Atherogenic Dyslipidemias: Unmet Needs and the Therapeutic Potential of Emerging and Novel Approaches and Drugs.

Innovative lipid-modifying agents are valuable resources to improve the control of atherogenic dyslipidemias and reduce the lipid-related residual cardiovascular risk of patients with intolerance or who are not fully responsive to a consolidated standard of care (statins plus ezetimibe). Moreover, some of the upcoming compounds potently affect lipid targets that are thus far considered "unmodifiable". The present paper is a viewpoint aimed at presenting the incremental metabolic and cardiovascular benefits of the emerging lipid-modulating agents and real-life barriers, hindering their prescription by physicians and their assumption by patients, which need to be worked out for a more diffuse and appropriate drug utilization.

Bullous pemphigoid induced by dipeptidyl peptidase-4 (DPP-4) inhibitors: a pharmacovigilance-pharmacodynamic/pharmacokinetic assessment through an analysis of the vigibase®.

Objectives: To examine the signals of bullous pemphigoid (BP) with dipeptidyl peptidase-4 inhibitors (DPP-4i) in VigiBase® and the potential role of their pharmacodynamic/pharmacokinetic parameters in the occurrence of BP. Methods: Case/non-case analyses were performed in VigiBase® to examine the signal of BP [reporting odds ratio (ROR)] for gliptins. Secondly, the authors performed linear regression analyses to explore the association between DPP-4i signals for BP and their affinities toward different target enzymes (DPP-2, DPP-4, DPP-8, and DPP-9) and their volume of distribution (Vd). Results: A significant BP signal was found for DPP-4i. The ROR for pooled DPP-4i was 179.48 (95% CI: 166.41-193.58). The highest ROR was found for teneligliptin 975.04 (801.70-1185.87) and lowest for saxagliptin 18.9 (11.5-30.9). Linear regression analyses showed a considerable trend to significance for the linear correlation between the BP signal and gliptin affinity at DPP-4 (slope = 1.316 [-0.4385-3.21], p = 0.067, R2 = 0.40) but not the other enzyme targets, nor for Vd. Conclusion: The findings suggest a clinical relevance of gliptins selectivity for DDP-4 in the development of BP as a result of exposure to these drugs. Future preclinical and clinical studies are needed for a better understanding of this correlation.

Association of Hyponatraemia and Antidepressant Drugs: A Pharmacovigilance-Pharmacodynamic Assessment Through an Analysis of the US Food and Drug Administration Adverse Event Reporting System (FAERS) Database.

BACKGROUND: Hyponatraemia induced by antidepressant drugs is a rare but potentially life-threatening adverse reaction. Whether it is associated with all or only some antidepressant drugs is still unclear. This needs to be clarified to guide antidepressant therapies, especially in patients with electrolytic imbalances. OBJECTIVES: The primary objective of this study was to quantify the strength of association between the use of different antidepressant drugs and hyponatraemia by using information reported to the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS). The secondary objective was to investigate the putative relationship between different antidepressant pharmacological targets and the risks of hyponatraemia induced by antidepressant drugs using the 'pharmacovigilance-pharmacodynamic' method. METHODS: We used the FAERS database to conduct a case/non-case analysis on spontaneous reports, focusing on events of hyponatraemia/syndrome of inappropriate antidiuretic hormone secretion (SIADH) reported in connection with the use of antidepressant drugs. Risk was expressed as a measure of disproportionality using the reporting odds ratio while adjusting for sex, age and concomitant medications associated with hyponatraemia/SIADH. We assessed to what extent the receptor-binding properties of antidepressant drugs could associate with the reporting odds ratios of hyponatraemia/SIADH of antidepressant drugs, building a linear regression model that included as independent variables the binding affinities (pKi) to the serotonin transporter, dopamine transporter, norepinephrine transporter, and serotonin 5-HT2C, 5-HT2A and 5-HT1A, and α1- and α2-adrenergic receptors. RESULTS: There were 2233 reports identified. The adjusted reporting odds ratio for the association between antidepressant drug use and hyponatraemia was 1.91 (95% confidence interval 1.83-2.00). The association was strongest for mirtazapine, followed by selective serotonin reuptake inhibitors, and lowest with serotonin-modulating antidepressant drugs. A significant linear correlation was found between the adjusted reporting odds ratios for hyponatraemia and pKi for the adrenergic receptors α1 and α2. CONCLUSIONS: Hyponatraemia is reported at a disproportionately higher level with classes of antidepressant drugs (noradrenergic and specific serotonergic antidepressant [mirtazapine] and serotonin modulators [vortioxetine]) that are in general considered to have a better profile of tolerability in terms of hyponatraemia. With regard to the presented results, the risk of hyponatraemia with mirtazapine appears to be greater than what was reported in the literature; however, confounding by indication cannot be ruled out. Our pharmacovigilance-pharmacodynamic analysis also indicates that inhibition of the serotonin transporter may not be involved in the hyponatraemia linked to the use of antidepressant drugs.

On the Policy of the Italian Government in the Discovery, Development, and Access to Medicines.

This commentary outlines how discovery, development, and access to medicines are regulated and promoted in Italy by the government through the Ministry of University and Research, the Ministry of Health, and the Italian Medicines Agency. We describe and comment on the existing research programs stimulating preclinical, translational, and clinical research and how access to medicines and their pricing is regulated by Italy's National Health Service both at the national and regional levels. Finally, we describe the current scenario of industrial research and medicines manufacturing. The resulting picture shows a country in which high-level competitive research on medicines is promoted alongside an excellent national health system working toward fairness of access to health care services for all citizens and fiscal solidarity as a fundamental form of system financing. Critical challenges still exist, including the relative scarcity of public funding for research and the non-uniform access to the benefits of the National Health Service across Italian regions.

Combination evidence-based therapy is effective in the oldest 'old patients' following myocardial infarction. The "Salute e Benessere nell'Anziano" (SeBA) observational study.

Antiplatelet drugs, statins, angiotensinogen-converting enzyme inhibitors or angiotensin-II receptor blockers, and ß-blockers improve survival following myocardial infarction (MI). However, in old age they are under-prescribed, and their effectiveness in combination regimens is unproven. The aim of the study was to evaluate prescription of recommended cardiovascular drug classes and impact of a combination regimen on long-term mortality and hospitalizations. Records of 65+ years MI survivors, discharged from hospitals in four Local Health Units in Italy, were selected from administrative databases and analyzed. All-cause mortality and cardiovascular re-hospitalization in 12 months were compared across participants prescribed 0, 1, 2, 3, or 4 recommended drug classes. Out of 2626 participants (56 % men, 25 % aged 85+ years), 42 % were prescribed all, 14 % none of the recommended drug classes. The prescription rate decreased with advancing age. At all ages, mortality decreased with increasing number of drug classes prescribed: in participants aged 85+ years, adjusted hazard ratios (95 % confidence interval) for death were 0.74 (0.47-1.17), 0.52 (0.33-0.82), 0.30 (1.19-0.48), and 0.33 (0.20-0.53) for 1, 2, 3, and 4 classes prescribed, compared with none. The risk of cardiovascular re-hospitalizations decreased with an increasing number of drug classes prescribed through the age of 84 years. After MI, a combination regimen of recommended drug classes prevents long-term mortality at any age, and cardiovascular re-hospitalizations through the age of 84. Enhancing compliance with treatment guidelines may reduce the burden of mortality and hospitalizations in older MI survivors.

Clinical features and therapeutic management of patients admitted to Italian acute hospital psychiatric units: the PERSEO (psychiatric emergency study and epidemiology) survey.

BACKGROUND: The PERSEO study (psychiatric emergency study and epidemiology) is a naturalistic, observational clinical survey in Italian acute hospital psychiatric units, called SPDCs (Servizio Psichiatrico Diagnosi e Cura; in English, the psychiatric service for diagnosis and management). The aims of this paper are: (i) to describe the epidemiological and clinical characteristics of patients, including sociodemographic features, risk factors, life habits and psychiatric diagnoses; and (ii) to assess the clinical management, subjective wellbeing and attitudes toward medications. METHODS: A total of 62 SPDCs distributed throughout Italy participated in the study and 2521 patients were enrolled over the 5-month study period. RESULTS: Almost half of patients (46%) showed an aggressive behaviour at admission to ward, but they engaged more commonly in verbal aggression (38%), than in aggression toward other people (20%). A total of 78% of patients had a psychiatric diagnosis at admission, most frequently schizophrenia (36%), followed by depression (16%) and personality disorders (14%), and no relevant changes in the diagnoses pattern were observed during hospital stay. Benzodiazepines were the most commonly prescribed drugs, regardless of diagnosis, at all time points. Overall, up to 83% of patients were treated with neuroleptic drugs and up to 27% received more than one neuroleptic either during hospital stay or at discharge. Atypical and conventional antipsychotics were equally prescribed for schizophrenia (59 vs 65% during stay and 59 vs 60% at discharge), while atypical drugs were preferred in schizoaffective psychoses (72 vs 49% during stay and 70 vs 46% at discharge) and depression (41 vs 32% during stay and 44 vs 25% at discharge). Atypical neuroleptics were slightly preferred to conventional ones at hospital discharge (52 vs 44%). Polypharmacy was in general widely used. Patient attitudes toward medications were on average positive and self-reported compliance increased during hospital stay. CONCLUSION: Results confirm the widespread use of antipsychotics and the increasing trend in atypical drugs prescription, in both psychiatric in- and outpatients.

Main clinical features in patients at their first psychiatric admission to Italian acute hospital psychiatric wards. The PERSEO study.

BACKGROUND: Few data are available on subjects presenting to acute wards for the first time with psychotic symptoms. The aims of this paper are (i) to describe the epidemiological and clinical characteristics of patients at their first psychiatric admission (FPA), including socio-demographic features, risk factors, life habits, modalities of onset, psychiatric diagnoses and treatments before admission; (ii) to assess the aggressive behavior and the clinical management of FPA patients in Italian acute hospital psychiatric wards, called SPDCs (Servizio Psichiatrico Diagnosi e Cura = psychiatric service for diagnosis and management). METHOD: Cross-sectional observational multi-center study involving 62 Italian SPDCs (PERSEO--Psychiatric EmeRgency Study and EpidemiOlogy). RESULTS: 253 FPA aged < or = 40 were identified among 2521 patients admitted to Italian SPDCs over the 5-month study period. About half of FPA patients showed an aggressive behavior as defined by a Modified Overt Aggression Scale (MOAS) score greater than 0 Vs 46% of non-FPA patients (p = 0.3651). The most common was verbal aggression, while about 20% of FPA patients actually engaged in physical aggression against other people. 74% of FPA patients had no diagnosis at admission, while 40% had received a previous psychopharmacological treatment, mainly benzodiazepines and antidepressants. During SPDC stay, diagnosis was established in 96% of FPA patients and a pharmacological therapy was prescribed to 95% of them, mainly benzodiazepines, antipsychotics and mood stabilizers. CONCLUSION: Subjects presenting at their first psychiatric ward admission have often not undergone previous adequate psychiatric assessment and diagnostic procedures. The first hospital admission allows diagnosis and psychopharmacological treatment to be established. In our population, aggressive behaviors were rather frequent, although most commonly verbal. Psychiatric symptoms, as evaluated by psychiatrists and patients, improved significantly from admission to discharge both for FPA and non-FPA patients.