The Effects of Lumbricus rubellus Extract on Staphylococcus aureus Colonization and IL-31 Levels in Children with Atopic Dermatitis.

Background and Objectives: The ineffective combination of corticosteroids and antibiotics in treating some atopic dermatitis (AD) cases has been concerning. The skin barrier defects in AD ease the colonization of Staphylococcus aureus (S. aureus), which results in a rise in interleukin-31 (IL-31). Lumbricus rubellus (L. rubellus) has shown antimicrobial and antiallergic effects but has not been studied yet to decrease the growth of S. aureus and IL-31 levels in AD patients. This study aimed to analyze the effect of L. rubellus extract in reducing S. aureus colonization, the IL-31 level, and the severity of AD. Materials and Methods: A randomized controlled trial (RCT) (international registration number TCTR20231025004) was conducted on 40 AD patients attending Dermatology and Venereology Polyclinic, Mother and Child Hospital (RSIA), Aceh, Indonesia, from October 2021 to March 2022. AD patients aged 8-16 who had a Scoring Atopic Dermatitis (SCORAD) index > 25, with total IgE serum level > 100 IU/mL, and had healthy weight were randomly assigned into two groups: one received fluocinolone acetonide 0.025% and placebo (control group) and one received fluocinolone acetonide 0.025% combined with L. rubellus extract (Vermint®) (intervention group). The S. aureus colony was identified using a catalase test, coagulase test, and MSA media. The serum IL-31 levels were measured using ELISA assay, while the SCORAD index was used to assess the severity of and improvement in AD. Mean scores for measured variables were compared between the two groups using an unpaired t-test and Mann-Whitney U test. Results: A significant decline in S. aureus colonization (p = 0.001) and IL-31 (p = 0.013) in patients receiving L. rubellus extract was found in this study. Moreover, fourteen AD patients in the intervention group showed an improvement in the SCORAD index of more than 35% (p = 0.057). Conclusions: L. rubellus extract significantly decreases S. aureus colonization and the IL-31 level in AD patients, suggesting its potential as an adjuvant therapy for children with AD.

Molecular dissection of an inhibitor targeting the HIV integrase dependent preintegration complex nuclear import.

Human immunodeficiency virus (HIV) continues to be a major contributor to morbidity and mortality worldwide, particularly in developing nations where high cost and logistical issues severely limit the use of current HIV therapeutics. This, combined HIV's high propensity to develop resistance, means that new antiviral agents against novel targets are still urgently required. We previously identified novel anti-HIV agents directed against the nuclear import of the HIV integrase (IN) protein, which plays critical roles in the HIV lifecycle inside the cell nucleus, as well as in transporting the HIV preintegration complex (PIC) into the nucleus. Here we investigate the structure activity relationship of a series of these compounds for the first time, including a newly identified anti-IN compound, budesonide, showing that the extent of binding to the IN core domain correlates directly with the ability of the compound to inhibit IN nuclear transport in a permeabilised cell system. Importantly, compounds that inhibited the nuclear transport of IN were found to significantly decrease HIV viral replication, even in a dividing cell system. Significantly, budesonide or its analogue flunisolide, were able to effect a significant reduction in the presence of specific nuclear forms of the HIV DNA (2-LTR circles), suggesting that the inhibitors work though blocking IN, and potentially PIC, nuclear import. The work presented here represents a platform for further development of these specific inhibitors of HIV replication with therapeutic and prophylactic potential.

Identification of fluocinolone acetonide to prevent paclitaxel-induced peripheral neuropathy.

Paclitaxel (PTX) is among the most commonly used cancer drugs that cause chemotherapy-induced peripheral neuropathy (CIPN), a debilitating and serious dose-limiting side effect. Currently, no drugs exist to prevent CIPN, and symptomatic therapy is often ineffective. In order to identify therapeutic candidates to prevent axonal degeneration induced by PTX, we carried out a phenotypic drug screening using primary rodent dorsal root ganglion sensory neurons. We identified fluocinolone acetonide as a neuroprotective compound and verified it through secondary screens. Furthermore, we showed its efficacy in a mouse model of PTX-induced peripheral neuropathy and confirmed with four different cancer cell lines that fluocinolone acetonide does not interfere with PTX's antitumor activity. Our study identifies fluocinolone acetonide as a potential therapy to prevent CIPN caused by PTX.

Fitness and competitive ability of Botrytis cinerea field isolates with dual resistance to SDHI and QoI fungicides, associated with several sdhB and the cytb G143A mutations.

Respiration inhibitors such as the succinate dehydrogenase inhibitors (SDHIs) and the quinone outside inhibitors (QoIs) are fungicide classes with increasing relevance in gray mold control. However, recent studies have shown that dual resistance to both fungicide classes is a common trait in Botrytis cinerea populations from several hosts throughout the world. Resistance of B. cinerea to SDHIs is associated with several mutations in the sdhB, sdhC, and sdhD genes, while resistance to QoIs, in most cases, is associated with the G143A mutation in the cytb gene. The objective of the current study was to investigate the fitness and the competitive ability of B. cinerea field strains possessing one of the H272Y/R/L, N230I, or P225F sdhB substitutions and the G143A mutation of cytb. Fitness parameters measured were (i) mycelial growth and conidia germination in vitro, (ii) aggressiveness and sporulation capacity in vivo, (iii) sclerotia production in vitro and sclerotia viability under different storage conditions, and (iv) sensitivity to oxidative stress imposed by diquat treatments. The competitive ability of the resistant isolates was measured in the absence and presence of the SDHI fungicides boscalid and fluopyram selection pressure. The measurements of individual fitness components showed that the H272R/G143A isolates had the lower differences compared with the sensitive isolates. In contrast, the groups of H272Y/L/G143A, N230I/G143A, and P225F/G143A isolates showed reduced fitness values compared with the sensitive isolates. Isolates possessing only the cytb G143A substitution did not show any fitness cost. The competition experiments showed that, in the absence of fungicide selection pressure, after four disease cycles on apple fruit, the sensitive isolates dominated in the population in all the mixtures tested. In contrast, when the competition experiment was conducted under the selection pressure of boscalid, a gradual decrease in the frequency of sensitive isolates was observed, whereas the frequency of H272L and P225F isolates was increased. When the competition experiment was conducted in the presence of fluopyram, the sensitive isolates were eliminated even after the first disease cycle and the P225F mutants dominated in the population. Such results suggest that the sdhB mutations may have adverse effects on the mutants. The observed dominance of sensitive isolates in the competition experiments conducted in the absence of fungicides suggest that the application of SDHIs in alternation schemes may delay the selection or reduce the frequency of SDHI-resistant mutants.

[Comparison of available clinical and imaging tools to assess good positioning of a fluocinolone acetonide implant (Iluvien®) in the vitreous cavity after injection]. / Comparaison des moyens clinique et d'imagerie disponibles en pratique clinique pour objectiver la présence de l'implant d'acétonide de fluocinolone (Iluvien®) dans la cavité vitréenne après injection.

INTRODUCTION: Sustained-release corticosteroid implants are injected into the vitreous cavity using preloaded pens. The fluocinolone (FAc) implant is approximately half the size of the dexamethasone implant (Dex-I). It is simply introduced in the vitreous base rather than propelled into the vitreous cavity as is Dex-I. Verification of its positioning after injection is thus difficult by indirect ophthalmoscopy. The goal of our study is to compare the performance of available clinical and imaging tools to confirm the presence of the FAc in the vitreous cavity following injection. METHODS: Twelve eyes of 12 consecutive patients were included in a retrospective, single-center, observational study carried out at the Bordeaux University Hospital, France. All patients were injected with the FAc after pupil dilation, and presence of the implant was immediately checked by indirect biomicroscopy, wide-field retinography (Clarus®, Carl-Zeiss-Meditec, Dublin, CA, USA) and ultra-wide-field retinography (California®, Optos, Edinburgh, United-Kingdom). Seven days later, a B-mode ultrasonography (10MHz, AVISO, Quantel-medical, France) and an UBM ultrasonography (50MHz, AVISO, Quantel-medical, France) were performed. RESULTS: Indirect biomicroscopy and wide-field retinography detected 4/12 implants (33.3%). Ultra-wide-field retinophotography detected 6/12 implants (50%). All the implants seen using indirect biomicroscopy and wide-field retinography were also visualized with ultra-wide-field. B-mode ultrasonography showed 5/12 implants (41.6%) and UBM 9/12 implants (75%). Finally, one implant dislocated into the anterior chamber and was seen in the iridocorneal angle on gonioscopy. CONCLUSION: Objective confirmation of the proper positioning of the FAc implant in the vitreous cavity is mandatory. If both indirect ophthalmoscopy and anterior examination fail to detect it, ultra-wide field retinography along with UBM ultrasonography, if necessary, appear to be the two best imaging modalities to use.

Intravitreal Fluocinolone Acetonide Implant (ILUVIEN®) for the Treatment of Retinal Conditions. A Review of Clinical Studies.

Fluocinolone acetonide (FAc) intravitreal implant (Iluvien®) is a corticosteroid implant indicated for the treatment of diabetic macular oedema (DMO) in patients who have previously received conventional treatment without good response, non-infectious posterior uveitis, and as an off-label treatment of the macular oedema secondary to retinal vein occlusion. FAc is a non-biodegradable 0.19 mg intravitreal implant which is designed to release FAc over 3 years at a rate of approximately 0.2 mcg per day. The aim of this review is to describe the special pharmacological properties of Iluvien and display the outcomes of the most important clinical trials and real-world studies regarding its efficacy and safety for the management of the above retinal disorders.

Characterization of Transcriptomic and Proteomic Changes in the Skin after Chronic Fluocinolone Acetonide Treatment.

While topical corticosteroid (TCS) treatment is widely used for many skin diseases, it can trigger adverse side effects, and some of such effects can last for a long time after stopping the treatment. However, molecular changes induced by TCS treatment remain largely unexplored, although transient changes in histology and some major ECM components have been documented. Here, we investigated transcriptomic and proteomic changes induced by fluocinolone acetonide (FA) treatment in the mouse skin by conducting RNA-Seq and quantitative proteomics. Chronic FA treatment affected the expression of 4229 genes, where downregulated genes were involved in cell-cycle progression and ECM organization, and upregulated genes were involved in lipid metabolism. The effects of FA on transcriptome and histology of the skin largely returned to normal by two weeks after the treatment. Only a fraction of transcriptomic changes were reflected by proteomic changes, and the expression of 46 proteins was affected one day after chronic FA treatment. A comparable number of proteins were differentially expressed between control and FA-treated skin samples even at 15 and 30 days after stopping chronic FA treatment. Interestingly, proteins affected during and after chronic FA treatment were largely different. Our results provide fundamental information of molecular changes induced by FA treatment in the skin.

Emerging drugs for diabetic retinopathy.

INTRODUCTION: Diabetes mellitus with its ophthalmic complications is the major cause for legal blindness in industrialized countries. Diabetic macular edema and its complex pathophysiology as part of diabetic retinopathy are the leading cause of vision loss among diabetic patients. In recent years, treatment options have developed involving the intravitreal applications of several compounds. AREAS COVERED: Current treatment options for diabetic macular edema including laser therapy and scientific basis of new drugs are discussed. Possible benefits and drawbacks of these new approaches are addressed. EXPERT OPINION: In recent years, new drugs against retinal diseases have been developed consisting mainly of steroid or anti-vascular endothelial growth factor compounds. Targeting macular edema, the second shows a possible therapeutic role in the proliferative form of diabetic retinopathy, requiring further investigation. New biodegradable delivery systems show an advantage in sustaining effective compound concentrations for longer times and have positive impact on safety profile and cost-effectiveness of the drug, a factor of grave importance when considering the future of any new drug in the market. All these new therapeutic approaches alone or in combination with the existing treatments have to demonstrate their efficacy and safety in diabetic retinopathy in current and future trials.

Antitumor effect of non-steroid glucocorticoid receptor ligand CpdA on leukemia cell lines CEM and K562.

Glucocorticoids (GCs) are widely used in chemotherapy of hematological malignancies, particularly leukemia. Their effect is mediated by glucocorticoid receptor (GR), a well-known transcription factor. Besides their therapeutic impact, GCs may cause a number of side effects leading to various metabolic complications. The goal of immediate interest is testing glucocorticoid analogs capable of induction/enhancement of GR transrepression, but preventing GR dimerization and transactivation leading to side effects. In this work we have investigated effects of a promising new selective GR agonist, 2-(4-acetoxyphenyl)-2-chloro-N-methylethylammonium chloride (CpdA), on CEM and K562 leukemia cells. Both cell lines express functional GR. CpdA compared with the glucocorticoid fluocinolone acetonide (FA) exerted more prominent cytostatic and apoptotic effects on the cells. Both cell lines exhibited sensitivity to CpdA, demonstrating a good correlation with the effects of FA on cell growth and viability. In contrast to FA, CpdA did not induce GR transactivation evaluated by no obvious increase in expression of GR target (and dependent) gene FKBP51. At the same time, luciferase assay showed that CpdA efficiently activated transrepression of NF-κB and AP-1 factors. We also evaluated the effect of combined action of CpdA and the proteasome inhibitor Bortezomib. The latter induced a caspase-dependent apoptosis in both T-cell leukemia cell lines. By treatment of CEM cells with different CpdA/GC and Bortezomib doses, we have designed a protocol where CpdA shows potentiating effect on Bortezomib cytotoxic activity. Generally, the present work characterizes a novel non-steroid GR ligand, CpdA, as a promising compound for possible application in leukemia chemotherapy.

Modulation by flunisolide of tumor necrosis factor-alpha-induced stimulation of airway epithelial cell activities related to eosinophil inflammation.

BACKGROUND: Tumor necrosis factor (TNF)-alpha, a proinflammatory cytokine involved in the pathogenesis of asthma, displays multiple functions on a variety of cells, including bronchial epithelial cells (BECs). OBJECTIVE: To characterize in vitro changes induced by TNF-alpha on the function of BECs that may be related to eosinophilic inflammation and to evaluate their modulation by an inhaled corticosteroid, flunisolide. METHODS: A normal human bronchial epithelial cell line (BEAS-2B) was incubated with TNF-alpha (10 ng/ml) to evaluate (a) intercellular adhesion molecule (ICAM)-1 expression and granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin (IL)-5 release by BEAS-2B; (b) eosinophil adhesion to BEAS-2B; and (c) the modulation of these activities by flunisolide (0.1 to 10 microM). RESULTS: Stimulation of BEAS-2 with TNF-alpha generated an increase in ICAM-1 expression (p = .0012), in GM-CSF and IL-5 release (p < .01), and in eosinophil adhesion to BEAS-2B, but this latter effect did not reach statistical significance. Flunisolide at all the tested concentrations effectively inhibited ICAM-1 expression and GM-CSF and IL-5 release (p < .05). The percent inhibition induced by the highest flunisolide concentration (10 muM) for the various BEAS-2B functions was 30%, 60%, and 70%, respectively. The effect of flunisolide appeared to be related to an inhibition of "TNF-alpha-induced" ICAM-1 expression and cytokine release with little or no involvement of the "constitutive" expression and release. CONCLUSION: An increase in ICAM-1 expression in BECs was found to be induced by TNF-alpha and associated with enhancement of the constitutive secretion of GM-CSF and IL-5, cytokines related to eosinophilic inflammation. The ability of flunisolide to modulate these BECs activities appears to be mostly related to the inhibition of the "TNF-alpha-induced" responses.

The Effects of Steroids on Survival of Mouse and Human Tympanic Membrane Fibroblasts.

OBJECTIVE: Tympanic membrane (TM) fibroblast cytotoxicity of quinolone ear drops is enhanced by dexamethasone and fluocinolone. Hydrocortisone has not been evaluated. We aimed to assess the effects of these 3 steroids on mouse and human TM fibroblast survival. STUDY DESIGN: In vitro. SETTING: Academic laboratory. SUBJECTS AND METHODS: Mouse and human TM fibroblasts were exposed to hydrocortisone, dexamethasone, or fluocinolone at concentrations in commercial ear drops (1%, 0.1%, or 0.025%, respectively) and at steroid potency equivalents (1%, 0.033%, or 0.0033%, respectively), or dilute ethanol (control), twice within 24 hours or 4 times within 48 hours for 2 hours each time. Cells were observed with phase-contrast microscopy until the cytotoxicity assay was performed. RESULTS: Mouse and human TM fibroblasts treated with any of the steroids had lower survival after 24 and 48 hours compared to control (all P < .0001). After 24 hours, viability of mouse fibroblasts treated with the steroids was not different (P > .05), while treatment with hydrocortisone decreased human TM fibroblast viability (P < .0001). After 48 hours, at concentrations found in ear drops and at equivalent steroid potency, dexamethasone and fluocinolone had similar survival in mouse and human fibroblasts (all P > .05), but hydrocortisone had lower survival in both mouse (P = .02 and P < .0001) and human (P < .0001) fibroblasts. Phase-contrast images mirrored the cytotoxicity findings. CONCLUSION: Steroids found in commercial ear drops reduce survival of mouse and human TM fibroblasts. Hydrocortisone appears to be more cytotoxic than the more potent steroids, dexamethasone and fluocinolone. These findings should be considered when assessing clinical outcomes of ototopical preparations.

Desipramine inhibits the growth of a mouse skin squamous cell carcinoma cell line and affects glucocorticoid receptor-mediated transcription.

The purpose of this study was to examine the effect of tricyclic antidepressant desipramine (DMI) on the growth inhibition and translocation of the glucocorticoid receptor (GR) from the cytoplasm to the nucleus in cancerous and noncancerous cell lines and the effect of DMI on GR-mediated transcription. Nontumorigenic, immortalized keratinocytes cell line (3PC), papilloma (MT1/2), and squamous cell carcinoma (Ca3/7) cell lines were initially used to study the cell growth inhibition by DMI. Although, the growth of all three cell lines was suppressed by DMI, it was more effective in Ca3/7 cells. Therefore, we next examined the effect of DMI on Ca3/7 cells, resistant to growth inhibition by the synthetic glucocorticoid fluocinolone acetonide (FA). DMI inhibited cell proliferation in a time-dependent manner. The translocation of GR was induced by FA alone, DMI alone, and combination of both agents. FA induced GR-mediated transcription in Ca3/7 cells transfected with a luciferase reporter gene under the control of glucocorticoid response element (GRE), but DMI alone did not affect GR-mediated transcription. However, DMI inhibited FA-induced, GR-mediated transcription when both agents were given together. Pretreatment with DMI followed by combination of DMI and FA decreased GR-mediated transcription more than pretreatment with FA. The expression of metallothionein-1 (Mt-1) gene, which is regulated by GR, was induced significantly by the combination of DMI and FA, and enhanced significantly by pretreatment with FA but not DMI. DMI is suggested to inhibit the growth of Ca3/7 cells and to affect GR-mediated transcription.

Intravitreal fluocinolone acetonide implant (ILUVIEN®) for diabetic macular oedema: a literature review.

Diabetic macular oedema (DMO) is a common complication of diabetic retinopathy and may lead to severe visual loss. In this review, we describe the pathophysiology of DMO and review current therapeutic options such as macular laser photocoagulation, anti-vascular endothelial growth factor agents, and steroid implants with a focus on the new fluocinolone acetonide implant, ILUVIEN®. The results of the Fluocinolone Acetonide in Diabetic Macular Edema (FAME) studies are also presented together with the results of real-world studies to support the clinical use of ILUVIEN® in achieving efficient resolution of DMO and improving vision and macular anatomy in this challenging group of patients.

The Potential of Fluocinolone Acetonide to Mitigate Inflammation and Lipid Accumulation in 2D and 3D Foam Cell Cultures.

Inflammation plays an important role in all stages of atherosclerosis development. Therefore, the use of anti-inflammatory drugs could reduce the risk of major adverse cardiovascular events due to atherosclerosis. Herein, we explored the capacity of fluocinolone acetonide (FA), a glucocorticoid (GC), in modulating foam cell formation and response. Human THP-1 derived foam cells were produced using 100 µg/mL oxidized low-density lipoproteins (OxLDL) and fetal bovine serum (1 and 10%). 2D cultures of these cells were treated with FA (0.1, 1, 10, and 50 µg/mL) in comparison with dexamethasone (Dex). Results showed that treatment with 0.1 and 1 µg/mL FA and Dex improved foam cell survival. FA and Dex also inhibited inflammatory cytokine (CD14, M-CSF, MIP-3α, and TNF-α) secretion. Notably, at the concentration of 1 µg/mL, both FA and Dex reduced cholesteryl ester accumulation. Compared to Dex, FA was significantly better in reducing lipid accumulation at the therapeutic concentrations of 1 and 10 µg/mL. In a novel 3D foam cell spheroid model, FA was shown to be more effective than Dex in diminishing lipid accumulation, at the concentration of 0.1 µg/mL. Taken together, FA was demonstrated to be effective in preventing both lipid accumulation and inflammation in foam cells.

Strength and endurance of the respiratory and handgrip muscles after the use of flunisolide in normal subjects.

OBJECTIVE: To evaluate the effects of the inhaled flunisolide upon the strength and endurance of the respiratory and peripheral muscles of normal subjects. DESIGN: A randomized, double blind and placebo-controlled study. SETTING: A university-affiliated teaching hospital. PARTICIPANTS: Thirteen normal volunteers selected from a graduation course. INTERVENTION: Subjects were randomly allocated to receive a placebo or corticosteroid (flunisolide) to be inhaled twice a day for 4 weeks. After 2 weeks of a washout period, subjects who were receiving the placebo, received flunisolide and vise versa for another 4-week period. MEASUREMENTS AND RESULTS: Spirometry was used to define the volunteers as being normal in terms of pulmonary function. During the study, subjects performed tests of respiratory muscle function (strength and endurance), measurements of handgrip strength and endurance and anthropometric measurements. Muscle strength was measured each week while muscle endurance was measured every 2 weeks. There was no significant difference in the maximal inspiratory and expiratory pressure and handgrip strength during weeks 1-4 when the subjects used either flunisolide or placebo. However, we observed an increase in the endurance time of the respiratory and handgrip muscles in the 4th week of both flunisolide and placebo use, what may be considered due to a learning effect. CONCLUSION: Inhalation of flunisolide by normal subjects for 1 month does not cause any acute or clinically perceived effect in the peripheral or respiratory muscles.

A comprehensive review of the long-term and short-term treatment of melasma with a triple combination cream.

Melasma is a common disorder of hyperpigmentation and generally involves areas of the face and neck. Hyperpigmentation is especially prevalent in darker complected patients and is often difficult to treat. Hydroquinone, tretinoin, and topical corticosteroids are well established monotherapeutic agents for treating melasma and hyperpigmentation; however, a stable, once-daily formulation triple combination cream containing 0.05% tretinoin, 4.0% hydroquinone, and 0.01% fluocinolone acetonide (Tri-Luma) represents the only commercially available combination of all three agents. This product is approved by the US FDA for the treatment of facial melasma. A number of publications have described the safety and efficacy of triple combination cream in over 2000 patients with melasma, some of whom were treated for >12 months. In the initial 8-week study, 29% of patients experienced complete clearing of melasma by week 8, and 77% were clear or almost clear by week 8. Similarly, good results were seen in the two long-term studies, with the clear/mild rate ranging from 78% to 84% of patients at month 6 and from 81% to 94% of patients at month 12. Adverse events were almost always mild in severity and typically occurred only at the application site. The primary concern for most physicians using corticosteroid-containing products on the face is skin atrophy. However, only two cases of skin atrophy were reported across the three published studies. Overall, the results of these extensive studies indicate that triple combination cream is efficacious in treating melasma and exhibits a safe profile with low potential for adverse events.

Inhaled flunisolide suppresses the hypothalamic-pituitary-adrenocortical axis, but has minimal systemic immune effects in healthy cats.

Feline bronchial disease is commonly treated with oral glucocorticoids (OGC), which might be contraindicated in cats with certain infectious, endocrine, renal, or cardiac diseases. Inhalant GC (IGC) maximize local efficacy and minimize systemic bioavailability. We evaluated systemic endocrine and immune effects of IGC (flunisolide, 250 microg/puff q12h) versus OGC (prednisone, 10 mg/d PO) and placebo. Six healthy cats received each drug for 2 weeks followed by a 1-month washout. Testing included determination of single early morning cortisol concentration, results of ACTH stimulation, the urine cortisol-to-creatinine ratio (UC: Cr), lymphocyte phenotype, lymphocyte blastogenesis, serum total IgA and IgM concentrations, and cytokine profiles. Significant differences between treatments were not apparent for serum immunoglobulin concentrations, or expression (mRNA) for the cytokines, interleukin (IL-) 2, IL-4, and IL-10, or gamma interferon. Single early morning cortisol concentration was lower for IGC (0.68 - 0.74 microg/dL), compared with that associated with placebo (2.82 +/- 1.94 microg/dL; P = .033). The ACTH-stimulated peak cortisol concentrations were lower after treatment in cats receiving IGC (before, 8.5 +/- 50.2 microg/dL; after, 2.9 +/- 3.3 microg/dL, P = .0004), but not OGC (before, 8.0 +/- 6.1 microg/dL; after, 6.0 +/- 4.5 microg/dL, P = .07). Similarly, UC: Cr (0.8 +/- 0.8) before IGC was lower than the value (5.02 +/- 3.62; P = .019) after IGC. Compared with placebo, cats given OGC, but not IGC, had significantly lower total percentages of T and B cells. Lymphocyte proliferation was decreased in cats receiving OGC, but not IGC, in comparison with placebo (6.9 +/- 3.3; 24.0 +/- 6.5; 18.8 +/- 14.0, respectively). Significantly more IL-10 mRNA transcription was detected in cats administered OGC or IGC, compared with placebo. Although IGC suppress the hypothalamic-pituitary-adrenocortical axis, IGC had minimal effects on the systemic adaptive immune system.

Topical glucocorticosteroids in rhinitis: clinical aspects.

The introduction of nasal glucocorticosteroids, 30 years ago, has been the most important therapeutic progress in rhinitis management since the introduction of the first generation of antihistamines. Our knowledge of the mode of action of glucocorticosteroids in the nose has improved as the airway mucous membrane of the nose is easily accessible for investigation. However, the exact mechanism behind the marked clinical effect remains unclear. Topical glucocorticosteroids are highly effective in diseases characterized by eosinophil-dominated inflammation (allergic rhinitis, nasal polyposis), but not in diseases characterized by neutrophil-dominated inflammation (common cold, infectious rhinosinusitis). Experience for 30 years and a long series of controlled studies have shown that the treatment is highly effective and that the side effects are few and benign. Intranasal glucocorticosteroids can therefore be considered as first-line treatment for allergic and non-allergic, non-infectious rhinitis and nasal polyps.

Murine epidermal xanthine oxidase activity: correlation with degree of hyperplasia induced by tumor promoters.

Topical application of the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) to SENCAR mouse skin results within 48 h in a 3-fold elevation of xanthine oxidase (XO) activity, an enzyme capable of generating the reactive oxygen species superoxide and hydrogen peroxide. The antiinflammatory steroid fluocinolone acetonide, an inhibitor of TPA-induced hyperplasia, as well as the multiple stages of tumor promotion as defined in SENCAR mice (Stages I and II), inhibited the TPA-dependent elevation of epidermal XO activity. Neither tosylphenylalanyl chloromethyl ketone nor retinoic acid, inhibitors of promotion Stages I and II, respectively, had significant effects on TPA-induced hyperplasia or elevated XO activity. The nonpromoting but hyperplasiogenic agents ethyl phenylpropiolate and acetic acid significantly elevated XO activity within 48 h of topical application. The non-phorbol ester tumor promoter benzoyl peroxide also elevated XO activity consistent with the degree of induced hyperplasia. Multiple treatments with TPA or ethyl phenylpropiolate resulted in a sustained elevation of XO activity which peaked at five treatments and then declined. Sustained inhibition of XO activity by p.o. administration of allopurinol did not inhibit the TPA-induced hyperplasia as determined histologically. These results suggest that the TPA-dependent elevation of epidermal XO activity is associated with the hyperplasia induced by the agent, and is a consequence of the hyperplasia rather than the cause of it.

Further evidence for the involvement of gap-junctional intercellular communication in induction and maintenance of transformed foci in BALB/c 3T3 cells.

In order to investigate further the role of gap-junctional intercellular communication in the process of cell transformation, we examined the effects of chemicals that modulate gap-junctional communication on the induction and maintenance of transformed foci in BALB/c 3T3 cells. When dibutyryl cyclic AMP, retinoic acid, fluocinolone acetonide, or dexamethasone was added during the induction of cell transformation by standard (3-methylcholanthrene alone) or two-stage (low dose of 3-methylcholanthrene plus phorbol ester) protocols, there was a significant decrease in the number of transformed foci. When BALB/c 3T3 cells are transformed, there is selective intercellular communication between transformed and between surrounding nontransformed cells: transformed cells communicate among themselves but not with surrounding normal cells. Addition of dibutyryl cyclic AMP, retinoic acid, fluocinolone acetonide, or dexamethasone to culture dishes in which transformed foci were present induced communication between transformed cells and surrounding normal cells. In the continuous presence of these chemicals, there was a clear decrease in the number of transformed foci. These chemicals therefore appear capable of reestablishing intercellular communication between transformed and nontransformed cells and of diminishing the number of transformed foci. However, when transformed cells were isolated and placed in culture dishes at clonal density in the presence of these chemicals, there was hardly any decrease in the number of transformed colonies, suggesting that the chemicals cannot revert the phenotype of transformed cells in the absence of normal cells. These results suggest that chemicals that modulate intercellular communication not only inhibit the induction of transformed foci but also revert transformed cells to the normal phenotypes by establishing intercellular communication with surrounding normal cells.