Mario Negri Institute

Bergamo, Italy

Mario Negri Institute

Bergamo, Italy

The Mario Negri Institute for Pharmacological Research is a nonprofit research institute dedicated to clinical and biomedical research. It was made possible by a special bequest of Milan philanthropist it:Mario Negri . It was founded in 1961 although it started working in Milan from 1st Feb 1963. There are branches of the institute in Bergamo, Ranica , and at Santa Maria Imbaro, near Chieti.Founder and director from 1961 is prof. it:Silvio Garattini. Wikipedia.

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News Article | April 26, 2017

Amsterdam, The Netherlands, April 26, 2017 - The use of animals in biomedical research has long been the focus of campaigns by animal rights activists. Two leading scientists writing in the European Journal of Internal Medicine give their expert view of the importance of animal testing to medical progress and present ways it could be further improved to yield more useful clinical results. "It cannot be stressed enough that animal studies have led to the production of drugs that have affected the epidemiology of human pathology, contributing to prolonging life. There is no magic formula at present to predict - at the preclinical level - the therapeutic value of a drug for people with a disease. Preclinical studies are needed in order to formulate hypotheses that justify clinical trials. Without these preliminary in vitro and in vivo studies in selected animal species, it would be unethical to test still unproven chemicals in humans," explains Silvio Garattini, MD, Founder and Director of the Mario Negri Institute for Pharmacological Research, Milan, Italy. His co-author, Giuliano Grignaschi, PhD, head of the Animal Care Unit at the Mario Negri Institute and vice president of the Basel Declaration Society in Switzerland, which promotes information about animal testing, adds that "the pressure of public opinion, particularly of organized groups of 'animalists,' obliges preclinical and clinical scientists to come out of their 'ivory tower' to explain the complexity of translating research results from animals to man." Vaccines against poliomyelitis, meningitis, and rotaviruses are excellent examples in which animal testing, and the translation from animals to man, have proved effective, as are a number of antibiotics and the recent agents against HIV and hepatitis C viruses. However, the authors acknowledge that at the other extreme, there have been poor correlations between results in animals and man in several diseases such as stroke, amyotrophic lateral sclerosis (ALS), and Alzheimer's disease, and they summarize several analyses that have set out to understand why results in animals and man differ in these cases. The authors present four ways in which animal experiments could be improved in order to increase their probability of predicting useful clinical results. First, studies need to be intensified and techniques developed to improve and reduce the use of animals following the 3R rule (Replace, Reduce, and Refine). These guiding principles underpin the humane use of animals in scientific research and any researcher planning to use animals in their research must first show why there is no alternative and what will be done to minimize numbers and suffering, Second, rules developed to improve clinical trials should be incorporated into animal testing to minimize bias. Third, research is needed to improve the translation of animal research to patients, they argue, pointing out that the National Institutes of Health (NIH) in the U.S. has recently launched a program to train preclinical scientists to plan their experimental trials better by applying the same rules as for clinical trials. "There is, however, a pressing need for responsibility in the scientific community, not only among scientists, but also in the editorial boards of journals and funding bodies to focus more on the quality of articles and research proposals dealing with animal investigation," they note. Fourth, once bias has been taken care of, difficulties remain for each specific demand for therapy - symptomatic, preventive, or curative - of finding the animal species that best mimics the human condition. Animals with specific pathology such as diabetes, high cholesterol, and hypertension have helped scientists develop antidiabetic, hypocholesterolemic, and antihypertensive drugs, which have been effective in man and are widely used. More studies are needed in aged animals to mimic the condition of elderly people with co-morbidities that require several drugs. Different chemical mediators may be important tools for discovering new drugs once they have been found to exert similar effects in a given animal species and man. "Limitations to the use of animals, particularly other than rodents, are an obstacle to obtaining a wider spectrum of activity across species which may help in deciding when a treatment is suitable for patients," says Dr Grignaschi. "Nevertheless, there is room for substantial improvement in the protocols of animal tests to boost their credibility and reproducibility. "For the time being, animal models remain the best alternative given the limited usefulness of computer and in vitro models, and their use must continue, considering that patients cannot just wait for better tests to cure their suffering," concludes Prof. Garattini.

Esperite's (Euronext: ESP) biotech subsidiary The Cell Factory develops extracellular vesicles (EVs) biologic drug (CF-MEV-117) for treatment of drug-resistant epilepsy in children. The consortium sponsored by The Cell Factory have achieved an important milestone in the CF-MEV-117 drug development confirming an anti-inflammatory and immunosuppressive activity of the CF-MEV-117 in a dose response manner. Full results will be presented during the International Society for Extracellular Vesicles (ISEV) meeting in Toronto, Canada from 18-21 May, 2017. The Cell Factory, a company of Esperite Group in collaboration with Bambino Gesù Children's Hospital in Rome, Mario Negri Institute for Pharmacological Research in Milan and Women's and Children's Health Department of the University of Padua are developing the EVs drug candidate (CF-MEV-117) for treatment of drug resistant epilepsy in children. The consortium is investigating the immunomodulatory properties of EVs derived from MSCs in several in vitro and in vivo models. It has been demonstrated by independent research groups that inhibitory effects of MSCs on human leukocytes was mediated by secreted EVs. Subsequently, it was demonstrated by our partners that MSC-derived EVs were responsible for inhibition of B-cell proliferation and differentiation and activation of T-cell apoptosis (Budoni et al., 2013; Del Fattore et al., 2015). These results have been recently confirmed with the CF-MEV-117 drug candidate manufactured by The Cell Factory. Preclinical and clinical study demonstrate that brain inflammation could be responsible for severe epileptic seizures. Pro-inflammatory molecules secreted by the stimulated glial cells are responsible for a status epilepticus. Therefore, immunomodulatory and anti-inflammatory treatment focused on astrocytes and microglia cells are reducing or eliminating symptoms of epilepsy and can prevent a relapse of the disease in the future. The project is investigating anti-inflammatory and anti-epileptic effect of the CF-MEV-117 drug candidate in both an acute phase of epilepsy and preventing development of a chronic disease. In addition, we expect that CF-MEV-117 will demonstrate much broader therapeutic effect in neurology influencing neural cells apoptosis, neurons hyperexcitability, and neurogenesis process leading to faster brain regeneration. This will allow using the MSC-derived EVs in treatment of unmet medical needs e.g. stroke, TBI, spinal cord injury. EVs stability and small size are the key advantages allowing their immediate use in acute injuries and the drug penetration through the blood brain barrier. CF-MEV-117 is produced using a proprietary technology developed by The Cell Factory for a large-scale production of ultra-pure EVs, using fully defined, serum-free, xeno-free culture media with no use of animal-derived components and human platelet lysates at any stage of the production process. Production is performed in a closed and scalable stirring bioreactors including a downstream processing based on the integrated sequential filtration system. EVs are continuously secreting by expanded MSCs allowing multiple harvests during one production cycle. This approach significantly reduces the contamination risk, production time, staff, GMP labs use and the cost of goods. Effectively the production of the single EVs dose is now up to 10 times cheaper when comparing to the allogenic MSCs dose equivalent. CF-MEV-117 product is sterilised by filtration during production process what is not possible for any cell therapy products (ATMPs). CF-MEV-117 product has very high batch-to-batch reproducibility. Product analysis is performed using broad range of state-of-the-art techniques i.e. NTA, immunophenotyping, proteomics, among others. Several surface markers have been analysed for CF-MEV-117 product including the tetraspanin transmembrane proteins characteristic for EVs (CD9+, CD63+ and CD81+). Interestingly, CF-MEV-117 EVs do not express HLA-ABC and HLA-DRPQ what increases the drug's safety in human use. The consortium is fully focused on demonstration of the CF-MEV-117 product's anti-inflammatory and immunosuppressive activity and its mode of action. For that purpose T-cells and B-cells have been isolated from human peripheral blood and the cells were stimulated using anti-CD3/CD28 and CpG, respectively. CF-MEV-117 product has increased the activated T reg proliferation and effectively the T reg / T eff ration. In addition, reduction of the activated B cells proliferation and plasma cell differentiation have been observed in response to CF-MEV-117. This confirms previous results obtained using the research-grade EVs. It is worth stressing that the experiments were performed in parallel with the MSCs used for the CF-MEV-117 production. The results have confirmed the same anti-inflammatory effect of the MSCs and the MSC-derived EVs (CF-MEV-117) on stimulated human leukocytes. The CF-MEV-117 drug's effect was observed in a dose responsive manner. The next step is confirmation of the CF-MEV-117 in in vivo models before the clinical translation. EVs including exosomes are nanometre-size, natural biological particles secreted by different types of cells in vivo and in vitro. They contain proteins, growth factors, mRNA and other molecules responsible for the therapeutic effect of MSCs. In addition, EVs have several advantages over allogenic MSCs e.g.: up to 10-times lower production costs, no risk of uncontrolled proliferation and differentiation, lower risk of immune response and easy and safe delivery into different tissues and organs in vivo. High stability allows for easy transport and storage of the "ready-to-use" products. The Cell Factory is developing MSC-EVs drug candidate (CF-MEV-117) for treatment of untreatable-yet acute and chronic drug-resistant epilepsy. Epilepsy carries significant detrimental effects on the quality of life and can lead to a secondary brain damage. The disease can have different etiology, including stroke, brain trauma, and neuro-inflammation. Epilepsy is one of the most common brain diseases affecting about 1 in 100 children under 17-year old according to CDC. Severity of the seizures is variable and the antiepileptic drugs are effective only in about 2/3 of the patients. CDC estimated annual costs related to epilepsy exceeds 15 billion USD in the United States alone. It is expected that EVs products will be effective in treatment of other neuroinflammatory-related injuries of central nervous system. Moreover, EVs will be able to target an acute diseases i.e. TBI, brain stroke, spinal cord injury, more effectively when comparing to allogenic MSCs, due to the EV's stability and easier administration at shorter time what is critical for successful therapy. Diseases of central nervous system are among most devastating for patients and their relatives. Neurological disorders are generating a significant additional cost related to hospitalisation, rehabilitation, often eliminate the patients and their relatives from a job market. CDC estimated that annual costs related to epilepsy exceeds 15 billion USD in the United States alone with 50 million patients worldwide (WHO). Cost related to brain stroke in the United States is estimated to 34 billion USD per year (CDA), with 15 million new patients worldwide each year (WHO). Cumulative cost related to traumatic brain injury (TBI) and spinal cost injury in the United States is over 80 billion USD per year (CDA and AANS), with up to 0.5 million new incidents of spinal cord injury and 10 million of TBI per year (WHO). Most of these diseases have no effective therapy yet. The consortium led by Esperite's The Cell Factory is gathering the leading teams in paediatric regenerative medicine, neurology, gastroenterology, immunology and EVs science. The CF-MEV-107 product is developing in collaboration with Professor Maurizio Muraca's team at the Department of Women's and Children's Health at the University of Padova in Italy. The CF-MEV-117 product is developing in collaboration with Professor Federico Vigevano and Dr Alessandra Fierabracci team at Bambino Gesù Children's Hospital in Rome, Italy and with Dr. Annamaria Vezzani at Mario Negri Institute in Milan, Italy. Frederic Amar, CEO: "The Cell Factory is focused on development, clinical translation and commercialization of the advanced extracellular vesicles (EVs) biologic drugs and autologous stem cell therapies. The Cell Factory goal is to master the development and production of extracellular vesicles drugs in treatment of different indications." ESPERITE Group, listed at Euronext Amsterdam and Paris, is a leading international company in regenerative and predictive medicine established in 2000. The Cell Factory is a biotech company, a subsidy of the Esperite group, developing highest quality therapeutic tools for affordable regenerative medicine. The Cell Factory led by Dr. Marcin Jurga is focused on development, clinical translation and commercialization of the advanced extracellular vesicles (EVs) biologic drugs and autologous stem cell therapies. The Cell Factory goal is to become a leader in development and production of extracellular vesicles drugs in treatment of different indications i.e. graft versus host disease (GvHD) after solid organ and cell transplantations, arthritis, multiple sclerosis, cystic fibrosis, stroke, traumatic brain and spinal cord injury, newborn encephalopathy, and type 1 diabetes among others. The Cell Factory focuses on development of the selected EVs drug candidates from a TRL 4 (non-GLP POC) until TRL 6-7 (Clinical phase II). The Cell Factory is looking for partners and investors who are interested in a rapidly growing, disruptive technology of EVs biological drugs. We are looking for different collaboration models including out-licencing, technology transfer and joint venture product development and dilutive investments. The Cell Factory owns the full rights of a broad international patent family enabling MSC-derived extracellular vesicles (EVs) use in treatment of autoimmune, chronic and acute inflammatory diseases. The patents have been already granted in Europe and recently in China. The Cell Factory is developing the EVs biologic drug products for multiple indications in immunology, neurology and gastroenterology. The leading products are CF-MEV-107 for treatment of Crohn's disease (drug resistant perianal fistulae) and CF-MEV-117 for treatment of drug resistant epilepsy in children. The CF-MEV-107 product is ready for clinical translation and the consortium of leading academic and clinical teams sponsored by The Cell Factory is preparing the CF-MEV-107 product for first in man clinical translation in 2017. To learn more about ESPERITE Group, or to book an interview with CEO Frederic Amar: +31 575 548 998 - or visit the websites at,, and

News Article | May 15, 2017

New research from the University of Liverpool, in collaboration with the Mario Negri Institute in Milan, published today in the Journal of Clinical Investigation, has identified a protein that could help patients with epilepsy respond more positively to drug therapies. Epilepsy continues to be a serious health problem and is the most common serious neurological disease. Despite 30 years of drug development, approximately 30% of people with epilepsy do not become free of fits (also called seizures) with currently available drugs. New, more effective drugs are therefore required for these individuals. We do not fully understand why some people develop seizures, why some go onto develop epilepsy (continuing seizures), and most importantly, why some patients cannot be controlled with current drugs. There is now increasing body of evidence suggesting that local inflammation in the brain may be important in preventing control of seizures. Inflammation refers to the process by which the body reacts to insults such as having a fit. In most cases, the inflammation settles down, but in a small number of patients, the inflammation continues. The aim of the research, undertaken by Dr Lauren Walker while she was a Medical Research Council (MRC) Clinical Training Fellow, was to address the important question of how can inflammation be detected by using blood samples, and whether this may provide us with new ways of treating patients in the future to reduce the inflammation and therefore improve seizure control. The research focused on a protein called high mobility group box-1 (HMGB1), which exists in different forms in tissues and bloodstream (called isoforms), as it can provide a marker to gauge the level of inflammation present. The results showed that there was a persistent increase in these isoforms in patients with newly-diagnosed epilepsy who had continuing seizure activity, despite anti-epileptic drug therapy, but not in those where the fits were controlled. An accompanying drug study also found that HMGB1 isoforms may predict how an epilepsy patient's seizures will respond to anti-inflammatory drugs. Dr Lauren Walker, said: "Our data suggest that HMGB1 isoforms represent potential new drug targets, which could also identify which patients will respond to anti-inflammatory therapies. This will require evaluation in larger-scale prospective trials." Professor Sir Munir Pirmohamed, Director of the MRC Centre for Drug Safety Science and Programme lead for the MRC Clinical Pharmacology scheme, said: "The MRC Clinical Pharmacology scheme is a highly successful scheme to train "high flyers" who are likely to become future leaders in academia and industry. "Dr Walker's research is testament to this and shows how this innovative scheme, which was jointly funded by the MRC and Industry, can tackle areas of unmet clinical need, and identify new ways of treating patients with epilepsy using a personalised medicine approach". The full paper, entitled 'Molecular isoforms of HMGB1 are novel mechanistic biomarkers for epilepsy', can be found on the journal website

Scarfone G.,Gynecology and Neonatology | Bergamini A.,University of Milan | Noli S.,Gynecology and Neonatology | Villa A.,Gynecology and Neonatology | And 6 more authors.
Gynecologic Oncology | Year: 2014

Objective Endometrioid and clear cell ovarian tumors have been referred to as "endometriosis associated ovarian cancers". However, very few studies have compared clinical and prognostic features of endometriosis- associated cancers or cancers not associated with endometriosis according to specific histotypes. We have investigated clinical and histological features of the largest published series of clear cell ovarian cancers arising in endometriosis using a retrospective database. Methods Seventy three patients with a primary diagnosis of either pure clear cell ovarian cancer and mixed endometrioid-clear cell ovarian cancer have been divided into two groups according to the detection of cancer strictly arising from ovarian endometriosis or not (n = 27 and n = 46, respectively). Clinical and pathological data have been compared. Results Patients with clear cell carcinomas arising from endometriosis tend to be significantly younger (51.4 ± 10.0 and 58.4 ± 11.2 years, p = 0.02). FIGO stage, laterality, prevalence of pure versus mixed histology, and presence of synchronous endometrial carcinoma were not significantly different between the two groups. Unilateral ovarian involvement was more frequent in cases arising in endometriosis (85% vs 63%, p = 0.04). Ascites was not found in any of the endometriosis-associated cancer cases vs 19.5% in patients without endometriosis. The presence of endometriosis did not affect 5-year overall survival rates. Conclusions Endometriosis per se does not appear to be associated with a lower stage tumor or to predict prognosis in ovarian clear cell cancers. Unilateral involvement and reduced presence of ascites may be linked to the cystic nature of endometriosis which frequently presents as monolateral and in which associated tumors are more likely to be longer confined to the ovary before spreading. © 2014 Elsevier Inc.

Bianchi M.,Mario Negri Institute | Clavenna A.,Mario Negri Institute | Bonati M.,Mario Negri Institute
European Journal of Clinical Pharmacology | Year: 2010

Objective: The objective of this study was to analyse inter-and intra-country quantitative and qualitative differences in anti-asthmatic prescriptions to children and adolescents. Methods: A literature search was performed in EMBASE and MEDLINE to identify pharmaco-epidemiological studies published from January 1, 2000 to December 31, 2008 in which anti-asthmatic prescription prevalence in out-hospital children was measured. A meta-analytic weighted average and 95% confidence intervals of prescription prevalences were calculated using a random-effect(s) model. Inter- and intra-country quantitative and, where possible, qualitative prescribing patterns were compared and assessed. Results: Twelve studies were identified (ten from Europe, one from Canada and one from the USA), but epidemiological indicators varied widely, and only eight were suitable for meta-analysis. The data from these studies revealed inter-country quantitative differences in prescription prevalences in the overall population ≤19 years, with Italy having a prescription prevalence of 19.0%, Canada, 18.0%, USA, 14.6%, Denmark, 13.9%, Norway, 9.1% and the Netherlands, 6.2%. The overall prevalence was 13.3%. The analysis of qualitative inter-country differences revealed that, except for Italy, inhalatory short-acting β-agonists were the most prescribed, followed by inhalatory corticosteroids. Conclusions: This first overall analysis of anti-asthmatic utilization studies in out-of-hospital children indicates a wide variability in anti-asthmatic prescription prevalence. It also reveals that epidemiological evaluations should be improved by using homogeneous indicators and, in order to validate the use of anti-asthmatic prescription as a proxy of disease, the diagnosis of asthma should accompany the data of prescriptions within the same population. © 2010 Springer-Verlag.

Erba G.,University of Rochester | Giussani G.,Mario Negri Institute | Juersivich A.,University of Rochester | Magaudda A.,Messina University | And 6 more authors.
Epilepsia | Year: 2016

Objective To investigate if, when, and to what extent visual information contained in a video-recorded event allows experienced epileptologists to predict the diagnosis of psychogenic nonepileptic seizures (PNES) without the aid of electroencephalography (EEG). Methods Five neurologists actively practicing in epilepsy centers in Italy and the United States were asked to review 23 videos capturing representative events of 21 unselected consecutive patients admitted for long-term video-EEG monitoring (VEM). Four raters were blind to EEG and clinical information; one rater was not. They were requested to (1) rate the videos for quality and content; (2) choose among four diagnoses: (a) epileptic seizures (ES); (b) PNES; (c) Other nonepileptic seizures (NES; (syncope, movement disorder, migraine, etc.); (d) "Cannot Say"; and (3) explain in their own words the main reasons leading to the diagnosis of choice. Results All raters predicted the diagnosis correctly in 7 of 23 videos (all ES or PNES) (30.4%), whereas all raters failed in 5 of 23 cases (three Other NES, one PNES, one Cannot Say) (21.7%). The conditions that facilitate, and those that interfere with, a confident diagnosis were predictable. Degree of accuracy among raters was not uniform and was consistently better in three raters. Two among the four blind raters were as accurate as the rater who was not blinded. Interrater agreement was "moderate" (k = 0.52) for the overall group; "moderate" for ES (k = 0.53); "substantial" for PNES (k = 0.63); "fair" for Other NES (k = 0.21) - similar to the results obtained in a previous study evaluating the reliability of combined video-EEG. Significance In about one third of cases, a confident diagnosis of PNES/ES can be established on clinical grounds based on video data alone. Our results benefit all affected patients, particularly those with no access to video-EEG monitoring units. © 2016 International League Against Epilepsy.

Ricci E.,University of Milan | Cipriani S.,University of Milan | Chiaffarino F.,University of Milan | Malvezzi M.,Mario Negri Institute | Parazzini F.,University of Milan
Journal of Women's Health | Year: 2010

Background: Several randomized controlled trials (RCTs) have compared the effect of phytoestrogens (PEs) vs. placebos on bone density after menopause, with inconsistent results. Methods: We performed a systematic review to assess the overall effect of PEs on bone mineral density (BMD) in menopausal Western women. We searched for all RCTs comparing PEs with placebos conducted on perimenopausal or postmenopausal Western women, published from January 1990 to February 2010. The main outcome measure was the lumbar spine (LS) BMD. Results: We identified 17 studies on soy isoflavone (IFs) bone-sparing effects. Some studies did not report a difference between treated and untreated women, whereas others supported a significant role of IFs on slowing bone loss, although these studies suffered from an internal lack of consistency, as a positive effect emerged in some bone districts but not in others. Data on LS BMD were available in 12 studies including 1433 subjects overall. The effect of PEs on BMD (mg/cm2) was not statistically significant (mean difference 9.86?mg/cm2, 95% confidence interval [CI] -2.64-22.36) under a random-effects model. Excluding the genistein study, however, analyses of IF mixtures did not show a bone-sparing effect (0.73, 95% CI -2.79-4.25). No increasing effect emerged when dose and treatment duration were increased. Conclusions: Our review and meta-analysis suggest that IF mixtures are not effective in decreasing bone loss in perimenopausal and postmenopausal Western women. The role of isolated genistein and individual genetic capacity to metabolize IFs is still open to evaluation. © 2010, Mary Ann Liebert, Inc.

Bianchi M.,Mario Negri Institute | Clavenna A.,Mario Negri Institute | Sequi M.,Mario Negri Institute | Bortolotti A.,Regional Health Ministry | And 3 more authors.
Respiratory Medicine | Year: 2012

Aim: To estimate how many asthmatic children underwent spirometry testing in one year in a large Italian region, and evaluate sociodemographic determinants. Methods: Data were retrieved from the administrative databases that store all pharmacological and diagnostic prescriptions issued to individuals living in the Lombardy Region. The analysis involved prescriptions dispensed to all 6-17 year olds (1,047,241 subjects) during 2008. Youths were identified as asthmatics by a previously validated strategy. Number of subjects having ≥1 spirometry claims was calculated, and factors associated with the probability of undergoing spirometry were evaluated by multivariate analysis. Results: A total of 40,528 (3.9%) asthmatic subjects were identified. Only 30% of them underwent ≥1 spirometry during 2008, with differences between local health units (range 22-45%) and degree of anti-asthmatic use (26-35%). Moreover, in a multivariate analysis, the chance of undergoing spirometry was greater in boys than in girls (OR = 2.3). Conclusions: A low percentage of asthmatic children, especially girls (who are more at risk of developing severe disease in adulthood), underwent spirometry during 1-year period. This highlights a low compliance with guidelines in the monitoring of childhood asthma. Educational intervention is needed in order to encourage use of spirometry in primary care settings. © 2012 Elsevier Ltd. All rights reserved.

Kaguelidou F.,APHP | Pandolfini C.,Mario Negri Institute | Manzoni P.,Neonatology and Hospital Neonatal Intensive Care Unit | Choonara I.,University of Nottingham | And 2 more authors.
European Journal of Pediatrics | Year: 2012

Neonatal fungal infections are associated with substantial mortality and morbidity. Although prophylactic use of several antifungals has been proposed, this practice remains controversial. In order to evaluate the use of fluconazole prophylaxis in European NICUs, we conducted a cross-sectional survey by means of a structured questionnaire that was sent to European level II and III neonatal intensive care units, over a 9-month period, as part of a neonatal research FP7 European project. A total of 193 questionnaires from 28 countries were analysed. Use of antifungal prophylaxis was reported by 55% of the responders, and the most frequently used antifungal agent was fluconazole (92%). Main indications for prophylaxis were low gestational age (<28 weeks) and birth weight (<1,000 g). A dose of 3 mg/kg was used in 66% of NICUs using fluconazole, with an administration interval of 72 h in 52% of them. All responders acknowledged the need for additional trials on the efficacy of prophylactic fluconazole. Non-users of fluconazole prophylaxis were more likely to be influenced by the local incidence of candidiasis, the risk of increasing antifungal resistance and the absence of specific recommendations by paediatric societies. Conclusions: Major concerns about the use of fluconazole prophylaxis include its efficacy, the risk of emergence of resistant species and the absence of clear consensus to support routine use. Future studies that address these issues will contribute to a more rational use of fluconazole prophylaxis. © Springer-Verlag 2011.

Didoni A.,Mario Negri Institute | Sequi M.,Mario Negri Institute | Panei P.,National Health Research Institute | Bonati M.,Mario Negri Institute
European Journal of Clinical Pharmacology | Year: 2011

Objectives: To delineate the safety and tolerability profile of methylphenidate and atomoxetine in children and adolescents with attention deficit hyperactivity disorder (ADHD) monitored for more than 1 year. Design: A cohort study analyzing data from the national ADHD register on patients from the Lombardy Region treated with MPH or atomoxetine. Participants: A total of 229 children (median age 11 years, range 6-17), enrolled in 15 regional centers between June 2007 and May 2010. Results: The prevalence rate of pharmacological treatment for ADHD was 0.23%, whereas the estimated ADHD prevalence in the population was 0.95%. In total, 73.8% of patients had been treated with atomoxetine (10-90 mg daily) or MPH (10-75 mg daily); 22% of patients also received an additional psychotropic drug. Of the treated children, 26.9% discontinued the drug prior to 1 year of treatment, mostly because of adverse effects (28.6%). No new or unexpected adverse events (rate 39.2%) were encountered. Decreased appetite, headache, and unstable mood were the leading events. The most severe events occurred in two boys: one experienced absence seizures for the first time with MPH, the other experienced hallucinations with atomoxetine. Therapy was discontinued in ten male patients (7.7%) because of adverse events. All patients with adverse effects recovered well. Conclusions: A very low rate of ADHD prevalence was estimated in Italian children compared to that reported in other countries. Although the medications for ADHD are generally well tolerated, with only mild or minor adverse effects in most cases, their rational use can only be guaranteed by disseminating and monitoring evidence-based practices and by monitoring the safety and efficacy of treatments in both the short and long terms with appropriate tools and approaches. © 2011 Springer-Verlag.

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