The effect of therapeutic glucocorticoids on the adrenal response in a randomized controlled trial in patients with rheumatoid arthritis

Objective. To measure the effect of low-dose systemic glucocorticoid treatment on the adrenal response to adrenocorticotropic hormone (ACTH) in patients with rheumatoid arthritis (RA). Methods. Patients with RA who took part in a randomized double-blind placebo-controlled trial of budesonide (3 mg/day and 9 mg/day) and prednisolone (7.5 mg/day) underwent a short (60-minute) test with injection of ACTH (tetracosactide hexaacetate) at baseline and the day after completing the 3-month treatment program. Plasma cortisol measurements at baseline and 3 months were compared within and between the treatment groups. Individual patients were classified as normal responders to ACTH or as abnormal responders if changes were > 2 SD below the pretreatment value in the entire group of study patients. Results. Short tests with ACTH injection were performed on 139 patients before beginning the study medication and on 134 patients after cessation of the medication. There were no changes in the placebo group. Mean plasma cortisol levels following treatment were reduced in all active treatment groups. In addition, mean values were significantly reduced for the 30-minute and 60-minute responses to ACTH. The maximum reduction (35%) occurred in the prednisolone group at 60 minutes. Following treatment, 34% of patients taking budesonide 9 mg and 46% of those taking prednisolone 7.5 mg failed to reach the normal maximum cortisol response to ACTH. Four patients failed to achieve the normal percentage increase in cortisol levels, but only 1 patient failed to meet both criteria. Conclusion. Low doses of a glucocorticoid resulted in depression of baseline and ACTH-stimulated cortisol levels after 12 weeks of therapy. Although the responsiveness of the hypothalamic-pituitary-adrenal axis in individual patients generally remained within the normal range, these changes should be investigated further

Adverse events related to low dose corticosteroids in autoimmune hepatitis

Background: Autoimmune hepatitis requires long-term therapy, and systemic corticosteroids are the backbone of therapeutic management. Prolonged use of corticosteroids may lead to adverse events but data from long-term studies are mainly derived from studies in rheumatic diseases. Aim: To assess cataract, diabetes and fractures in relation to corticosteroid doses in the long-term maintenance treatment of patients with autoimmune hepatitis. Methods: We retrospectively collected data on 476 patients (77% women) with an established diagnosis of autoimmune hepatitis. Binary logistic regression with a generalised estimating equation was used to analyse the association between current corticosteroid use and the incidence of cataract, diabetes and fractures with onset after autoimmune hepatitis diagnosis. We corrected for sex, age, cirrhosis at diagnosis and predniso(lo)ne use in the prior 3 years to account for possible ongoing effects. Results: A total of 6634 years, with a median of 13 (range 1-40) per patient were recorded. The median age at diagnosis was 44 years (range 2-88). Adverse events were documented in 120 (25%) patients. Low-dose predniso(lo)ne (0.1-5.0 mg/d) increased the odds of fractures whereas higher doses (>5.0 mg/d) increased the odds of cataracts and diabetes. Budesonide increased the odds of cataract and fractures; this effect was independent of predniso(lo)ne use in the prior 1, 2 or 3 years. Conclusions: Even low doses of corticosteroids frequently lead to substantial adverse events refuting the assumption that adverse events are prevented by administering low doses

Evaluating the Suitability of Using Rat Models for Preclinical Efficacy and Side Effects with Inhaled Corticosteroids Nanosuspension Formulations

Inhaled corticosteroids (ICS) are often prescribed as first-line therapy for patients with asthma Despite their efficacy and improved safety profile compared with oral corticosteroids, the potential for systemic side effects continues to cause concern. In order to reduce the potential for systemic side effects, the pharmaceutical industry has begun efforts to generate new drugs with pulmonary-targeted topical efficacy. One of the major challenges of this approach is to differentiate both efficacy and side effects (pulmonary vs. systemic) in a preclinical animal model. In this study, fluticasone and ciclesonide were used as tool compounds to explore the possibility of demonstrating both efficacy and side effects in a rat model using pulmonary delivery via intratracheal (IT) instillation with nanosuspension formulations. The inhibition of neutrophil infiltration into bronchoalveolar lavage fluid (BALF) and cytokine (TNFα) production were utilized to assess pulmonary efficacy, while adrenal and thymus involution as well as plasma corticosterone suppression was measured to assess systemic side effects. Based on neutrophil infiltration and cytokine production data, the ED50s for ciclesonide and fluticasone were calculated to be 0.1 and 0.03 mg, respectively. At the ED50, the average adrenal involution was 7.6 ± 5.3% for ciclesonide versus 16.6 ± 5.1% for fluticasone, while the average thymus involution was 41.0 ± 4.3% for ciclesonide versus 59.5 ± 5.8% for fluticasone. However, the differentiation became less significant when the dose was pushed to the EDmax (0.3 mg for ciclesonide, 0.1 mg for fluticasone). Overall, the efficacy and side effect profiles of the two compounds exhibited differentiation at low to mid doses (0.03–0.1 mg ciclesonide, 0.01–0.03 mg fluticasone), while this differentiation diminished at the maximum efficacious dose (0.3 mg ciclesonide, 0.1 mg fluticasone), likely due to overdosing in this model. We conclude that the rat LPS model using IT administration of nanosuspensions of ICS is a useful tool to demonstrate pulmonary-targeted efficacy and to differentiate the side effects. However, it is only suitable at sub-maximum efficacious levels

Management of Allergic Rhinitis: Focus on Intranasal Agents

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/90304/1/j.1875-9114.1989.tb04148.x.pd

EFSA Panel on Food Contact Materials, Enzymes, Flavourings and Processing Aids (CEF); Scientific Opinion on Flavouring Group Evaluation 08, Revision 5 (FGE.08Rev5): Aliphatic and alicyclic mono-, di-, tri-, and polysulphides with or without additional oxygenated functional groups from chemical groups 20 and 30

<p>The CEF Panel of the European Food Safety Authority was requested to evaluate 80 flavouring substances in the Flavouring Group Evaluation 08, Revision 4, using the Procedure in Commission Regulation (EC) No 1565/2000. Since the publication of the last revision of this FGE, the EFSA has been requested to evaluate additional toxicological data submitted for two flavouring substances, one substance 2,5-dihydroxy-2,5-dimethyl-1,4-dithiane [FL-no: 15.006], which support the evaluation of the candidate substance 2,5-dihydroxy-1,4-dithiane [FL-no: 15.134] and one on the candidate substance spiro(2,4-dithia-1-methyl-8-oxabicyclo[3.3.0]octane-3,3’-(1’-oxa-2’-methyl)-cyclopentane) and spiro(2,4-dithia-6-methyl-7-oxabicyclo[3.3.0]octane-3,3’-(1’-oxa-2’-methyl)-cyclopentane) [FL-no: 15.007], which have been included in the present revision of FGE.08. For the substances methyl methanethiosulphonate [FL-no: 12.159], 2-methylbutane-2-thiol [FL-no: 12.172], 2-methylpropane-2-thiol [FL-no: 12.174], ethyl-2-mercapto-2-methyl propanoate [FL-no: 12.304] and 2,4,4-trimethyl-1,3-oxathiane [FL-no: 16.057] there is an indication of a genotoxic potential in vitro. Therefore, without further genotoxicity data, the Panel concluded that the Procedure could not be applied to these five substances. For four substances, 3-mercaptooctanal [FL-no: 12.268], 3-mercaptodecanal [FL-no: 12.269], methanedithiol diacetate [FL-no: 12.271] and 3,5-dimethyl-1,2-dithiolane-4-one [FL-no: 12.295] no data on use as flavouring substances in Europe are available and no intake figures could be calculated, which preclude the evaluation of the four substances using the Procedure. The remaining 71 substances were evaluated through a stepwise approach that integrates information on the structure-activity relationships, intake from current uses, toxicological threshold of concern, and available data on metabolism and toxicity. The Panel concluded that 59 substances do not rise safety concerns at their levels of dietary intake, estimated on the basis of the MSDI approach. For 12 substances [FL-no: 12.093, 12.094, 12.097, 12.100, 12.112, 12.116, 12.120, 12.164, 12.167, 12.199, 15.102 and 15.125], evaluated through the Procedure, no appropriate NOAEL was available and additional data are required. The specifications for the materials of commerce have also been considered and for three substances, information on the specifications is lacking.</p&gt

Liposomal Formulations of Inflammatory Bowel Disease Drugs: Local versus Systemic Drug Delivery in a Rat Model

Based on adherence to intestinal mucosa, intralumenally administered liposomal formulations of 5-aminosalicylate (5-ASA) and 6-mercaptopurine (6-MP) were studied for their potential to enhance local drug delivery to intestinal tissue for the treatment of inflammatory bowel disease.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/41509/1/11095_2005_Article_5376.pd