The management of moderate to severe atopic dermatitis in adults with topical fluticasone propionate

This study was designed to investigate a long-term therapeutic strategy for the management of recurring atopic dermatitis (AD) in adults using fluticasone propionate (FP) ointment (Cutivate^TM) whereby FP could help to prevent a relapse of AD once symptoms were under control. Adult patients with chronic, moderate to severe AD entered this multicentre study. All patients were initially treated with FP 0.005% (g/g) ointment in two different regimens. Patients whose AD had been completely healed by these treatments then entered a long-term treatment phase applying FP or placebo ointment once daily, two times per week for 16 weeks to 'known' healed lesions. By the end of the initial treatment period, mean SCORAD values had significantly ( P  < 0.0005) improved from baseline. Patients who entered the maintenance phase and were treated with intermittent FP for up to 16 weeks, demonstrated its superior efficacy ( P  = 0.018) over placebo, maintaining the improvements achieved after the initial treatment phase, reducing risk of relapse and delaying time to relapse ( P  = 0.013). No significant changes were detected in either treatment group in serum cortisol levels or in skin thickness measurements. Intermittent FP applied two times per week maintained a significant level of control, and delayed relapse of AD by comparison with placebo.     

Insulin-like growth factor binding proteins: regulation in chronic active plaques in multiple sclerosis and functional analysis of glial cells

Studies in experimental allergic encephalomyelitis, an animal model of multiple sclerosis (MS), suggest that astrocyte-secreted insulin-like growth factor binding protein-2 (IGFBP-2) helps target IGF-1 to IGF-1 receptor-expressing oligodendrocytes and promote remyelination. We examined the presence of IGFBPs 1-6 in astrocytes in normal post-mortem human brain tissue and lesions of MS by means of immunohistochemistry. Under normal conditions all six IGFBPs were detected. Compared to controls, hypertrophic astrocytes at the borders of chronic active MS lesions displayed increased immunoreactivity for IGFBP-2 and IGFBP-4. In vitro studies were performed to analyse the effects of IGFBPs on cellular proliferation of neonatal rat glial cells. Treatment of astrocytes with IGF-1 and -2 enhanced proliferation whereas IGFBP-2 and -4 inhibited cellular growth. Interestingly, combined treatment with IGFBP-2 and IGF-1 potentiated effects on cellular proliferation whereas combined treatment with IGFBP-2 and IGF-2 inhibited growth. Unlike IGFBP-2, IGFBP-4 inhibited proliferation in combined treatment with IGF-1. In contrast, combined treatment with IGFBP-2 and IGF-1 resulted in decreased cell survival of oligodendrocyte precursor cells. Our results suggest that the up-regulation of IGFBP-2 in reactive astrocytes in MS lesions may primarily serve to enhance the IGF-1-mediated mitogenic stimulus for astrocytes rather than supporting oligodendrocyte survival.     

Left-right comparison study of the combination of fluticasone propionate and UV-A vs. either fluticasone propionate or UV-A alone for the long-term treatment of vitiligo.

OBJECTIVE: To compare the efficacy and safety of using a combination of fluticasone propionate (FP) and UV-A with that of either drug used alone in the long-term treatment of vitiligo. DESIGN: Prospective, randomized, controlled, left-right comparison study. Repigmentation was judged by a single dermatologist (L.N.-K.) and skin thickness was scored by a pathologist (using biopsy samples), a dermatologist (L.N.-K.) (visually), and patients (using a standard questionnaire). SETTING: Netherlands Institute for Pigmentary Disorders, Amsterdam. PATIENTS: Patients with lesions on arms, legs, and trunk were treated on 2 symmetrical lesions for 9 months with FP alone and a combination of FP and UV-A (FP group) or with UV-A alone and a combination of FP and UV-A (UV-A group). Fluticasone propionate cream was applied once daily at about bedtime, and UV-A (10 J/cm2) exposure was twice a week. Patients attended the clinic at 3-month intervals. RESULTS: One hundred thirty-five patients were included, 96 of whom were evaluable after 9 months. Patients not reaching the end point withdrew because of insufficient repigmentation (n = 23), decreased motivation (n = 11), or protocol violations (n = 5). No patient (irrespective of whether they withdrew) experienced any adverse effects. The FP and UV-A groups were comparable with respect to sex, age, and location of lesions. On average, combination treatment was 3 times more effective than either UV-A or FP treatment alone. In the FP group, no atrophy was seen after 9 months with either treatment. In the UV-A group, a little atrophy was detected twice: as well during UV-A treatment alone as during combination treatment. CONCLUSIONS: Combination treatment with FP and UV-A is much more effective in reaching complete repigmentation than are FP and UV-A used alone, but large inter-individual differences occur. Fluticasone propionate, UV-A, and a combination of FP and UV-A seem to be safe for long-term treatment of vitiligo.     

The management of moderate to severe atopic dermatitis in adults with topical fluticasone propionate. The Netherlands Adult Atopic DermatitisStudy Group.

This study was designed to investigate a long-term therapeutic strategy for the management of recurring atopic dermatitis (AD) in adults using fluticasone propionate (FP) ointment (CutivateTM) whereby FP could help to prevent a relapse of AD once symptoms were under control. Adult patients with chronic, moderate to severe AD entered this multicentre study. All patients were initially treated with FP 0.005% (g/g) ointment in two different regimens. Patients whose AD had been completely healed by these treatments then entered a long-term treatment phase applying FP or placebo ointment once daily, two times per week for 16 weeks to 'known' healed lesions. By the end of the initial treatment period, mean SCORAD values had significantly (P < 0.0005) improved from baseline. Patients who entered the maintenance phase and were treated with intermittent FP for up to 16 weeks, demonstrated its superior efficacy (P = 0.018) over placebo, maintaining the improvements achieved after the initial treatment phase, reducing risk of relapse and delaying time to relapse (P = 0.013). No significant changes were detected in either treatment group in serum cortisol levels or in skin thickness measurements. Intermittent FP applied two times per week maintained a significant level of control, and delayed relapse of AD by comparison with placebo.     

Simvastatin inhibits interferon-γ-induced MHC class II up-regulation in cultured astrocytes

Based on their potent anti-inflammatory properties and a preliminary clinical trial, statins (HMG-CoA reductase inhibitors) are being studied as possible candidates for multiple sclerosis (MS) therapy. The pathogenesis of MS is unclear. One theory suggests that the development of autoimmune lesions in the central nervous system may be due to a failure of endogenous inhibitory control of MHC class II expression on astrocytes, allowing these cells to adapt an interferon (IFN)-γ-induced antigen presenting phenotype. By using immunocytochemistry in cultured astrocytes derived from newborn Wistar rats we found that simvastatin at nanomolar concentrations inhibited, in a dose-response fashion, up to 70% of IFN-γ-induced MHC class II expression. This effect was reversed by the HMG-CoA reductase product mevalonate. Suppression of the antigen presenting function of astrocytes might contribute to the beneficial effects of statins in MS.     

Pituitary steroids in two teleost species: immunohistological and biochemical studies

Antisera raised against steroid hormones [estradiol-17 beta (E2), testosterone (T), 11 beta-hydroxyandrostenedione (OHA)] were used to localize immunoreactive material in fixed and paraffin-embedded pituitaries of the African catfish and the rainbow trout. Organic extracts of pituitary homogenates were analyzed for steroid hormones by radioimmunoassay and gas chromatography-mass spectrometry (E2 in female catfish only). With the exception of an E2-positive cell type in the catfish neurointermediate lobe, steroid immunoreactivity was found to be restricted to the cytoplasm of adenohypophyseal cells, which were also labeled after incubation with catfish alpha,beta-gonadotropin and salmon gonadotropin antisera, respectively. Steroid levels determined by radioimmunoassay in the catfish ranged between 85 and 628 pg/pituitary, while lower levels (2-8 pg/pituitary) were found in the rainbow trout. E2 was identified by gas chromatography-mass spectrometry at a level of 84 pg/pituitary. The observation that immunolabeling after steroid antiserum incubation is confined mainly to gonadotrops provides morphological evidence for direct steroid effects on this particular cell type.     

Efficacy and safety of fluticasone propionate 0.005% ointment in the long‐term maintenance treatment of children with atopic dermatitis: Differences between boys and girls?

Treatment of atopic dermatitis (AD) in children tends to stabilize the condition in the short term. 'Maintenance' treatment options in children are limited. To assess the efficacy and safety of twice daily treatment with fluticasone propionate 0.005% (FP) ointment during 4 wk and the efficacy and safety of twice weekly maintenance treatment with FP in preventing exacerbations or remissions of AD during a 16 wk follow-up period. Ninety children (aged 4–10 yr) with moderate to severe AD were included in a randomized, multi-centre study and received FP ointment twice daily during the acute phase. Children whose AD was in remission after 4 wk of treatment, entered the maintenance phase. In addition to twice daily emollient, children were randomly allocated to receive FP or placebo ointment twice weekly on consecutive days. Efficacy was assessed by the objective SCORAD. Eighty-seven (97%) completed the 4-wk acute study period. Extensive remission was achieved in 78 (87%) children, and 75 children entered the maintenance phase. Intermittent treatment with FP resulted in less severe AD and significantly reduced risk of further relapse as compared with placebo. The risk of an exacerbation of AD was more than twice as high in the placebo group as in the FP group (hazard ratio 2.182, 95% CI). AD in girls was better controlled than in boys. This long-term study shows that the addition of twice weekly FP to standard maintenance therapy significantly reduces the risk of relapse in children with moderate severe AD.     

Validation of the inverse water volumetry method: a new gold standard for arm volume measurements

Background No consensus exists with respect to a commonly accepted and standardized method for measuring arm volumes in patients with lymphedema. Knowing the exact volume in (potential) lymphedemic arms and comparing this volume with healthy arms is important to detect the first signs of lymphedema and to study the effects of treatment.Methods A new apparatus, based upon the principle of measuring shortness of water, was developed to measure arm volumes. This measuring-method, inverse water volumetry, was prospectively validated in patients, suffering from lymphedema after complete or partial mastectomy for primary breast cancer. Healthy and lymphedemic arm were measured 3 times: twice by nurse A (A1 and A2) and once by nurse B (B). Subsequently, these differences in volumes were compared with differences in volumes obtained by the Herpertz method, which is based upon circumferential measurement.Results In every patient at every occasion volume of the lymphedemic arm was bigger than the corresponding volume of the control arm. Mean volumes of healthy arms were 3958(A1), 3966(A2) and 3961(B) ml respectively. Mean volumes of lymphedemic arms were 4721(A1), 4752(A2) and 4773(B) ml respectively, volume B being significantly different from volume A1. Volume difference of edemic arms minus control arms was not significant between measurements (A1 vs. A2 and A1 vs. B, respectively), while this difference was significant (A1 vs. B) using the Herpertz method.Conclusion Inverse water volumetry is an easy measuring device with a high inter- and intra-observer agreement. The small but significant volume increase of lymphedemic arms in time compared to the constant volumes of control arms is as well indicative for the accuracy of the method as for the volume of lymphedemic arms to increase when no therapeutic garment is carried.     

Respiratory sensitization: Advances in assessing the risk of respiratory inflammation and irritation

Respiratory sensitization provides a case study for a new approach to chemical safety evaluation, as the prevalence of respiratory sensitization has increased considerably over the last decades, but animal and/or human experimental/predictive models are not currently available. Therefore, the goal of a working group was to design a road map to develop an ASAT approach for respiratory sensitisers. This approach should aim at (i) creating a database on respiratory functional biology and toxicology, (ii) applying data analyses to understand the multi-dimensional sensitization response, and how this predisposes to respiratory inflammation and irritation, and (iii) building a systems model out of these analyses, adding pharmacokinetic–pharmacodynamic modeling to predict respiratory responses to low levels of sensitisers. To this end, the best way forward would be to follow an integrated testing approach. Experimental research should be targeted to (i) QSAR-type approaches to relate potential as a respiratory sensitizer to its chemical structure, (ii) in vitro models and (iii) in vitro–in vivo extrapolation/validation.