Towards a validated definition of the clinical transition to secondary progressive multiple sclerosis: A study from the Italian MS Register.

BACKGROUND: Definitions for reliable identification of transition from relapsing-remitting multiple sclerosis (MS) to secondary progressive (SP)MS in clinical cohorts are not available. OBJECTIVES: To compare diagnostic performances of two different data-driven SPMS definitions. METHODS: Data-driven SPMS definitions based on a version of Lorscheider's algorithm (DDA) and on the EXPAND trial inclusion criteria were compared, using the neurologist's definition (ND) as gold standard, in terms of sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), Akaike information criterion (AIC) and area under the curve (AUC). RESULTS: A cohort of 10,240 MS patients with ⩾5 years of follow-up was extracted from the Italian MS Registry; 880 (8.5%) patients were classified as SPMS according to the neurologist definition, 1806 (17.6%) applying the DDA and 1134 (11.0%) with the EXPAND definition. The DDA showed greater discrimination power (AUC: 0.8 vs 0.6) and a higher sensitivity (77.1% vs 38.0%) than the EXPAND definition, with similar specificity (88.0% vs 91.5%). PPV and NPV were higher using the DDA than considering EXPAND definition (37.5% vs 29.5%; 97.6% vs 94.0%). CONCLUSION: Data-driven definitions demonstrated greater ability to capture SP transition than neurologist's definition and the global accuracy of DDA seems to be higher than the EXPAND definition.

Epidemiology and determinants of chronic migraine: A real-world cohort study, with nested case-control analysis, in primary care in Italy.

BACKGROUND: The proper identification of chronic migraine is one of the mainstays for general practitioners. This study therefore aims to assess the epidemiology and determinants of chronic migraine in primary care in Italy by testing five operational case definition algorithms. METHODS: Five case definition algorithms defining chronic migraine were developed to estimate the prevalence and incidence rate of chronic migraine in the Health Search database. For each algorithm, we conducted a nested case-control analysis to quantify the level of association between certain determinants and incident cases of chronic migraine. RESULTS: Considering a cohort of 1,091,032 patients (52% were females), the prevalence rate of chronic migraine increased from the first to the fifth case definition algorithm ranging from 0.03 to 0.28%. No 95% confidence interval overlapped the others, and every confidence interval reliably maintained 2% precision. Incidence rates showed a growing trend (0.008-0.056 per 100,000 person-years) as well. All case definition algorithms were able to capture sex (i.e. female) and nonsteroidal anti-inflammatory drug (NSAID) overuse as statistically significant determinants of incident cases of chronic migraine. Depression was associated with a statistically significant increase of incidence rate of chronic migraine only for two case definition algorithms. CONCLUSION: Our findings show that prevalence and incidence rate of chronic migraine are underestimated when compared with current literature. On the other hand, we found acceptable correctness of chronic migraine definition in the light of the association with well-known determinants.

Effectiveness of fingolimod in real-world relapsing-remitting multiple sclerosis Italian patients: the GENIUS study.

BACKGROUND: Fingolimod is the first oral agent approved for treatment of relapsing-remitting multiple sclerosis (RRMS). We aimed to evaluate fingolimod effectiveness in a real-world sample of RRMS patients. METHODS: A retrospective, multicentre study in patients treated with fingolimod, whom clinical and radiological data were collected in the 2 years preceding and following the initiation of fingolimod. RESULTS: Out of 414 patients, 56.8% received prior first-line injectable disease-modifying therapies, 25.4% were previously treated with natalizumab, 1.2% with immunosuppressant agents, and 16.7% were treatment naive. The annualized relapse rate decreased by 65% in the first year and by 70% after two years of treatment. Age ≤ 40 years, ≥ 1 relapse in the 24 months before fingolimod initiation and previous treatment with natalizumab were risk factors for relapses. Overall, 67.9% patients had no evidence of disease activity (NEDA-3) after 1 year and 54.6% after 2 years of treatment. A higher proportion of naïve (81.2% in 1 year and 66.7% after 2 years) or first-line injected patients (70.2% and 56.6%) achieved NEDA-3 than those previously treated with natalizumab (54.3% and 42.9%). CONCLUSIONS: Fingolimod appeared to be effective in naive patients and after first-line treatment failure in reducing risk of relapse and disease activity throughout the 2-year follow-up.

Literature review of gender differences in respiratory conditions: a focus on asthma and Chronic Obstructive Pulmonary Disease (COPD).

BACKGROUND: Gender differences are evident in many common health conditions, especially respiratory diseases such as asthma and chronic obstructive pulmonary disease (COPD). The aim of this review was to identify published studies describing gender differences in asthma and COPD, in particular regarding pathophysiology, diagnosis and treatment, with a focus on Italian data. METHODS: a literature review was performed from April to November 2015, using the PubMed scientific database and the following ??eywords: "gender differences" and "asthma" for the asthma review and "gender differences" and "COPD" for the COPD review. RESULTS: Gender differences in asthma are related to age groups. In the female population, asthma is generally more severe and disabling, and presents higher mortality rates with respect to same-age males. COPD prevalence is growing and is underestimated in women, because it tends to be diagnosed with difficulty and at a delayed stage. The same findings were observed when restricting the review to Italian data. CONCLUSION: Clinicians should collaborate to develop a more gender-oriented approach towards diagnosis and treatment of asthma and COPD. In Italy, this would also facilitate measures to improve compliance, particularly among women.

Exploring Deep Eutectic Solvents as Pharmaceutical Excipients: Enhancing the Solubility of Ibuprofen and Mefenamic Acid.

Objectives: The study explores the potential of various deep eutectic solvents (DESs) to serve as drug delivery systems and pharmaceutical excipients. The research focuses on two primary objectives: evaluating the ability of the selected DES systems to enhance the solubility of two poorly water-soluble model drugs (IBU and MFA), and evaluating their physicochemical properties, including density, viscosity, flow behavior, surface tension, thermal stability, and water dilution effects, to determine their suitability for pharmaceutical applications. Methods: A range of DES systems containing pharmaceutically acceptable constituents was explored, encompassing organic acid-based, sugar- and sugar alcohol-based, and hydrophobic systems, as well as menthol (MNT)-based DES systems with common pharmaceutical excipients. MNT-based DESs exhibited the most significant solubility enhancements. Results: IBU solubility reached 379.69 mg/g in MNT: PEG 400 (1:1) and 356.3 mg/g in MNT:oleic acid (1:1), while MFA solubility peaked at 17.07 mg/g in MNT:Miglyol 812®N (1:1). In contrast, solubility in hydrophilic DES systems was significantly lower, with choline chloride: glycerol (1:2) and arginine: glycolic acid (1:8) showing the best results. While demonstrating lower solubility compared to the MNT-based systems, sugar-based DESs exhibited increased tunability via water and glycerol addition both in terms of solubility and physicochemical properties, such as viscosity and surface tension. Conclusions: Our study introduces novel DES systems, expanding the repertoire of pharmaceutically acceptable DES formulations and opening new avenues for the rational design of tailored solvent systems to overcome solubility challenges and enhance drug delivery.

Development and Evaluation of Docetaxel-Loaded Nanostructured Lipid Carriers for Skin Cancer Therapy.

This study focuses on the design, characterization, and optimization of nanostructured lipid carriers (NLCs) loaded with docetaxel for the treatment of skin cancer. Employing a systematic formulation development process guided by Design of Experiments (DoE) principles, key parameters such as particle size, polydispersity index (PDI), zeta potential, and entrapment efficiency were optimized to ensure the stability and drug-loading efficacy of the NLCs. Combined XRD and cryo-TEM analysis were employed for NLC nanostructure evaluation, confirming the formation of well-defined nanostructures. In vitro kinetics studies demonstrated controlled and sustained docetaxel release over 48 h, emphasizing the potential for prolonged therapeutic effects. Cytotoxicity assays on human umbilical vein endothelial cells (HUVEC) and SK-MEL-24 melanoma cell line revealed enhanced efficacy against cancer cells, with significant selective cytotoxicity and minimal impact on normal cells. This multidimensional approach, encompassing formulation optimization and comprehensive characterization, positions the docetaxel-loaded NLCs as promising candidates for advanced skin cancer therapy. The findings underscore the potential translational impact of these nanocarriers, paving the way for future preclinical investigations and clinical applications in skin cancer treatment.

Cost-effectiveness and budget impact analysis of siponimod in the treatment of secondary progressive multiple sclerosis in Italy.

BACKGROUND: Siponimod is an effective treatment for patients with secondary progressive multiple sclerosis (SPMS), with active disease evidenced by relapses or imaging features characteristic of multiple sclerosis inflammatory activity, however there is a need to evaluate its economic value and sustainability compared to other disease modifying-therapies (DMTs). OBJECTIVE: To estimate the siponimod cost-effectiveness profile and its relative budget impact compared with other DMTs, by using the Italian National Healthcare System perspective. METHODS: We performed: 1) a cost-effectiveness analysis (CEA) vs interferon beta-1b using an analytical Markov model and a life time-horizon, and 2) a budget impact analysis by using 3-years time-horizon. The results were reported as incremental cost-effectiveness ratio (ICER) and net-monetary benefit (NMB) for CEA, using a willingness to pay threshold of €40,000 per QALY gained, and as difference in the overall budget (Euro) between the scenario with and without siponimod for budget impact. RESULTS: In the base case scenario siponimod resulted cost-effective compared with interferon beta-1b 28,891€ per QALY. Overall, the market access of siponimod was associated to an increased budget of about 3€ millions (+0.9%) in the next 3 years simulated. CONCLUSION: Compared to interferon beta-1b, siponimod seems to be cost-effective in SPMS patients and sustainable, with less than 1% overall budget increased in the next 3 years. Future studies need to confirm our results in the real word setting and in other countries.

Patients with multiple sclerosis: a burden and cost of illness study.

BACKGROUND: Multiple sclerosis (MS) is a chronic neuroinflammatory and neurodegenerative disease negatively impacting patients' physical, psychological and social well-being with a significant economic burden. OBJECTIVES: The study estimates MS burden and cost of illness in Italy from a societal perspective in 2019. METHODS: Information on the impact of the disease on daily activities, symptoms, employment, resource utilization and the role of caregivers was collected through questionnaires completed by 944 patients and caregivers. Results were stratified according to both disease severity and payer. Mean costs and overall costs were extrapolated from the sample to the Italian MS population considering published distribution of severity. RESULTS: The study showed a great impact of the disease on daily and work activities increasing with the disability. The overwhelming burden of fatigue emerged. Mean annual costs were estimated at €39,307/patient (€29,676, €43,464 and €53,454 in mild, moderate and severe cases, respectively). Direct healthcare costs were the major component (€21,069), followed by indirect costs (€15,004). The overall cost of the disease in Italy was €4.8 billion. The National Healthcare System (NHS) sustained most of the costs (80%), most notably direct healthcare costs, while patients paid almost all non-healthcare expenses. CONCLUSIONS: This study confirmed that MS carries a substantial burden to patients and society, highlighting the need for awareness of this disease.

The Epidemiology, Treatment Patterns and Economic Burden of Different Phenotypes of Multiple Sclerosis in Italy: Relapsing-Remitting Multiple Sclerosis and Secondary Progressive Multiple Sclerosis.

Purpose: A retrospective analysis of real-world data was performed to assess the epidemiology and economic burden of multiple sclerosis (MS), relapsing-remitting MS (RRMS), and secondary-progressive MS (SPMS) in Italy. Patients and Methods: An observational study on administrative databases from a sample of Italian entities was carried-out. Between 01/2010-12/2017, patients with ≥1 MS diagnosis code (ICD-9-CM:340 and/or exemption code:046) and/or ≥1 disease-modifying therapies (DMTs) prescription, were included. Among MS-cohort, SPMS patients were identified by ≥2 hospitalizations or by ≥2 drug prescriptions related to MS progression. MS patients not fulfilling SPMS criteria were included as RRMS. Mean annual healthcare costs were reported during follow-up and stratified by DMT treatment/untreatment. Results: Overall, 9543 MS patients were included; 8397 with RRMS and 1146 with SPMS. Estimated prevalence of MS was 141.6/100,000 inhabitants (RRMS 124.4/100,000 and SPMS 17.2/100,000). Mean annual cost for untreated and treated patient was respectively: €3638 and €11796 (MS-cohort), €3183 and €11486 (RRMS-cohort), €6317 and €15511 (SPMS-cohort). The first-line DMT treatment duration averaged 27.4 ± 22.8 months; the mean cost was 19004€ for the whole period. The second-line DMT treatment lasted on average 31.1 ± 24.5 months; the mean cost was 47293€ for the whole period. Conclusion: This study provided insights into the MS epidemiology in Italy and its economic burden. Healthcare costs associated with MS management were mainly driven by DMTs expenditure. A trend of higher healthcare-resource consumption was observed among SPMS-cohort.

[Heart failure in Apulia Region - Italy (Local Health Unit Barletta-Andria-Trani): analysis of the therapeutic pathways, healthcare resource consumption and related costs.] / Lo scompenso cardiaco nella ASL Barletta-Andria-Trani (BT): analisi dei trattamenti farmacologici, del consumo di risorse e relativo costo per il Servizio Sanitario Nazionale.

BACKGROUND: Heart failure (HF) is commonly reported, it is estimated to affect 10% of subjects aged over 70 years. Objectives of this study were to describe clinical and demographic characteristics of patients with HF diagnosis, to analyze therapeutic pathways and to estimate healthcare resources consumption. METHODS: Data on patients aged ≥18 years with a hospitalization discharge diagnosis of HF between 01/01/2010 and 31/12/2014 and in treatment with HF-related drugs were extracted from the administrative databases of the Italian Local Health Unit of Barletta-Andria-Trani (BT). We described the pharmacological treatment prescribed and the use of drugs in combination both at the beginning and at the end of the 12-month follow-up period. The costs analysis was conducted with the perspective of the Italian National Health System. RESULTS: A total of 2 669 patients with HF were enrolled in the study, 1 960 as primary and 709 as secondary diagnosis (average age 77.0±10.4/76.5±11.1 years respectively, 49% and 55% were male, respectively). Mortality during 12 months of follow-up was 46% and 43% respectively. Mostly prescribed pharmacological treatments were diuretics (90.4% of patients with primary HF diagnosis and 79.4% of patients with secondary HF diagnosis), beta-blockers (53.7% and 58.8%, respectively) and aldosterone antagonists (57.5% and 42.5%, respectively); moreover, during the follow-up period, half of the patients presented a switch from the original therapy and 10% of the patients required an add-on. Healthcare resource consumption for patients discharged alive was € 11 872.4 for patients with primary diagnosis and € 12 493.7 for patients with secondary diagnosis of HF. Cost for hospitalizations during follow-up was around € 3 800 (32.3% of total costs) and € 3 600 (29.0% of total costs), respectively. CONCLUSIONS: Our findings are in accordance with what already published, both in a National and International context, on mortality rates in HF patients and related costs for the National Healthcare System. Results from the present study highlight the under-prescriptions of ACEi/ARBs, aldosterone antagonists and beta-blockers in HF patients.

The Burden of Chronic Heart Failure in Primary Care in Italy.

INTRODUCTION: Chronic heart failure (CHF) is a major public health concern. From a public health perspective, the epidemiology of CHF needs to be distinguished from that of its related acute form. Data stemming from primary care are crucial to better know and update the prevalence and incidence rates of CHF. AIM: To update the epidemiology of CHF in an Italian primary care setting and to describe socio-demographic, lifestyle, and clinical characteristics of these patients. METHODS: A population-based study was conducted among 800 Italian general practitioners collecting data in a dedicated database. Information was extracted from adult subjects with a diagnosis of CHF from 2002 to 2013, and the prevalence and incidence rate of CHF were calculated. The study population was described in terms of socio-demographic, lifestyle, and clinical characteristics. RESULTS: A total of 13,633 patients with CHF were identified. Overall, the prevalence of CHF was 1.25% (95% CI 1.23-1.27), and the incidence rate was 1.99 per 1000 person-years (95% CI 1.81-2.08). In this population, smoking, alcohol use, and obesity were present in 2.93, 0.45, and 10.80% of cases, respectively. Hypertension (58.40%), chronic kidney disease (51.36%), dyslipidaemia (44.62%), ischaemic heart disease (25.75%), and atrial fibrillation (25.32%) were the most represented comorbidities. CONCLUSION: This study provides an updated epidemiological scenario of CHF in a primary care setting in Italy. These data may be useful to weight the social and economic impact of CHF and to plan strategies for improving the clinical care of CHF in general practice.

Gender differences in the adverse events' profile registered in seven observational studies of a wide gender-medicine (MetaGeM) project: the MetaGeM safety analysis.

BACKGROUND: MetaGeM is a wide gender-medicine project comprising post hoc and meta-analyses by gender of clinical outcomes, therapeutic approaches, and safety data from previously conducted observational studies to explore possible gender differences in real-life clinical settings. We report the results of the safety meta-analysis of seven MetaGeM studies, evaluating gender differences in adverse event (AE) incidence and severity. METHODS: Data were collected between February 2002 and July 2013. Male and female patients were compared for the main safety variables, using Student's t-test, χ2 test, or Fisher's exact test as appropriate. As supportive analysis, a logistic regression model was estimated to evaluate associations between gender and outcome. RESULTS: In total, 4,870 patients (46% females, 54% males) were included in the analysis; age was higher for females (mean ± standard deviation 61.2±18.3 years) than males (56.3±16.6 years). Overall, 264 AEs were reported (59.1% in males). There were no significant gender differences in the percentage of patients with at least one AE: 3.0% for females versus 3.9% for males, χ2 test P>0.05. According to the logistic regression model results, no association between gender and AEs occurrence seems to exist. A statistically significant gender difference in the percentage of drug-related AEs emerged (37.6% in females vs 20.8% in males, χ2P=0.0039). Slightly significantly more AEs in females were addressed with treatment compared with males (78.1% vs 66.7%, χ2P=0.0485). Total serious AEs (SAEs) were 47 (72% in males). The frequency of patients with ≥1 SAE was 0.6% in females versus 1.2% in males (χ2 test P=0.0246). CONCLUSION: This safety analysis on a large sample of almost 5,000 patients with different diseases and treated with a wide range of different drugs provides a useful overview on possible gender differences in drug tolerability, which may be helpful in more accurately designing future clinical trials from a gender-specific perspective.

No substantial gender differences in suspected adverse reactions to ACE inhibitors and ARBs: results from spontaneous reporting system in Campania Region.

BACKGROUND: Today, there is a poor knowledge about gender differences in adverse drug reactions (ADRs) to cardiovascular drugs such as angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs). Therefore, the aim of this study was to analyze spontaneous reports of suspected ADRs induced by ACE-inhibitors and ARBs, between January 2001 and June 2015, recorded in a Region of Southern Italy (Campania Region). METHODS: We performed a descriptive gender-related analysis of regional safety data, obtained from the spontaneous reporting system. RESULTS: In the considered period, 772 suspected ADRs to ACE inhibitors and ARBs (in monotherapy or in combination) were reported with a slightly higher frequency in men compared with women. In both genders, the most involved category was ARBs in combination, whereas the most prescribed active substance was ramipril. General and administration site conditions, vascular disorders and modification of laboratory parameters were more common in men, while respiratory disorders were most common in women. In 88.2% of cases, not serious ADRs were described more by men than women. CONCLUSIONS: This analysis suggested no substantial gender differences. Further studies such as randomized population studies or meta-analysis of ACE inhibitors and ARBs randomized studies are needed to clarify whether gender differences exist in the safety profile of these drugs.