to indicate the type of T helper cell involved, the highest values were obtained with AOO and lowest with DMF and DMSO, while acetone and ethanol were in between. Moreover, no correlation was found between oxazolone-specific antibody production and cellular responses, measured as [3H]thymidine incorporation of draining lymph node cells after sensitization and increased ear thickness after challenge. From this study it can be concluded that cellular and humoral responses in CHS to oxazolone are dissimilarly affected by the vehicles used.

Topics: Adjuvants, Immunologic; Animals; Antibody Formation; Cell Division; Dermatitis, Contact; Edema; Enzyme-Linked Immunosorbent Assay; Female; Immunity, Cellular; Immunoglobulin G; Lymph Nodes; Mice; Mice, Inbred BALB C; Oxazolone; Pharmaceutical Vehicles; Serum Albumin, Bovine; Thymidine

Increasing evidence shows that contact allergens and skin irritants can induce or upregulate the cutaneous expression of cytokines, including those that are required for the initiation of immune responses and which participate in inflammatory reactions.. The present investigation compared the ability of the skin allergens oxazolone and 2,4-dinitrochlorobenzene (DNCB) and the skin irritant benzalkonium chloride (BZC) to stimulate the cutaneous expression of interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) in mice.. Each chemical tested induced the dose-dependent production of IL-6 with similar kinetic profiles. BZC was less effective at provoking increases in this cytokine; concentrations (1%) that caused marked edema failed to stimulate significant changes in IL-6 expression. Under conditions of topical exposure in which each of these chemicals caused a vigorous inflammatory response in the skin, as measured by induced edema and the increased production of IL-6, only oxazolone and DNCB stimulated expression of TNF-alpha. The failure of BZC to initiate TNF-alpha production in the skin was not attributable to inhibition of the bioassay used to measure this cytokine and was apparently independent of the stimulation by this chemical of TNF-alpha inhibitory factors.. These data indicate that not all chemicals that have the ability to cause skin irritation and cutaneous inflammation will elicit detectable TNF-alpha responses and that characterization of cutaneous irritants and allergens on the basis of induced cytokine expression patterns in the skin must be approached with caution.

Topics: Adjuvants, Immunologic; Administration, Cutaneous; Allergens; Animals; Benzalkonium Compounds; Cytokines; Dinitrochlorobenzene; Dose-Response Relationship, Drug; Edema; Inflammation Mediators; Interleukin-6; Irritants; Mice; Mice, Inbred BALB C; Oxazolone; Preservatives, Pharmaceutical; Skin; Time Factors; Tumor Necrosis Factor-alpha; Up-Regulation

Ear edema models are regularly used for topical testing of antiinflammatory compounds. However, test compounds are usually applied simultaneously with proinflammatory agents at the same site which may result in mutual interactions. In order to avoid the occurrence of false antiinflammatory effects, a model of oxazolone-induced contact hypersensitivity has been described in which the hapten and test compound are each applied separately to only one side of the ear. By splitting and weighing the dorsal and ventral cutis of the ears, it was shown that the edemateous response of the control nonhapten side was comparable with the hapten-treated side. Some agents with antiinflammatory properties, as for example, dapsone, cimetidine, cyclosporine A, and budesonide, were tested simultaneously with oxazolone on both sides of the ear or applied separately on the dorsal and ventral ear sides, respectively. When dissolving the compounds in solutions of oxazolone, marked colorations of the test solutions were noted, indicating the occurrence of a chemical interaction. On simultaneous application at the same area, almost complete inhibition of the edemateous response was obtained for all compounds tested. In contrast, when applied separately, only budesonide appeared to exhibit antiinflammatory activity. The results indicate that the proposed model can be used to avoid the occurrence of interactions between oxazolone, and possibly other sensitizers, and substances that are being evaluated for topical antiinflammatory activity. By use of this model spurious antiinflammatory activity can be detected.

Topics: Adjuvants, Immunologic; Animals; Artifacts; Budesonide; Dermatitis, Contact; Disease Models, Animal; Drug Interactions; Ear; Edema; False Positive Reactions; Female; Haptens; Mice; Mice, Inbred BALB C; Organ Size; Oxazolone; Toxicity Tests

A MeOH extract from Z. africana was examined for topical antiinflammatory activity and proved to be active against arachidonic acid (AA) acute edema, 12-O-tetradecanoylphorbol 13-acetate (TPA)-induced chronic inflammation, and oxazolone delayed-type hypersensitivity in mice. The extract also showed significant inhibitory activity of Naja naja phospholipase A2 when a polarographic method was used. Two oleanane-type triterpene saponins, zanhasaponins A (1) and B (2), and the cyclitol pinitol (4), isolated from the extract, were active as inhibitors of PLA2. A further saponin, zanhasaponin C (3) was inactive in this assay.

Topics: Adjuvants, Immunologic; Animals; Anti-Inflammatory Agents; Dermatitis, Contact; Edema; Enzyme Inhibitors; Female; Mice; Oxazolone; Peroxidase; Phospholipases A; Phospholipases A2; Saponins; Skin; Tetradecanoylphorbol Acetate; Triterpenes

In a hamster model, we compared contact sensitivity to the metal salt, potassium dichromate, to that of oxazolone, a well-known strong sensitizing agent. Using the ear swelling test, originally developed in mice, no significant differences could be observed between animals treated with potassium dichromate and controls, although oxazolone-treated animals showed a significant increase in ear thickness compared to controls. These observations were confirmed using the local lymph node assay (LLNA) where oxazolone proved to be a strong sensitizing agent, and potassium dichromate only resulted in a weak response. When the draining auricular lymph nodes were compared with the inguinal lymph nodes in the LLNA, more pronounced effects were obtained with the auricular lymph nodes. This study indicates that, also in hamsters, the LLNA is a feasible sensitization test system.

Topics: Animals; Cricetinae; Dermatitis, Contact; Ear, External; Edema; Female; Immunologic Tests; Lymph Nodes; Male; Mesocricetus; Mice; Mice, Inbred BALB C; Oxazolone; Potassium Dichromate

Leukocyte rolling and emigration in response to inflammatory stimuli appears to involve both E-selectin- and P-selectin-dependent adhesion, which suggests that these molecules have overlapping functions. To clarify their relative contributions in chronic inflammation, we examined delayed-type contact hypersensitivity (DTH) responses in P-selectin, E-selectin, and E-/P-selectin-deficient mice. Oxazolone-induced increases in ear thickness and ear weight were equivalent in wild-type mice and in P-selectin and E-selectin mutants, but were significantly reduced in E-/P-selectin mutants. The number and area of microabscesses on the ears of E-/P-deficient mice were decreased by 72% and 93%, and the number of leukocytes invading the subdermal ear tissue was reduced. T cells from E-/P-deficient mice transferred oxazolone reactivity into naive wild-type mice. However, when donor T cells from wild-type mice were transferred into E-/P-selectin-deficient mice, the DTH response was significantly impaired. These results show that leukocyte recruitment into a subacute inflammatory reaction can occur when either P-selectin or E-selectin is present, but is significantly reduced when both selectins are absent. Both P- and E-selectin are likely to play important roles in the development and maintenance of inflammatory diseases.

Topics: Abscess; Adoptive Transfer; Animals; Chemotaxis, Leukocyte; E-Selectin; Edema; Hypersensitivity, Delayed; Leukocyte Count; Mice; Mice, Knockout; Oxazolone; P-Selectin; T-Lymphocyte Subsets

We have examined the role of endogenously produced interleukin (IL) 4 and IL-10 in the regulation of inflammatory and immune reactions in the skin. In these experiments, irritant and contact hypersensitivity (CH) responses were elicited in mice with targeted disruptions of the IL-4 (IL-4T) or IL-10 (IL-10T) gene. Our study showed that IL-4T and wild-type (wt) mice exhibited equivalent responses to the irritant croton oil. In contrast, the response of IL-10T mice challenged with croton oil was abnormally increased. When IL-10T mice were exposed to a higher dose of irritant, irreversible tissue damage occurred. By comparison, any treatment of wt mice with croton oil resulted in far less tissue damage and resolution of inflammation. Neutralizing antibody studies demonstrated that the necrosis that occurred in IL-10T mice was due to the overproduction of tumor necrosis factor. The anti-tumor necrosis factor antibody treatment of IL-10T mice did not significantly reduce the edema or the influx of inflammatory cells, suggesting that these changes were due to the uncontrolled production of other proinflammatory cytokines. T cell-dependent immune responses were also evaluated using the contact sensitizer oxazolone. The response of IL-4T mice did not differ from wt mice. In contrast, IL-10T mice mounted an exaggerated CH response, increased in both magnitude and duration as compared with wt mice. Based on these studies, we have concluded that IL-10, but not IL-4, is a natural suppressant of irritant responses and of CH, and it limits immunopathologic damage in the skin.

Topics: Animals; Antibodies, Monoclonal; CD4-Positive T-Lymphocytes; Croton Oil; Cytokines; Dermatitis, Allergic Contact; Drug Eruptions; Edema; Interleukin-10; Interleukin-4; Irritants; Mice; Mice, Inbred C57BL; Mice, Knockout; Necrosis; Oxazolone; Tumor Necrosis Factor-alpha

Previous studies have shown that prenatal exposure to the organochlorine pesticide chlordane significantly decreases the ear swelling response to the contact allergen oxazolone in BALB/c mice. Alterations of macrophage function in the efferent arm of the contact hypersensitivity response have also been reported. In the current study, chlordane was applied topically and the effects of oxazolone-induced contact hypersensitivity were determined. Initially, the reduction in oxazolone-induced ear swelling in topically-exposed female BALB/c mice was compared to 30-day-old BALB/c female mice exposed prenatally to chlordane. Prenatal chlordane exposure induced a 36% reduction in ear swelling compared to a 60% reduction following topical treatment at the challenge phase. Topically-applied chlordane also reduced the oxazolone-induced ear swelling by 40% when applied at sensitization. When applied at both sensitization and challenge, ear swelling was reduced by 71%. In a time-course study, it was determined that chlordane must be applied at the time of sensitization, challenge or both or within 1 h post-challenge to significantly reduce ear swelling. A dose-response study showed that the lowest concentration of chlordane resulting in a significantly reduced ear swelling response was 20 micrograms per ear.

Topics: Administration, Topical; Animals; Chlordan; Dermatitis, Contact; Dose-Response Relationship, Drug; Ear, External; Edema; Female; Immunity, Cellular; Insecticides; Male; Mice; Mice, Inbred BALB C; Oxazolone; Pregnancy; Prenatal Exposure Delayed Effects; Random Allocation

LCB 2183, an anti-allergic and potential anti-asthma compound, has been investigated for its ability to inhibit contact sensitivity in the mouse. The delayed response to epicutaneous hapten challenge in this model is a classical T-cell-mediated inflammatory reaction which is dependent on an early initiation phase. Both the early and late components of oxazolone-induced contact sensitivity were inhibited by oral administration of LCB 2183 in a dose-dependent manner. The drug appears to act on the efferent limb of the response since administration before hapten challenge was effective, while administration before the initial sensitization was not. LCB 2183 acts early in the cascade of events leading to inflammation, since the initiation phase of the response was inhibited; nonetheless, an effect of the drug on the late acting inflammatory cells cannot be ruled out. In comparison with oral prednisolone, which was also able to inhibit both the early and late components of the response, LCB 2183 was less active. Sodium cromoglycate and nedocromil sodium, which are poorly absorbed from the gastrointestinal tract, were tested by intraperitoneal administration. Neither of these agents significantly altered the delayed response and only nedocromil sodium had a limited inhibitory effect on the early initiation phase. Thus, in this model, LCB 2183 demonstrated more anti-inflammatory potential and resembled prednisolone more closely than either nedocromil sodium or sodium cromoglycate. The possible relevance of these effects in relation to the inflammation which characterizes human asthma is considered.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Cromolyn Sodium; Dermatitis, Allergic Contact; Drug Administration Schedule; Drug Eruptions; Drug Evaluation, Preclinical; Ear; Edema; Female; Mice; Mice, Inbred CBA; Nedocromil; Oxazolone; Prednisolone; Pterins; T-Lymphocyte Subsets

ETH615 (4-[2-quinolylmethoxy]-N-[3-fluorobenzyl]-phenylaminometh yl-4-benzoic acid) is a potent inhibitor of leukotriene biosynthesis in A23187-stimulated leukocytes, and of IL-8 gene expression in LPS-stimulated PBMC. It shows anti-inflammatory activity in a canine model of dermal inflammation. A topical formulation is present in phase II clinical trials. In the present study the effect of ETH615 on oxazolone-induced acute inflammation and phorbol ester-induced chronic inflammation in the mouse ear was investigated. Betamethasone (0.04 mg/ear) and ETH615 (1-1.5 mg/ear) significantly inhibited both the oedema formation and the PMN infiltration. The cream and ointment formulations of ETH615 developed for clinical studies were equally active. ETH615 is thus an anti-inflammatory agent in these murine models of dermatosis.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Betamethasone; Dermatitis; Disease Models, Animal; Ear; Edema; Gene Expression; Interleukin-8; Leukotriene B4; Mice; Oxazolone; Peroxidase; Quinolines; T-Lymphocytes; Tetradecanoylphorbol Acetate

Topics: Animals; Drug Hypersensitivity; Edema; Female; Hypersensitivity, Delayed; Kinetics; Mice; Mice, Inbred BALB C; Oxazoles; Oxazolone; Peroxidase

Methyl 20 beta-dihydroprednisolonate, a new local antiinflammatory steroid, and its ester hydrolysis product, 20 beta-dihydroprednisolonic acid, were evaluated for potential immunosuppressive actions as determined by the splenic plaque-forming cell response assay. The parent compound, prednisolone, was used as a comparative agent. All three corticosteroid agents, when administered intraperitoneally or subcutaneously by separate injections given at the same time as antigen, demonstrated significant dose-related suppression of this immunologic parameter. In a croton oil-induced inflammation test (ear challenge in mice), methyl 20 beta-dihydroprednisolonate demonstrated significant antiinflammatory effects, but only in the ear to which it was applied. The comparative drug, prednisolone, significantly reduced inflammation in the ear to which it was applied and in the contralateral ear as well. The methyl ester derivative demonstrated effective antiinflammatory activity when applied topically in the oxazolone delayed-type hypersensitivity test (ear challenge in mice). The results seen in the plaque-forming cell response are in contrast to the generally noted lack of systemic glucocorticoid actions of the steroid acid ester derivatives reported in other studies.

Topics: Animals; Dose-Response Relationship, Drug; Edema; Female; Hemolytic Plaque Technique; Hypersensitivity, Delayed; Immunosuppressive Agents; Inflammation; Mice; Oxazolone; Prednisolone; Spleen

Various models of delayed hypersensitivity (DH) were used in mice: contact hypersensitivity reactions to picryl chloride and oxazolone and reactions to methylated bovine serum albumin (MBSA) and sheep red blood cells (SRBC). Drugs of different classes were tested in these models by systemic treatment around the challenge period: non-steroidal anti-inflammatory drugs (cyclooxygenase inhibitors, and inhibitors of both cyclooxygenase and lipoxygenase); glucocorticoids and immunosuppressants (cyclosporin A. CsA; cyclophosphamide, Cy; methotrexate, Mtx; azathioprine, Aza). These compounds were also studied and compared for their effects on the 3-h and 24-h phase of the carrageenin mouse-paw edema (in which inflammation is maximal after 24 h). Non-steroidal anti-inflammatory drugs (including double inhibitors of cyclooxygenase and lipoxygenase) had little or no effect on DH models, except indometacin. Glucocorticoids inhibited all immune reactions except that to MBSA. Of the immunosuppressants, CsA reduced all the DH reactions while Aza mainly reduced the reaction to SRBC; Cy and Mtx were mainly active on SBRC and MBSA inflammations. On another hand CsA, Cy and Mtx were inactive on the 3-h phase but decreased the 24-h phase of carrageenin edema. At doses active on the DH models and on carrageenin inflammation, Cy induced a lasting blood leukopenia, but CsA and Mtx did not. This combination of tests in the mouse seems to be of interest to demonstrate any action on DH and any anti-inflammatory effect and to suggest whether these activities are related to a possible leukopenic effect.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Carrageenan; Dermatitis, Contact; Edema; Glucocorticoids; Hypersensitivity, Delayed; Immunosuppressive Agents; Inflammation; Kinetics; Leukocyte Count; Male; Mice; Oxazolone; Picryl Chloride; Serum Albumin, Bovine; Sheep

Contact sensitization induces two different kinds of T cells (both Ly 1) that act in sequence to produce upon challenge with antigen a classical 24-hour local skin swelling reaction. One of these cells produces an antigen-specific factor. It has been suggested that it sensitizes mast cells, similar to IgE antibody, and causes them to release vasoactive amines in the presence of antigen. This results in an early (2-hour) swelling reaction. Increased vascular permeability facilitates the entry of the second, lymphokine-producing Ly 1 cell into the site of reaction to elicit the classical 24-hour delayed-type hypersensitivity reaction. In alloxan diabetic mice, contact sensitivity reactions are reduced significantly, and our experiments show that insulin deficiency affects only the activity of the late acting, lymphokine-producing cell and leaves the factor-producing cell responsible for the early swelling reaction unaffected. Our experiments demonstrate that insulin deficiency has different effects on distinct subpopulations of T lymphocytes.

Topics: Animals; Antigens, Ly; Dermatitis, Contact; Diabetes Mellitus, Experimental; Edema; Glucose; Immunity, Cellular; Immunization, Passive; Mice; Mice, Inbred CBA; Oxazolone; Picryl Chloride; T-Lymphocytes; Time Factors

R-830, a di-tert-butylphenol, has been shown to be anti-inflammatory in a number of animal models. These include conventional systems such as carrageenan-induced edema and adjuvant arthritis of the rat and ultraviolet-induced erythema in the guinea pig in which the acidic nonsteroidal anti-inflammatory drugs (e.g., indomethacin) are effective. The anti-inflammatory activity of R-830 has also been demonstrated in other models (e.g., graft vs. host reaction and reversed passive cutaneous Arthus reaction in the rat, contact sensitivity in the mouse) in which the acidic nonsteroidal drugs are not effective. In vitro, R-830 inhibits guinea pig lung lipoxygenase and bovine seminal vesicle cyclo-oxygenase. The antioxidant properties of R-830 were demonstrated in two in vitro systems. We speculate that the antioxidant activity of this molecule might be related to its unusual profile of pharmacological activity.

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Arthritis, Experimental; Butylated Hydroxytoluene; Dermatitis, Contact; Edema; Graft vs Host Reaction; Granuloma; Lipoxygenase Inhibitors; Male; Oxazolone; Passive Cutaneous Anaphylaxis; Prostaglandins; Rats; Rats, Inbred Strains

11 beta-Hydroxy-16 alpha, 17 alpha, 21-trimethyl-pregna-1,4-diene-3,20-dione(ORG 6216) is a novel type of anti-inflammatory steroid which displays a dissociation of local from systemic effects in a range of animal models. Moreover, ORG 6216 is exceptional in that it has not shown any significant atrophogenic activity in the skin when administered either topically or intracutaneously in animal models.

Topics: Administration, Topical; Animals; Anti-Inflammatory Agents; Collagen; Edema; Erythema; Glucocorticoids; Injections, Subcutaneous; Liver Glycogen; Male; Mice; Oxazolone; Pregnadienes

In the oxazolone-induced delayed hypersensitivity inflammation in the rat ear, betamethasone 17-valerate, in contrast to other topical corticosteroids, is incapable of suppressing oedema. When given in combination with triamcinolone acetonide, betamethasone 17-valerate competitively antagonizes the anti-inflammatory action of the active steroid. When tested in the mouse, betamethasone 17-valerate behaved as an anti-inflammatory agent 15 and 80 times as potent as betamethasone and hydrocortisone respectively. In an in vivo lymphocyte culture system in which preincubation with corticosteroids prevents subsequent phytohaemagglutinin induced DNA synthesis, betamethasone 17-valerate was less active than even hydrocortisone when rat lymph node cells were used, but with human cell preparations it was more potent than either hydrocortisone or betamethasone. Betamethasone 17-valerate behaves uniquely in the rat as an anticorticosteroid; in mouse and in man the compound behaves as a normal corticosteroid.

Topics: Administration, Topical; Adrenal Cortex Hormones; Animals; Anti-Inflammatory Agents; Betamethasone; Betamethasone Valerate; Dose-Response Relationship, Drug; Edema; Fluocinolone Acetonide; Hypersensitivity, Delayed; Lymphocyte Activation; Male; Mice; Oxazolone; Rats; Triamcinolone Acetonide