Prognostic Value of 18F-Fluorocholine PET Parameters in Metastatic Castrate-Resistant Prostate Cancer Patients Treated with Docetaxel.

Background and Aim: The availability of new treatments for metastatic castrate-resistant prostate cancer (mCRPC) patients increases the need for reliable biomarkers to help clinicians to choose the better sequence strategy. The aim of the present retrospective and observational work is to investigate the prognostic value of 18F-fluorocholine (18F-FCH) positron emission tomography (PET) parameters in mCRPC. Materials and Methods: Between March 2013 and August 2016, 29 patients with mCRPC were included. They all received three-weekly docetaxel after androgen deprivation therapy, and they underwent 18F-FCH PET/computed tomography (CT) before and after the therapy. Semi-quantitative indices such as maximum standardized uptake value (SUVmax), mean standardized uptake value (SUVmean) with partial volume effect (PVC-SUV) correction, metabolically active tumour volume (MATV), and total lesion activity (TLA) with partial volume effect (PVC-TLA) correction were measured both in pre-treatment and post-treatment 18F-FCH PET/CT scans for each lesion. Whole-body indices were calculated as sum of values measured for each lesion (SSUVmax, SPVC-SUV, SMATV, and STLA). Progression-free survival (PFS) and overall survival (OS) were considered as clinical endpoints. Univariate and multivariate hazard ratios for whole-body 18F-FCH PET indices were performed, and p < 0.05 was considered as significant. Results: Cox regression analysis showed a statistically significant correlation between PFS, SMATV, and STLA. No correlations between OS and 18F-FCH PET parameters were defined probably due to the small sample size. Conclusions: Semi-quantitative indices such as SMATV and STLA at baseline have a prognostic role in patients treated with docetaxel for mCRPC, suggesting a potential role of 18F-FCH PET/CT imaging in clinical decision-making.

Model-Based Assessment of Alternative Study Designs in Pediatric Trials. Part II: Bayesian Approaches.

This study presents a pharmacokinetic-pharmacodynamic based clinical trial simulation framework for evaluating the performance of a fixed-sample Bayesian design (BD) and two alternative Bayesian sequential designs (BSDs) (i.e., a non-hierarchical (NON-H) and a semi-hierarchical (SEMI-H) one). Prior information was elicited from adult trials and weighted based on the expected similarity of response to treatment between the pediatric and adult populations. Study designs were evaluated in terms of: type I and II errors, sample size per arm (SS), trial duration (TD), and estimate precision. No substantial differences were observed between NON-H and SEMI-H. BSDs require, on average, smaller SS and TD compared to the BD, which, on the other hand, guarantees higher estimate precision. When large differences between children and adults are expected, BSDs can return very large SS. Bayesian approaches appear to outperform their frequentist counterparts in the design of pediatric trials even when little weight is given to prior information from adults.

Model-Based Assessment of Alternative Study Designs in Pediatric Trials. Part I: Frequentist Approaches.

Alternative designs can increase the feasibility of pediatric trials when compared to classical parallel designs (PaD). In this work we present a model-based approach based on clinical trial simulations for the comparison of PaD with the alternative sequential, crossover, and randomized withdrawal (RWD) designs. Study designs were evaluated in terms of: type I and II errors, sample size per arm (SS), trial duration (TD), treatment exposures, and parameter estimate precision (EP). The crossover requires the lowest SS and TD, although it implies higher placebo and no treatment exposures. RWD maximizes exposure to active treatment while minimizing that to placebo, but requires the largest SS. SS of sequential designs can sometimes be smaller than the crossover one, although with poorer EP. This pharmacometric framework allows a multiscale comparison of alternative study designs that can be used for design selection in future pediatric trials.

Successful private-public funding of paediatric medicines research: lessons from the EU programme to fund research into off-patent medicines.

UNLABELLED: The European Paediatric Regulation mandated the European Commission to fund research on off-patent medicines with demonstrated therapeutic interest for children. Responding to this mandate, five FP7 project calls were launched and 20 projects were granted. This paper aims to detail the funded projects and their preliminary results. Publicly available sources have been consulted and a descriptive analysis has been performed. Twenty Research Consortia including 246 partners in 29 European and non-European countries were created (involving 129 universities or public-funded research organisations, 51 private companies with 40 SMEs, 7 patient associations). The funded projects investigate 24 medicines, covering 10 therapeutic areas in all paediatric age groups. In response to the Paediatric Regulation and to apply for a Paediatric Use Marketing Authorisation, 15 Paediatric Investigation Plans have been granted by the EMA-Paediatric Committee, including 71 studies of whom 29 paediatric clinical trials, leading to a total of 7,300 children to be recruited in more than 380 investigational centres. CONCLUSION: Notwithstanding the EU contribution for each study is lower than similar publicly funded projects, and also considering the complexity of paediatric research, these projects are performing high-quality research and are progressing towards the increase of new paediatric medicines on the market. Private-public partnerships have been effectively implemented, providing a good example for future collaborative actions. Since these projects cover a limited number of off-patent drugs and many unmet therapeutic needs in paediatrics remain, it is crucial foreseeing new similar initiatives in forthcoming European funding programmes.

Determinants of Risk Infection During Therapy with Anti TNF-Alpha Blocking Agents in Rheumatoid Arthritis.

The use of TNF-alpha antagonists (infliximab, etanercept, adalimumab) has changed the course of many rheumatic diseases including rheumatoid arthritis (RA). Since their approval, some questions regarding their safety including infections have been observed. The aim of the study was to evaluate the changes in cytokines levels and cells subsets in patients with RA during anti TNF blocking agents treatment and the possible effect on infections' development. We evaluated in 89 RA patients [39 treated with etanercept (ETN), 29 with adalimumab (ADA) and 21 with infliximab (IFN)] at baseline and after 6 months the following parameters: procalcitonin, ESR, CRP, cytokines as TNF, IL-6, IL-10, IL-8 and the TNF/IL-10 ratio, and peripheral mononuclear cells as CD3+, CD3+/CD4+, CD3+/CD8+, CD19+, CD3- /CD16+/56+, CD14+HLADR+, CD20+, CD19+/CD38+. Peripheral mononuclear cells were detected by flow cytometric system Cytomics FC500 and cytokines circulating levels by a quantitative sandwich enzyme immunoassay technique (Human IL-8 Instant ELISAe Bioscience, Human IL-6 Instant ELISA e Bioscience, Human IL-10 Instant ELISAe Bioscience and Human TNF-a Quantikine immunoassay RD system). A lower reduction of CD14+HLADR+ in ADA group 54.6±10.4% vs ETA 48.4±15.7% vs INF 40.7±16.5%, p<0.039 was found. No differences in all three groups on peripheral mononuclear cells CD3+, CD3+/CD4+, CD3+/CD8+, CD19+, CD 20+, CD19+/CD38+, CD3-/CD16+/56+, and cytokine circulating levels were found. The number of infections at 6 months was: 10.3% in ADA group, 12.8% in ETN group and 19.04% in IFN group. A correlation was found between the reduction in CD14+HLADR+ cells and IFN treatment. Our data showed that the level of CD14+HLADR+ cells was reduced during therapy with IFN. ADA and ETN don't reduce lymphocyte populations and their subsets such as CD14+HLADR+ cells that play an important role host defence.

[Malignant mesothelioma: analysis of a hospital case series]. / Mesotelioma maligno: analisi di una casistica ospedaliera.

The 2000-2010 case record of our Institute includes 77 cases of malignant mesothelioma (MM) [67 pleural (40 males, 27 females; mean age 63.9 years), 9 peritoneal (7 males, 2 females; 67.9 years) and one testicular (38 year-old man)], often associated, with various degree of probability, to previous asbestos exposure (occupational or environmental). Twenty-four patients with pleural MM had undergone surgery (12 pleural decortication and 12 pneumonectomy), with median survival, respectively, of 14 +/- 4.33 (standard error) and 38 +/- 4.27 months, longer than that recorded without surgery (8 +/- 0.94 months). Four peritoneal cases underwent peritonectomy with hyperthermic intraoperative chemotherapy: one is still alive 20 months after diagnosis, the others died at 8, 18 and 36 months. The testicular case is still living 6 years after radical orchidectomy. In conclusion, due to past asbestos use, MM is often observed in the current clinical practice. Patients treated surgically present longer survivals.

Impact of the new european paediatric regulatory framework on ethics committees: overview and perspectives.

AIM: To evaluate the impact of the new European paediatric regulatory framework on the activities of Ethics Committees operating in Europe and to assess their involvement and interest in paediatric research. METHODS: Task-force in Europe for Drug Development for the Young Network of Excellence and Relating Expectations and Needs to the Participation and Empowerment of Children in Clinical Trials project set up an inventory of Ethics Committees existing in Europe and conducted a survey on their approach to paediatric trials. RESULTS: Ethics Committees operating in 22 European Countries participated in this survey. Results showed a high lack of knowledge, understanding and awareness of the current European paediatric regulatory framework and a lack of involvement of Ethics Committees in paediatric research, especially in terms of training and education, demonstrated also by the decreasing number of Ethics Committees answering exhaustively to the whole questionnaire. The majority of participating Ethics Committees expressed interest in future initiatives related to paediatric research. CONCLUSIONS: Despite a limited knowledge and understanding of the current paediatric regulatory framework, a significant number of Ethics Committees operating in Europe show interest in initiatives related to paediatric research. Networking may be an essential tool to be used to enhance Ethics Committees role in supporting paediatric research. Any initiative should be undertaken at European level in collaboration with European Union Institutions.

Efficacy and safety of leflunomide or methotrexate plus subcutaneous tumour necrosis factor-alpha blocking agents in rheumatoid arthritis.

Several smaller retrospective case series have concluded that leflunomide (LEF) in combination with anti-TNF-alpha blocking agents appears to be effective and safe. Prospective case series and cohort studies have generally confirmed the efficacy of this combination. Overall, there is currently no evidence from controlled trials that an anti-TNF-alpha combination with LEF is as effective as an anti-TNF-alpha combination with methotrexate (MTX). We compared the effectiveness and safety of a therapeutic regimen associating subcutaneous anti-TNF-alpha agents, etanercept (ETN) and adalimumab (ADA), with leflunomide (LEF) or methotrexate (MTX), in a two year open-label study performed in clinical practice. We evaluated 96 patients with active rheumatoid arthritis undergoing therapy with ADA at the dose of 40 mg every other week, or with ETN at the dose of 50 mg/week for two years added to prednisolone (PDN) at the mean dose of 5.2±2.6 mg/day. Fifty-four of these patients were also undergoing therapy with MTX at the mean dose of 11.7±2.6 mg/week, while 42 patients were undergoing therapy with LEF at the daily dose of 20 mg. At 12 months, the analysis of variance showed an improvement of DAS28 in both groups (p<0.001), with a reduction in 33.3% of the patients in treatment with LEF and in 51.8% of the patients in treatment with MTX (p = 0.20). At 18 months, improvement was present in 33.3% of the patients in the LEF group and in 81.5% of the patients in the MTX group (p=0.001). This improvement seems to be independent of the anti-TNF-alpha agent, even if MTX produces the highest DAS28 reduction when used in association with ETN (p<0.078). We found no difference in drug discontinuation rates or in effectiveness measures between anti-TNFalpha+MTX and anti-TNFalpha+LEF. Our data showed a greater reduction of DAS28 in the MTX group and, in combination with ETN, better results after two years of therapy.

In-label and off-label use of respiratory drugs in the Italian paediatric population.

AIM: To evaluate the prescription rate of respiratory drugs (ATC code R03) in an Italian community setting and to estimate the extent of off-label use by both age and indication. METHODS: A cohort study aimed at evaluating prescriptions of drugs with ATC code R03 was conducted for the period 2002-2006. Data source was the PEDIANET Database. RESULTS: Ninety percent of R03 prescriptions are covered by 11 active substances or combinations, corresponding to 67 medicinal products. Inhaled corticosteroids are the most prescribed anti-asthmatic agents, followed by short-acting beta2 mimetics. The mean off-label rate is 19 and 56%, by age and indication respectively. The majority of off-label uses is among children under the age of 2. Five active substances are used at dosages not supported by adequate dose-finding studies. CONCLUSION: In Italy, many respiratory drugs are approved for the treatment of paediatric respiratory diseases, but a remarkable percentage of their prescriptions is off-label. This pharmaco-utilization study demonstrates that there is a need to perform clinical studies aimed at increasing the current knowledge on marketed paediatric drugs, and to revise and re-label the existing regulatory documents to reduce their off-label uses.

Effects of monthly intramuscular neridronate in rheumatic patients in chronic treatment with low-dose glucocorticoids.

OBJECTIVES: To assess the effects of intramuscular (im) neridronate (NE) on lumbar and femoral neck BMD and on markers of bone turnover in rheumatic patients under chronic low-dose glucocorticoids (GC) therapy. METHODS: Sixty-nine osteopoenic and osteoporotic patients, affected by rheumatic diseases and gastric or esophageal conditions which contraindicated treatment with oral bisphosphonates (BPs), were randomly assigned to: Group A (23 patients) administered with daily calcium 1 g and vitamin D 800 UI; Group B (46 patients) receiving daily calcium 1 g, vitamin D 800 UI and im NE 25 mg monthly. RESULTS: After 12 months of therapy (M12) lumbar BMD was reduced of 2.97% in Group A, and improved of 3.34% (p=0.001) in Group B; at M12, femoral neck BMD was reduced of 2.40% in Group A and improved of 1.78% in Group B (p=0.010). After 6 (M6) and 12 months of therapy, the bone resorption markers were significantly reduced in Group B: OHPr-41.64% at M6 (p<0.001) and -37.91% at M12 (p<0.001); DPD-33.4% at M6 (p<0.001) and -33.18% (p<0.001) at M12: NTX -57.08% (p<0.001) at M6 and -55.95% (p<0.001) at M12; OC-11.62% (p=0.05) at M6 and -12.62% at M12 (p=0.06); B-ALP -13.95 % at M6 (p=0.04) and -0.85% at M12 (NS). CONCLUSION: A twelve-month intramuscular NE treatment in rheumatic patients under GCs therapy improves lumbar and femoral BMD and mainly reduces the markers of bone resorption.

Correlation between atopy and hypersensitivity reactions during therapy with three different TNF-alpha blocking agents in rheumatoid arthritis.

OBJECTIVE: The use of TNF-alpha antagon-ists (infliximab, etanercept, adalimumab) has changed the course of many rheumatic diseases including rheumatoid arthritis (RA). Since their approval, some questions regarding their safety have been raised. Both acute and delayed reactions have been described. METHODS: The aim of our work was to detect if there is a different incidence of hypersensitivity reactions - infusion reactions to infliximab or injection site reactions with etanercept or adalimumab - in atopic patients versus non- atopic patients. In 90 patients (82 females, 8 males) with rheumatoid arthritis we evaluated, during the first year of therapy with three different TNF-alpha blocking agents, total serum IgE (normal value <100 KU/L) (method ImmunoCAP PHADIA) and serum specific IgE performing a qualitative multi-allergen test for inhal-ant allergens (PHADIATOP, method ImmunoCAP PHADIA). In all patients we evaluated injection site reactions (ISR) to etanercept and adalimumab - erythema, edema and itching at the site of subcutaneous administration - and infusion reactions to infliximab - hypotension/hypertension, chest pain, dyspnea, laryngospasm, fever, urticaria angioedema. RESULTS: We obtained the following results: patients with high value of tot-al IgE were 15/90 (16.6 %), patients with total IgE in normal range were 75/90 (83.4.%), reactions in patients with high total IgE were 6.7% and in patients with normal total IgE were 18.7% (p=0.255 ns). As regards serum specific IgE, patients with specific IgE were 17/90 (18.8%) patients without specific IgE were 73/90 (81.2%), reactions in patients with specific IgE were 11.8% and in patients without specific IgE were 17.8% (p=0.547 ns). Also, when the data were divided for the three groups, the differences were not statistically significant. CONCLUSION: Adverse reactions to biological agents have been categorized into five types. In hypersensitivity reactions - the Beta type reactions - an immune mechanism is suspected. Our data showed that there was no correlation between the atopic status and the incidence of hypersensitivity reactions during the first year of therapy with three different TNF-alpha blocking agents.

Upper gastrointestinal symptoms in patients with advanced cancer: relationship to nutritional and performance status.

GOALS OF WORK: The goals of the study were to determine the relationship of upper gastrointestinal symptoms with nutritional status and to assess their association with performance status in patients with advanced cancer. MATERIALS AND METHODS: We studied 143 patients (50 F, 93 M, mean age 68 +/- 11 years, mean body mass index 22.39 +/- 4.3 kg/m(2)). Assessed symptoms were the following: anorexia, nausea, vomiting, dysphagia for solids, dysphagia for liquids, xerostomia, hypogeusia, dysgeusia, hiccup and chewing disturbances. We determined anthropometric parameters, daily energy intake and serum albumin, prealbumin and transferrin. MAIN RESULTS: The most common upper gastrointestinal symptoms were xerostomia (73%), anorexia (49%) and chewing disturbances (40%). Fifty-four percent of patients had weight loss greater than 10%. Seventy-three patients (51%) had daily energy intake lower than their resting energy expenditure. Mean serum prealbumin, albumin and transferrin were below normal range. Mean Eastern Cooperative Oncology Group performance status scale was 3.1 +/- 0.49. Symptoms were often strongly correlated, and usually, patients experienced at least three upper gastrointestinal symptoms at the same time. Anorexia, nausea and vomiting were the symptoms mostly correlated with other symptoms. A correlation was found between vomiting and hiccup. Energy intake (EI) was the nutritional parameter mostly affected by upper gastrointestinal symptoms; moreover, EI is the most predictive factor of upper gastrointestinal symptoms, particularly xerostomia, anorexia and dysphagia for solids. CONCLUSIONS: Upper gastrointestinal symptoms are linked to nutritional parameters: In particular, energy intake represents the most predictive variable of symptom occurrence. The performance status is not affected by upper gastrointestinal symptoms. A rigorous nutritional assessment and the managing of upper gastrointestinal symptoms are crucial in patients with advanced cancer.

The economic burden of biological therapy in rheumatoid arthritis in clinical practice: cost-effectiveness analysis of sub-cutaneous anti-TNFalpha treatment in Italian patients.

Rheumatoid arthritis (RA), with a prevalence of 0.46%, is found in about 272,004 patients in Italy. The socioeconomic cost of rheumatoid arthritis in Italy in 2002 has been estimated at Euro 1,600 million. Cost-effectiveness evaluations have been based on the concept that, with treatment, patients will not progress to the next level(s) of disease severity or will take a longer time to progress, thus avoiding or delaying the high costs and low utility associated with more severe disease. Many cost-effective studies have been based on the variation of Health Assessment Questionnaire (HAQ) in clinical trials. The objective of this study is to perform a cost-effective analysis of 86 patients with rheumatoid arthritis in therapy with adalimumab 40 mg every other week and etanercept 50 mg/week for two years in a population of patients observed in clinical practice. The group of patients in therapy with adalimumab had also taken methotrexate, mean dose 12.4+/-2.5 mg/week (22 patients) or leflunomide 20 mg/day (16 patients). The group of patients in therapy with etanercept had also taken methotrexate, mean dose 11.7+/-2.6 mg/week (24 patients) or leflunomide 20 mg/day (24 patients). Incremental costs and QALYs (quality adjusted life years) gains are calculated compared with baseline, assuming that without biologic treatment patients would remain at the baseline level through the year. Conversion HAQ scores to utility were based on the Bansback algorithm. The results after two years showed: in the group methotrexate+adalimumab the QALY gained was 0.62+/-0.15 with a treatment cost of Euro 26,517.62 and a QALY/cost of Euro 42,521.13. In the group methotrexate + etanercept the QALY gained was 0.64+/-0.26 with a treatment cost of Euro 25,020.96 and a QALY/cost of Euro 39,171.76. The result of using etanercept in association with methotrexate is cost-effectiveness with a QALY gained under the acceptable threshold of Euro 50,000. These are important data for discussion from an economic point of view when we choose a biologic therapy for rheumatoid arthritis in clinical practice.

Multicenter randomised trial on home-based telemanagement to prevent hospital readmission of patients with chronic heart failure.

BACKGROUND: Chronic heart failure (CHF) remains a common cause of disability, death and hospital admission. Several investigations support the usefulness of programs of disease management for improving clinical outcomes. However, the effect of home-based telemanagement programs on the rate of hospital readmission is still unclear and the cost-effectiveness ratio of such programs is unknown. The aim of the study was to determine whether a home-based telemanagement (HBT) programme in CHF patients decreased hospital readmissions and hospital costs in comparison with the usual care (UC) follow-up programme over a one-year period. METHODS AND RESULTS: Four hundred-sixty CHF patients (pts), aged 57+/-10 years were randomised to two management strategies: 230 pts to HBT programme and 230 pts to UC programme. The HBT pts received a portable device, transferring, by telephone, a one-lead trace to a receiving station where a nurse was available for interactive teleconsultation. The UC pts were referred to their primary care physicians and cardiologists. The primary objective of the study was one-year hospital readmission for cardiovascular reasons. During one-year follow-up 55 pts (24%) in HBT group and 83 pts (36%) in UC group had at least one readmission (RR=0.56; 95% CI: 0.38-0.82; p=0.01). After adjusting for clinical and demographic characteristics, the HBT group had a significantly lower risk of readmission compared with the UC group (HR=0.50, 95% CI: 0.34-0.73; p=0.01). The intervention was associated with a 36% decrease in the total number of hospital readmissions (HBT group: 91 readmissions; UC group: 142 readmissions) and a 31% decrease in the total number of episodes of hemodynamic instability (101 in HBT group vs 147 in UC group). The rate of hearth failure-related readmission was 19% (43 pts) in HBT group and 32% (73 pts) in UC group (RR=0.49, 95% [CI]: 0.31-0.76; p=0.0001). No significant difference was found on cardiovascular mortality between groups. Mean cost for hospital readmission was significantly lower in HBT group (euro 843+/-1733) than in UC group (euro 1298+/-2322), (-35%, p<0.01). CONCLUSIONS: This study suggests that one-year HBT programme reduce hospital readmissions and costs in CHF patients.

Bronchoalveolar lavage, sputum and exhaled clinically relevant inflammatory markers: values in healthy adults.

Bronchoalveolar lavage (BAL), induced sputum and exhaled breath markers (exhaled nitric oxide and exhaled breath condensate) can each provide biological insights into the pathogenesis of respiratory disorders. Some of their biomarkers are also employed in the clinical management of patients with various respiratory diseases. In the clinical context, however, defining normal values and cut-off points is crucial. The aim of the present review is to investigate to what extent the issue of defining normal values in healthy adults has been pursued for the biomarkers with clinical value. The current authors reviewed data from literature that specifically addressed the issue of normal values from healthy adults for the four methodologies. Most studies have been performed for BAL (n = 9), sputum (n = 3) and nitric oxide (n = 3). There are no published studies for breath condensate, none of whose markers yet has clinical value. In healthy adult nonsmokers the cut-off points (mean+2sd) for biomarkers with clinical value were as follows. BAL: 16.7% lymphocytes, 2.3% neutrophils and 1.9% eosinophils; sputum: 7.7 x 10(6).mL(-1) total cell count and 2.2% eosinophils; nitric oxide: 20.2 ppb. The methodologies differ concerning the quantity and characteristics of available reference data. Studies focusing on obtaining reference values from healthy individuals are still required, more evidently for the new, noninvasive methodologies.

Efficacy of pulmonary rehabilitation in chronic respiratory failure (CRF) due to chronic obstructive pulmonary disease (COPD): The Maugeri Study.

UNLABELLED: While the effectiveness of pulmonary rehabilitation (PR) in chronic obstructive pulmonary disease (COPD) is well established, its effectiveness in the most severe category of COPD, i.e. patients with chronic respiratory failure (CRF), is less well known. OBJECTIVE: To verify the effects of PR in patients with CRF, and compare the level of improvement with PR in these patients to that of COPDs not affected by CRF. METHODS: A multi-centre study was carried out on COPD patients with versus without CRF. The PR program included educational support, exercise training, and nutritional and psychological counselling. Lung function, arterial gases, walk test (6MWT), dyspnoea (MRC; BDI/TDI), and quality of life (MRF(28); SGRQ) were evaluated. RESULTS: Thousand forty seven consecutive COPD inpatients (327 with CRF) were evaluated. In patients with CRF all parameters improved after PR (0.001). Mean changes: FEV(1), 112 ml; PaO(2), 3.0 mmHg; PaCO(2), 3.3 mmHg; 6MWT, 48 m; MRC, 0.85 units; MRF(28) total score, 11.5 units. These changes were similar to those observed in patients without CRF. CONCLUSIONS: This study, featuring the largest cohort so far reported in the literature, shows that PR is equally effective in the more severe COPD patients, i.e. those with CRF, and supports the prescription of PR also in these patients.

Medicines for children licensed by the European Medicines Agency (EMEA): the balance after 10 years.

OBJECTIVE: The 1995-2005 balance of EMEA activities in the field of paediatric medicines was evaluated, taking into account the number both of drugs authorised for children and paediatric studies supporting the Marketing Authorisation (MA). METHODS: Data on drugs authorised by EMEA were extracted from EPARs (European Public Assessment Reports). Active substance, year of approval, anatomical, therapeutic and chemical (ATC) code, indication, orphan status, ages, and registrative clinical studies characteristics were assessed. RESULTS: The percentage of authorised substances for paediatrics is 33.3%. This percentage decreased or increased when different subsets of medicines were considered [medicines for children under 2 years (23.4%), N-ATC code drugs (6%) and orphan drugs (46.4%)]. A total of 165 trials were included in the MA dossiers of 51 drugs at the time of approval, and additional 22 studies were added to the dossiers of 12 active substances submitted for paediatric variations. PK and Efficacy/Safety studies were performed for 32 (52%) active substances, while either one PK or one Efficacy/Safety study was carried out for 43 (69%) and 45 (73%) substances, respectively. CONCLUSIONS: This report demonstrates that the total number of paediatric medicines approved by EMEA is stable over the 10-year period, while an increase in drugs to treat serious or orphan diseases has been observed. In addition, under the Centralised Procedure, a valuable number of paediatric trials have been submitted to support drug approval.

[A group therapy assessment tool (GrETha-Q)]. / Uno strumento per la valutazione dell'attività terapeutica di gruppo (GrEThA-Q).

This paper presents a questionnaire designed to assess the aspecific treatment efficacy and subjective perceived efficacy of group therapy. A preliminary version of the instrument was administered to a sample of 151 subjects undergoing group therapy. The psychometric properties of the instrument were evaluated by means of the Rasch model, and showed a good score range, good reproducibility and adequate coherence. The hierarchy of difficulty of the items remained stable among the respective categories of sex, age and professional level.

Role of galanin receptor 1 in peristaltic activity in the guinea pig ileum.

Galanin effects are mediated by distinct receptors, galanin receptor 1 (GAL-R1), GAL-R2 and GAL-R3. Here, we analyzed 1) the role of GAL-R1 in cholinergic transmission and peristalsis in the guinea-pig ileum using longitudinal muscle-myenteric plexus preparations and intact segments of the ileum in organ bath, and 2) the distribution of GAL-R1 immunoreactivity in the myenteric plexus with immunohistochemistry and confocal microscopy. Galanin inhibited electrically stimulated contractions of longitudinal muscle-myenteric plexus preparations with a biphasic curve. Desensitization with 1 microM galanin suppressed the high potency phase of the curve, whereas the GAL-R1 antagonist, RWJ-57408 (1 microM), inhibited the low potency phase. Galanin (3 microM) reduced the longitudinal muscle contraction and the peak pressure, and decreased the compliance of the circular muscle. All these effects were antagonized by RWJ-57408 (1 or 10 microM). RWJ-57408 (10 microM) per se did not affect peristalsis parameters in normal conditions, nor when peristalsis efficiency was reduced by partial nicotinic transmission blockade with hexamethonium. In the myenteric plexus, GAL-R1 immunoreactivity was localized to neurons and to fibers projecting within the plexus and to the muscle. GAL-R1 was expressed mostly by cholinergic neurons and by some neurons containing vasoactive intestinal polypeptide or nitric oxide synthase. This study indicates that galanin inhibits cholinergic transmission to the longitudinal muscle via two separate receptors; GAL-R1 mediates the low potency phase. The reduced peristalsis efficiency could be explained by inhibition of the cholinergic drive, whereas the decreased compliance is probably due to inhibition of descending neurons and/or to the activation of an excitatory muscular receptor. Endogenous galanin does not appear to affect neuronal pathways subserving peristalsis in physiologic conditions via GAL-R1.