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Drug use during pregnancy should be evidence-based and favor the safest and most appropriate prescription. The Italian Medicines Agency (AIFA) coordinates a network focusing on monitoring medication use in pregnancy. Hypertensive disorders are common medical complication of pregnancy and antihypertensive therapy is prescribed to reduce the risk of adverse feto-maternal complications. The objective of this study is to highlight the prescription pattern of antihypertensive drugs before pregnancy, during pregnancy and in the postpartum period in Italy and to evaluate their use with a specific attention to the prescription pattern of drugs considered safe during pregnancy. A multi-database cross-sectional population study using a Common Data Model (CDM) was performed. We selected all women aged 15–49 years living in eight Italian regions who gave birth in hospital between 1 April 2016 and 31 March 2018. In a cohort of 449.012 women, corresponding to 59% of Italian deliveries occurred in the study period, the prevalence of prescription of antihypertensive drugs in the pre-conceptional period was 1.2%, in pregnancy 2.0% and in the postpartum period 2.9%. Beta-blockers were the most prescribed drugs before pregnancy (0.28%–0.30%). Calcium channel blockers were the most prescribed drugs during pregnancy, with a prevalence of 0.23%, 0.33%, 0.75% in each trimester. Alfa-2-adrenergic receptor agonists were the second most prescribed during pregnancy with a prevalence of 0.16%, 0.26% and 0.55% in each trimester. The prescription of drugs contraindicated during pregnancy was below 0.5%. Only a small percentage of women switched from a contraindicated drug to a drug compatible with pregnancy. The analysis showed little variability between the different Italian regions. In general, the prescription of antihypertensive drugs in the Italian Mom-Network is coherent with the drugs compatible with pregnancy.

BackgroundMany countries use the WHO Essential Medicines List (EML) as a guide for health policy choices to promote the efficient use of healthcare resources or adopt the concept of essential medicines (EMs) to develop their own national list of essential medicines. The aim of this study is to analyse the availability and use of medicines included in the 22nd WHO EML in Italy.MethodsUsing the ATC code (5th level), a comparison was made between the medicines included in the WHO EML and those retrieved from the Italian Medicines Agency (AIFA) database. The availability (regulatory and reimbursement status) of EMs, as well as the market share in expenditure (million euros) and consumption [measured in WHO-defined daily doses (DDDs)], compared to all reimbursed medicines in 2021, were analysed.ResultsIn 2021, approximately 85.2% (n = 414) of medicines included in the WHO EML were commonly marketed in Italy. Of these, 396 EMs were fully reimbursed by the Italian National Healthcare Service (INHS), corresponding to 81.5% (396/486) of the WHO EML, while the remaining 18.5% (90/486) were neither authorised (n = 72) nor reimbursed (n = 18). The study found a low coverage for anti-parasitic, insecticides, and repellent products (ATC P) in addition to medicines for the genitourinary system and sex hormones (ATC G). Even though medicines on the WHO EML, including therapeutic alternatives, accounted for ~48.5% of the expenditure for medicines reimbursed by INHS, the list covered 74% of all national drug consumed. Novel high-cost therapies indicated in high-prevalence diseases and rare conditions, mostly antineoplastic and immune-modulating agents (ATC L) not included in the WHO EML, were also guaranteed.ConclusionsIn Italy, high coverage of EMs was found. It was largely reimbursed by the INHS, even when compared to other European countries. Essential medicines represented a high percentage of the overall expenditure and consumption in Italy. The WHO EML could be an important tool to guide the health policy choices of high-income countries, although a more frequent update and easier access to information on rejected medicines are needed.

BackgroundItaly has the highest per capita alcohol consumption among European countries. Several pharmacological treatments for alcohol use disorders (AUDs) are currently available in Italy, but no consumption data are available. A first analysis of national drug consumption, comprising the whole Italian population over a long-term period covering the COVID-19 pandemic, was performed.MethodsTo analyze the consumption of medications indicated for therapy of alcohol dependence, different national data sources were used. Consumption was measured as a defined daily dose (DDD) per 1,000,000 inhabitants per day.ResultsIn 2020, the total consumption of medicines used in the treatment of AUDs amounted to 310.3 DDD per 1 million inhabitants per day (0.018% of the overall drug consumption in Italy) with a decreasing gradient from the north (373.9 DDD) to the south (250.7 DDD). 53.2% of the overall doses were dispensed by public healthcare facilities and 23.5% by community pharmacies, while the remaining 23.3% were purchased privately. The temporal trend of consumption seemed to be stable across the last few years, although an impact of the COVID-19 pandemic was observed. Disulfiram was the most consumed medicine over years.ConclusionAll Italian regions offer pharmacological treatments to patients with AUDs, but differences in the number of dispensed doses suggest a different local organization of patient care, which can be partly explained by the different severity of the clinical condition of residing patients. Pharmacotherapy of alcoholism should be deeply investigated to describe the clinical characteristics of treated patients (i.e., comorbidities) and evaluate the appropriateness of prescribed medications.

ObjectiveThis investigation aimed to guarantee the principles of transparency in public administration; to inform citizens about the time to patient access to reimbursed medicines; to assess the duration of the P&R process for the first time in the period 2018–2020; and to evaluate whether and how the SARS-CoV-2 (COVID-19) pandemic affected the P&R activity. This study analyzed the timelines of pricing and reimbursement procedures submitted in Italy by the pharmaceutical marketing authorization holder (MAH) from 2018 to 2020.MethodsThe analysis was run through an AIFA web-based platform that collects data about P&R procedures for each step of the Italian Price and Reimbursement (P&R) procedure, including dates of the Technical Scientific Committee (CTS) and Price and Reimbursement Committee (CPR) meetings from January 2018 to December 2020. On this basis, four indicators were developed relating to the completion time of each stage of the P&R negotiation process and were defined in terms of days. In this regard, descriptive analyses, graphical boxplots, and survival curves (Kaplan–Meier) were carried out, studying these indicators in relation to the typology of pharmaceutical procedures.ResultsOverall, in the period 2018–2020, 57.1% of the 2,445 procedures entered were represented by the Off-patent pharmaceuticals procedures (generics, biosimilars, copies, and/or parallel trade). In 2020, the overall process duration for Off-patent pharmaceuticals procedures was equal to 129.8 average days [95% CI: (122.3–137.2)], with a median value of 108.0, whereas for In-patent pharmaceuticals procedures, it was equal to 283.1 average days [95% CI: (267.8–298.5)], with a median value of 284.0. Over time, the trend of the entire duration of the P&R process tended to decrease. In terms of estimated timing for the conclusion of each stage of the P&R negotiation process, the difference between Off-patent and In-patent pharmaceutical procedures was statistically significant by the Log-Rank test.Discussion and conclusionThis is the first study to examine the time of the P&R process in Italy, from MAH submission to the publication of the final decision in the Italian Official Journal. The time span considered is 3 years, including the first year of the COVID-19 pandemic. Compared to European average times, in Italy, the time necessary for evaluation, authorization for reimbursement, and definition of the price of a medicine can be considered satisfactory.

IntroductionThe aim of the study was to evaluate, in a regulated generics market, the effect of the number of manufacturers of generic drugs on the amplitude of off-patent products price reduction and the price evolution of originators and generics after the patent expiry of pharmaceuticals dispensed by community pharmacies and reimbursed by the Italian National Health Service (INHS).MethodsThe AIFA “transparency list” was utilized to select unbranded and branded off-patent drug dispensed by community pharmacies and reimbursed by the Italian National Health Service between 2012 and 2018. The unbranded drug entry in the transparency list database was considered as a proxy of its patent expiry.ResultsA total of 42 different active ingredients were included in the analysis. The relative price per dose at time t of unbranded and branded drugs, considering as common denominator the price per dose a year before the patent expiry, (t-1) decreased with the increase of unbranded manufacturers. At the time of the patent expiry, the price of unbranded drugs was almost 50% less than that of branded drugs at t-1 and the price of branded drugs started to decrease before the first unbranded entry.ConclusionAn inverse relation between the number of generic drug entrants and the price of generics and originators was detected. The patent expiry determines a price decline, more concentrated in the first year of patent expiry.

AimsHuman epicardial adipose tissue, a dynamic source of multiple bioactive factors, holds a close functional and anatomic relationship with the epicardial coronary arteries and communicates with the coronary artery wall through paracrine and vasocrine secretions. We explored the hypothesis that T-cell recruitment into epicardial adipose tissue (EAT) in patients with non-ST segment elevation myocardial infarction (NSTEMI) could be part of a specific antigen-driven response implicated in acute coronary syndrome onset and progression.Methods and ResultsWe enrolled 32 NSTEMI patients and 34 chronic coronary syndrome (CCS) patients undergoing coronary artery bypass grafting (CABG) and 12 mitral valve disease (MVD) patients undergoing surgery. We performed EAT proteome profiling on pooled specimens from three NSTEMI and three CCS patients. We performed T-cell receptor (TCR) spectratyping and CDR3 sequencing in EAT and peripheral blood mononuclear cells of 29 NSTEMI, 31 CCS, and 12 MVD patients. We then used computational modeling studies to predict interactions of the TCR beta chain variable region (TRBV) and explore sequence alignments. The EAT proteome profiling displayed a higher content of pro-inflammatory molecules (CD31, CHI3L1, CRP, EMPRINN, ENG, IL-17, IL-33, MMP-9, MPO, NGAL, RBP-4, RETN, VDB) in NSTEMI as compared to CCS (P < 0.0001). CDR3-beta spectratyping showed a TRBV21 enrichment in EAT of NSTEMI (12/29 patients; 41%) as compared with CCS (1/31 patients; 3%) and MVD (none) (ANOVA for trend P < 0.001). Of note, 11/12 (92%) NSTEMI patients with TRBV21 perturbation were at their first manifestation of ACS. Four patients with the first event shared a distinctive TRBV21-CDR3 sequence of 178 bp length and 2/4 were carriers of the human leukocyte antigen (HLA)-A*03:01 allele. A 3D analysis predicted the most likely epitope able to bind HLA-A3*01 and interact with the TRBV21-CDR3 sequence of 178 bp length, while the alignment results were consistent with microbial DNA sequences.ConclusionsOur study revealed a unique immune signature of the epicardial adipose tissue, which led to a 3D modeling of the TCRBV/peptide/HLA-A3 complex, in acute coronary syndrome patients at their first event, paving the way for epitope-driven therapeutic strategies.

Background: Evidence-based recommendations for outpatient management of COVID-19 were published by the Italian Medicines Agency (AIFA) to limit the use of off-label treatments. The aim of this study is to measure the use of outpatient drug treatments in a COVID-19-positive population, taking into account the Italian regulatory agency’s advices.Methods: A descriptive observational study was conducted. All patients testing positive for COVID-19 residing in Lazio region, Italy, with diagnosis date between March 2020 and May 2021 were selected, and outpatient medicine prescription patterns were identified.Results: Independent of AIFA recommendations, the use of drug therapy in the management of outpatient COVID-19 cases was frequent (about one-third of the cases). The most used drug therapy was antibiotics, specifically azithromycin, despite the negative recommendation of AIFA, while the use of corticosteroids increased after the positive recommendation of regulatory agency for the use in subjects with severe COVID-19 disease. The use of hydroxychloroquine was limited to the early pandemic period where evidence on its potential benefit was controversial. Antithrombotics were widely used in outpatient settings, even if their use was recommended for hospitalized patients.Conclusion: In this study, we show a frequent use of drug therapy in the management of outpatient cases of COVID-19, mainly attributable to antibiotics use. Our research highlights the discrepancy between recommendations for care and clinical practice and the need for strategies to bridge gaps in evidence-informed decision-making.

IntroductionIt is well acknowledged that the price of orphan drugs is normally higher than that resulting from the value-based pricing. A correlation between the cost of therapy for orphan drugs and the epidemiology (prevalence and incidence) of the related rare disease can be hypothesized.MethodsThis analysis includes all approved orphan drugs by European Medicines Agency whose reimbursement was granted for the first therapeutic indication in the years 2014–2019 in Italy. Regression and correlation analyses were performed to analyze the possible correlations between the logarithm of the annual therapy cost and the epidemiology of the rare diseases, between orphan drugs consumption and epidemiology of related rare disease and between therapy cost and the consumption.ResultsThe regression analysis between the annual cost of therapy estimated on the published ex-factory price and the prevalence showed a slightly decreasing, not statistically significant, trend (coefficient: −0.10, p-value: 0.41). The results were similar when using the price resulting from the application of Managed Entry Agreements (coefficient: −0.11, p-value: 0.40). The regression analysis between sales volume and prevalence showed a positive slope without an acceptable level of significance (p-value: 0.04). The correlation analysis between the therapy cost and the sales volume highlighted again an absence of significant association, similarly if considering only ATC L orphan drugs, or the incidence.DiscussionThe definition of the price of an orphan drug seems not to depend on the rarity of the disease, and sales volumes do not correlate with the epidemiology of the rare disease and with the annual cost of therapy.

Objectives: Starting from April 2017, the Italian Medicine Agency (AIFA) has approved new criteria for defining any new medicinal product with an innovative indication. The purpose of the study is to analyze the activity of innovativeness evaluation according to the new approach, to estimate the weight of each criterion considered for innovativeness definition, and to evaluate how the new approach works in terms of consistency and reproducibility.Methods: A retrospective analysis was performed on the final reports evaluating the drug innovativeness assessment published on the AIFA's website between April 2017 and January 2021. Descriptive statistics, chi-square test, whether the conditions were respected, or Fisher's exact test was used to explore the association between characteristics of drugs and the innovativeness status and the association between the three criteria. Profiles of the decision process and their relationship with innovativeness response were described. In order to evaluate the weight of each criterion in predicting the innovativeness status, a Classification Tree (CT) algorithm was applied.Results: Overall, of the 109 published drugs reports, 37 (33.9%) were recognized as fully innovative, 29 (26.6%) were considered conditionally innovative, while for 43 (39.4%) reports innovativeness was not recognized. Considering the three criteria of the decision process, the added therapeutic value was the only criterion statistically associated with a drug's degree of innovation (p < 0.001). The therapeutic need and the quality of clinical evidence were statistically associated (p = 0.008) even if only a mild association was observed. The added therapeutic value was the most important variable in predicting the innovativeness status according to the classification tree (CT) model applied, achieving an accuracy of 89.4%. No difference was found between orphans and non-orphan drugs or oncological and non-oncological drugs.Discussion: The added therapeutic value is the most important criterion of the multidimensional approach for the innovativeness status definition of a new medical product. A mild association was found between the therapeutic need and the quality of evidence. Overall, similar decision profiles bring the same evaluation of innovativeness status, indicating a good consistency and reproducibility between decisions.

There is an acute need for research to acquire high-quality information on the use of medicines in pregnancy, both in terms of appropriateness and safety. For this purpose, the Italian Medicines Agency established a Network for Monitoring Medication use in pregnancy (MoM-Net) through the conduction of population-based studies using administrative data available at regional level. This paper aimed to describe the experiences and challenges within the network. MoM-Net currently involves eight regions and several experts from public and academic institutions. The first study conducted aimed to identify drug use before, during and after pregnancy investigating specific therapeutic categories, analysing regional variability and monitoring drug use in specific subpopulations (i.e. foreign women/multiple pregnancies). Aggregated demographic, clinical, and prescription data were analysed using a distributed network approach based on common data model. The study population included all women delivering during 2016–2018 in the participating regions (n = 449,012), and corresponding to 59% of deliveries in Italy. Seventy-three per cent of the cohort had at least one drug prescription during pregnancy, compared to 57% before and 59% after pregnancy. In general, a good adherence to guidelines for pregnant women was found although some drug categories at risk of inappropriateness, such as progestins and antibiotics, were prescribed. A strong variability in the use of drugs among regions and in specific subpopulations was observed. The MoM-Net represents a valuable surveillance system on the use of medicines in pregnancy, available to monitor drug categories at high risk of inappropriateness and to investigate health needs in specific regions or subpopulations.

High-impact ocean weather events and climate extremes can have devastating effects on coastal zones and small islands. Marine Disaster Risk Reduction (DRR) is a systematic approach to such events, through which the risk of disaster can be identified, assessed and reduced. This can be done by improving ocean and atmosphere prediction models, data assimilation for better initial conditions and developing an efficient and sustainable impact forecasting methodology for Early Warnings Systems. A common user request during disaster remediation actions is for high-resolution information, which can be derived from easily deployable numerical models nested into operational larger-scale ocean models. The Structured and Unstructured Relocatable Ocean Model for Forecasting (SURF) enables users to rapidly deploy a nested high-resolution numerical model into larger-scale ocean forecasts. Rapidly downscaling the currents, sea level, temperature, and salinity fields is critical in supporting emergency responses to extreme events and natural hazards in the world’s oceans. The most important requirement in a relocatable model is to ensure that the interpolation of low-resolution ocean model fields (analyses and reanalyses) and atmospheric forcing is tested for different model domains. The provision of continuous ocean circulation forecasts through the Copernicus Marine Environment Monitoring Service (CMEMS) enables this testing. High-resolution SURF ocean circulation forecasts can be provided to specific application models such as oil spill fate and transport models, search and rescue trajectory models, and ship routing models requiring knowledge of meteo-oceanographic conditions. SURF was used to downscale CMEMS circulation analyses in four world ocean regions, and the high-resolution currents it can simulate for specific applications are examined. The SURF downscaled circulation fields show that the marine current resolutions affect the quality of the application models to be used for assessing disaster risks, particularly near coastal areas where the coastline geometry must be resolved through a numerical grid, and high-frequency coastal currents must be accurately simulated.

The Mediterranean community represented in this paper is the result of more than 30 years of EU and nationally funded coordination, which has led to key contributions in science concepts and operational initiatives. Together with the establishment of operational services, the community has coordinated with universities, research centers, research infrastructures and private companies to implement advanced multi-platform and integrated observing and forecasting systems that facilitate the advancement of operational services, scientific achievements and mission-oriented innovation. Thus, the community can respond to societal challenges and stakeholders needs, developing a variety of fit-for-purpose services such as the Copernicus Marine Service. The combination of state-of-the-art observations and forecasting provides new opportunities for downstream services in response to the needs of the heavily populated Mediterranean coastal areas and to climate change. The challenge over the next decade is to sustain ocean observations within the research community, to monitor the variability at small scales, e.g., the mesoscale/submesoscale, to resolve the sub-basin/seasonal and inter-annual variability in the circulation, and thus establish the decadal variability, understand and correct the model-associated biases and to enhance model-data integration and ensemble forecasting for uncertainty estimation. Better knowledge and understanding of the level of Mediterranean variability will enable a subsequent evaluation of the impacts and mitigation of the effect of human activities and climate change on the biodiversity and the ecosystem, which will support environmental assessments and decisions. Further challenges include extending the science-based added-value products into societal relevant downstream services and engaging with communities to build initiatives that will contribute to the 2030 Agenda and more specifically to SDG14 and the UN's Decade of Ocean Science for sustainable development, by this contributing to bridge the science-policy gap. The Mediterranean observing and forecasting capacity was built on the basis of community best practices in monitoring and modeling, and can serve as a basis for the development of an integrated global ocean observing system.

This study investigated the effects of free paclitaxel (PTX) and PTX-loaded in pyromellitic nanosponges (PTX-PNS) in reducing in vitro and in vivo melanoma cell growth and invasivity, and in inhibiting angiogenesis. To test the response of cells to the two PTX formulations, the cell viability was evaluated by MTT assay in seven continuous cell lines, in primary melanoma cells, both in 2D and 3D cultures, and in human umbilical vein endothelial cells (HUVECs) after exposure to different concentrations of PTX or PTX-PNS. Cell motility was assessed by a scratch assay or Boyden chamber assay, evaluating cell migration in presence or absence of diverse concentrations of PTX or PTX-PNS. The effect of PTX and PTX-PNS on angiogenesis was evaluated as endothelial tube formation assay, a test able to estimate the formation of three-dimensional vessels in vitro. To assess the anticancer effect of PTX and PTX-PNS in in vivo experiments, the two drug formulations were tested in a melanoma mouse model obtained by B16-BL6 cell implantation in C57/BL6 mice. Results obtained were as follows: 1) MTT analysis revealed that cell proliferation was more affected by PTX-PNS than by PTX in all tested cell lines, in both 2D and 3D cultures; 2) the analysis of the cell migration showed that PTX-PNS acted at very lower concentrations than PTX; 3) tube formation assay showed that PTX-PNS were more effective in inhibiting tube formation than free PTX; and 4) in vivo experiments demonstrated that tumor weights, volumes, and growth were significantly reduced by PTX-PNS treatment with respect to PTX; the angiogenesis and the cell proliferation, detected in the tumor samples with CD31 and Ki-67 antibodies, respectively, indicated that, in the PTX-PNS-treated tumors, the tube formation was inhibited, and a low amount of proliferating cells was present. Taken together, our data demonstrated that our new PTX nanoformulation can respond to some important issues related to PTX treatment, lowering the anti-tumor effective doses and increasing the effectiveness in inhibiting melanoma growth in vivo.

PurposeSomatropin [recombinant growth hormone (rGH)] is approved in children and adults for several conditions involving growth disturbances and the corresponding biosimilar is available in Italy since 2006. No population-based data are available on the pattern of rGH use in Italian clinical practice. This study aimed at exploring the pattern of biosimilar and originator rGH use in six Italian centers, where different policy interventions promoted biosimilar use.MethodsThis population-based, drug-utilization study was conducted in the years 2009–2014, using administrative databases of Umbria, Tuscany, and Lazio Regions and Local Health Units of Caserta, Treviso, and Palermo. Naïve rGH users were characterized, and prevalence of use and discontinuation were assessed over time.ResultsAmong 6,785 patients treated with rGH during the study years, 4,493 (66.2%) were naïve users (males/females = 1.3), mostly affected by GH deficiency. The prevalence of rGH use increased from 2009 to 2010, remaining stable thereafter, but it was heterogeneous across centers (twofold higher prevalence of use in center n.2 than centers n.4 and 1 in 2014). Biosimilar rGH uptake increased over time but was low (7.8% in 2014) and heterogeneous as well. Discontinuation of rGH therapy occurred in 54.0% of naïve users, more frequently in females than males (58.1 vs. 50.9%). During the first year of treatment, discontinuation was frequent (39.9%), but no statistically significant differences were observed in treatment persistence for biosimilar vs. originator rGH (p > 0.05).ConclusionGeographical heterogeneity in the prevalence of rGH use was observed. Similarly, the biosimilar rGH uptake was low and variable across centers. Post-marketing monitoring is required to continuously monitor the benefit-risk profile of rGH, thus guaranteeing greater savings than only promoting lowest cost rGH.