Relative potencies of three glucocorticoids to induce hypoplasia of the physis and concomitant biochemical alterations in the rat.

Although inhaled glucocorticoids are known to have systemic effects on bone metabolism, there is little comparative information on their relative potencies. The effects of three standard glucocorticoids in causing changes in bone metabolism and growth, therefore, were investigated in relation to other systemic effects in the rat. Given to male Sprague-Dawley rats, 4.5-5.5 weeks old, subcutaneously (s.c.), at doses of 0.3-10 mg/kg daily for 7 days, beclomethasone dipropionate, prednisolone and ciclesonide all dose-dependently inhibited thymus body mass index (BMI) (by 57%, 44% and 76% at 3 mg/kg). Ciclesonide, potently and prednisolone, less effectively, also repressed femoral bone growth (by 41% and 18% at 10 mg/kg), significantly reducing body weight gain (both by 100% at 10 mg/kg), and serum concentrations of acid phosphatase (ACP) and tartarate resistant acid phosphatase (TRACP) (by >30% at 10 mg/kg); both increased serum glucose and triglycerides levels. Serum alkaline phosphatase (ALP) was not affected. Beclomethasone dipropionate had little or no effect on these additional variables. In conclusion, ciclesonide showed pronounced bone growth inhibiting activity after s.c. administration to the rat while other two glucocorticoids showed differences in activity on bone metabolism. However, this model is sufficiently sensitive and specific for testing the effect of glucocorticoids on bone metabolism.

Waterborne beclomethasone dipropionate affects the physiology of fish while its metabolite beclomethasone is not taken up.

Asthma is commonly treated with inhalable glucocorticosteroids, including beclomethasone dipropionate (BDP). This is a synthetic prodrug which is metabolized to the more active monopropionate (BMP) and free beclomethasone in humans. To evaluate potential effects of residual drugs on fish, we conducted a 14 day flow-through exposure experiment with BDP and beclomethasone using rainbow trout, and analyzed effects on plasma glucose, hepatic glutathione and catalase activity together with water and body concentrations of the BDP, BMP and beclomethasone. We also analyzed hepatic gene expression in BDP-exposed fish by microarray and quantitative PCR. Beclomethasone (up to 0.65 µg/L) was not taken up in the fish while BDP (0.65 and 0.07 µg/L) resulted in accumulation of both beclomethasone, BMP and BDP in plasma, reaching levels up to those found in humans during therapy. Accordingly, exposure to 0.65 µg/L of BDP significantly increased blood glucose as well as oxidized glutathione levels and catalase activity in the liver. Exposure to beclomethasone or the low concentration of BDP had no effect on these endpoints. Both exposure concentrations of BDP resulted in significantly higher transcript abundance of phosphoenolpyruvate carboxykinase involved in gluconeogenesis, and of genes involved in immune responses. As only the rapidly metabolized prodrug was potent in fish, the environmental risks associated with the use of BDP are probably small. However, the observed physiological effects in fish of BDP at plasma concentrations known to affect human physiology provides valuable input to the development of read-across approaches in the identification of pharmaceuticals of environmental concern.

Metabolic and reproductive effects of relatively low concentrations of beclomethasone dipropionate, a synthetic glucocorticoid, on fathead minnows.

Pharmaceuticals present in the aquatic environment could adversely affect aquatic organisms. Synthetic glucocorticoids (GC) are used in large quantities as anti-inflammatory drugs and have been reported to be present in river water. In order to assess the impact of environmental concentrations of GCs, an in vivo experiment was conducted with adult fathead minnows. Fish were exposed to 0.1 µg/L, 1 µg/L, or 10 µg/L beclomethasone dipropionate (BCMD) via a flow-through system over a period of 21 days. Similar duplicate tanks served as control, with no chemical added. There was a concentration-related increase in plasma glucose concentration and a decrease in blood lymphocyte count. Induction of male secondary sexual characters and a decreasing trend in plasma vitellogenin (Vtg) concentrations in female fish were observed with increasing exposure concentration of BCMD. Expression profiles of selected genes (phosphoenolpyruvate carboxykinase - PEPCK, glucocorticoid receptor - GR, and Vtg) in liver also demonstrated concentration-related effects at all three tested concentrations. The results suggest that GCs could cause effects in lower micrograms per liter concentrations that could be environmentally relevant for total GCs present in the environment. Therefore, studies to determine the environmental concentrations of GCs and no effect concentrations are needed to assess if GCs pose a risk to the aquatic environment.

Synthetic glucocorticoids in the environment: first results on their potential impacts on fish.

Human pharmaceuticals have been shown to be entering the aquatic environment in quantities that may produce adverse effects to aquatic organisms. This paper investigates the impacts of synthetic glucocorticoids (GCs), which are used in large amounts as anti-inflammatory drugs, on fish. Mammalian cell lines were transiently transfected with trout corticosteroid receptors (GR1, GR2, and MR) and the transactivation abilities of ten of the most prescribed GCs in the UK were measured in vitro. They showed significantly higher activity with GR2 than with GR1. In order to assess any impacts in vivo, adult fathead minnows were exposed to either 1 µg prednisolone/L or 1 µg beclomethasone dipropionate/L for 21 days. Plasma glucose concentrations were increased and leucocytes were reduced significantly in GC-exposed groups compared to the control group. In another experiment, fish were exposed to three different concentrations of Beclomethasone dipropionate and a dose-dependent increase of plasma glucose was found. The results suggest that low concentrations of synthetic GCs present in water could cause adverse effects on fish. Therefore, quantification of GCs in the aquatic environment and the effects of GCs at environmentally relevant concentrations are required in order to determine if GCs pose a threat to wild fish populations.

Oral candidiasis deteriorated by local application of a glucocorticoid-containing film in a mouse model.

In order to estimate predisposing activity of oral application of beclomethasone dipropionate (BDP)-containing mucoadhesive films for oral candidiasis, the effects of BDP on growth of Candida albicans were examined in vivo and in vitro. Murine neutrophils inhibited the mycelial growth of C. albicans in vitro, but this anti-Candida activity was clearly suppressed by the presence of 10(-6) M of BDP. In vitro, a BDP-release test showed that the amount of BDP released from BDP-containing films into the fluid phase increased in a time- and concentration-dependent manner and reached about 10-15% of the total amount of BDP in the film within 30 min. When the BDP-containing film was attached to the tongues of mice orally infected with C. albicans, oral infection by C. albicans deteriorated, but not as severely as in mice systemically immunosuppressed with prednisolone. Based on these findings, we also discuss the problems associated with the clinical application of BDP-film as an anti-inflammatory tool.

Efficacy and safety of oral beclomethasone dipropionate for ileal or ileal-right colon Crohn's disease of mild-to-moderate activity or in remission: Retrospective study.

Although conventional glucocorticosteroids are the main treatments for active Crohn's disease, several problems are associated with steroid dependence and steroid-related adverse events. To assess the efficacy and safety of oral beclomethasone dipropionate (BDP) coated tablets in adults with mild-to-moderate Crohn's disease. Thirty-four patients (age 18-70years) with a diagnosis of Crohn's disease confirmed by conventional criteria (barium enema, clinical criteria, colonoscopy, histology) were retrospectively evaluated in the study. All subjects received a treatment schedule with BDP 5-10mg/day for 24weeks. BDP significantly (p=0.005) reduced mean Crohn's Disease Activity Index (CDAI) score from 169.6 at baseline to 123.2 after 24weeks. Clinical success was evident at 24weeks in 66.7% of patients with initial active disease, and remission was maintained at week 24 in 93.8% of patients with remission at baseline. Overall, female non-smokers had the best response to treatment. BDP was well tolerated and the only adverse events observed were nausea (n=1), facial erythema (n=1) and one patient with raised fasting blood glucose level. These results clearly suggest that oral BDP coated tablets are effective and safe for treatment of mild-to-moderate Crohn's disease of ileal or ileal-right colonic localisation.

The effects of topical nasal steroids on rat respiratory mucosa in vivo, with special reference to benzalkonium chloride.

Fifty rats were treated with topical nasal steroids with and without the preservative benzalkonium chloride in their right nostril twice daily for 21 days, while the left nostrils were exposed to 0.9% NaCl. By cutting the noses serially in frontal sections, the structure of the mucosal lining of all parts of the nose could be investigated. Areas with squamous cell metaplasia were observed in all nostrils exposed to topical steroids containing benzalkonium chloride. Such alterations were not observed in any nasal cavities exposed to the topical nasal steroid without the preservative or to 0.9% NaCl. In conclusion, benzalkonium chloride appears to be potentially toxic to the mucosa in vivo.

Review of the toxicology of beclomethasone dipropionate.

This paper reviews the published toxicity of beclomethasone dipropionate (BDP). BDP is a synthetic glucocorticosteroid which has a powerful local anti-inflammatory effect but little systemic action. It has been developed for both dermatological and inhaled applications. LD50 values and other acute studies indicated low toxicity. Findings published for repeat dose and reproductive toxicity studies embraced the known range of metabolic and physiological effects of glucocorticoids. For repeat dose studies, these included reduction in body weight gains, cushingoid syndrome in dogs, reductions in the numbers of lymphocytes and the weights of the tissues connected with the immune system, and hepatic glycogen deposition and fatty liver changes. In reproductive studies, there was an increase in the prevalence of cleft palate in mice and rabbits and in the number of dead foetuses, and ossification was retarded. Despite the route of administration, there was a general similarity of effects within and between species. All observations were characteristic of synthetic glucocorticoids and related to the intrinsic effects of these drugs.

[Cytological mechanisms of the development of mucosal candidiasis after exposure to a steroid aerosol preparation]. / Tsitologicheskie mekhanizmy razvitiia kandidoza slizistykh obolochek pri vozdeistvii steroidnogo aérozol'nogo preparata.

Mucosal candidosis was induced in CBA mice by intraoral inoculation following treatment with corticosteroid-containing aerosol (beclomethasone dipropionate). Histologically, in hormone treated mice the adherence of the pathogen to the mucosal surface was found during the first hours after inoculation. This is followed by the formation of the germ tubes and invasion in the epithelial layer. Pseudomycelial invasion in the malpighian layer is accompanied by the leukocyte response that limits the further spread of the fungal cells. In intact mice, the inoculation is not followed by the effective attachment of the fungal cells to the mucosal surface and induction of mycotic lesions. In vitro experiments have demonstrated the enhanced adherence of fungal blastospores to the epithelial cells of the hormone treated animals, that appears to be one of the mechanisms in the pathogenesis of candidosis in these animals.