Use of antiseizure medications and safety of branded versus generic formulations: A comparative study on Tuscan administrative databases.

PURPOSE: To assess patterns of use of antiseizure medications (ASMs) and to compare the safety of generic versus branded formulations in terms of admission to hospital or to emergency department (ED). METHODS: We conducted a drug utilization study with a propensity score-matched design using the administrative databases of the Italian Tuscany region. New users of ASMs during 2015 with no history of neoplasia were considered and their first prescription was classified as: available only as branded (only-B-ASM); branded with generic available (B-ASM); and generic (G-ASM). Patients with G-ASM first prescription were matched with four patients with B-ASM prescription. Participants were followed up for one year or until the date of death or diagnosis of neoplasia. Cox regression models were fitted to estimate the risk of admission to hospital or ED. RESULTS: We identified 36,601 ASM new-users, including 2094 (6.4%) with only-B-ASM as first prescription, 24,588 (74.9%) with B-ASM, and 5788 (17.6%) with G-ASM. We found no differences in the risk of admission to hospital or ED (Hazard Ratio (HR), 0.92; 95% Confidence Interval (CI), 0.85-1.02) among users of generic ASMs compared to those using branded ASMs. CONCLUSIONS: In our study population, generic ASMs were used less than branded ones. The similarity in the safety of branded and generic formulations suggests that generic ASMs could be the preferred formulation in current clinical practice resulting in a substantial decrease in the cost of treatment.

Medical Devices Made of Substances: Possible Innovation and Opportunities for Complex Natural Products.

The novel Regulation 2017/745/EC on medical devices introduces and strengthens the role of "medical devices made of substances", which mostly include substances of natural origin. Natural products may follow different regulations, from food to therapeutics. Concerning their isolated constituents, extracts are characterized by a complexity that is not easily tackled from both a scientific and a regulatory point of view, but more importantly, from a therapeutic point of view. The evidence-based approach applied to isolated molecules requires appropriate evidence of quality, efficacy, and safety. The same needs must be reached for complex substances by finding appropriate methods to generate this evidence, and in addition, defining an appropriate regulatory field for them. From a scientific point of view, new methods, such as those proposed by systems biology, are available and applicable to complex substances. From a regulatory point of view, Directive 2001/83/EC on medicinal products seems to be modeled on single (or combinations of single) molecule products. On the other hand, Regulation 2017/745/EC on medical devices seems to apply to complex substances without derogating on quality, efficacy, and safety. The regulation specifically names and strengthens medical devices that include substances, mostly of natural origin, introducing the official term "medical devices made of substances". This paper discusses and proposes an interpretation of important terms connected to this legislation, regarding both scientific and regulatory issues, and the opportunities the regulation may give for innovation and therapeutic improvement with natural complex substances.

Antidepressants and the Risk of Cardiovascular Events in Elderly Affected by Cardiovascular Disease: A Real-Life Investigation From Italy.

PURPOSE: The purpose of this study was to assess the possible relation between use of antidepressant (AD) drugs, that is, tricyclic ADs, selective serotonin reuptake inhibitors (SSRIs), and atypical ADs (AAs), and the risk of hospitalization for cardiovascular (CV) events among older patients with previous CV diseases. METHODS: A nested case-control study was carried out among patients aged 65 years and older from 5 Italian health care territorial units who were discharged for CV disease during 2008 to 2010. The cohort was composed by 344,747 individuals, and of these, 97,739 (28%) experienced hospital admission for CV events (myocardial infarction, arrhythmia, stroke, heart failure) during follow-up (until 2014) and were included as cases. Up to 5 controls were randomly selected and matched to each. A conditional logistic regression was fitted to estimate the risk of CV events associated with ADs past or current use. A within-patient comparison was performed by the case-crossover design to account the effect of depression. FINDINGS: Current users of SSRIs and AAs were at increased risk of CV events with odds ratios of 1.25 (95% confidence interval, 1.21-1.29) and 1.31 (1.25-1.37), respectively. An increased risk of arrhythmia and stroke was associated with current use of SSRIs and AAs, whereas an increased risk of heart failure was detected with current use of any ADs. The results were confirmed by the case-crossover approach. IMPLICATIONS: Evidence that AD use is associated with an increased risk of CV events in accordance with specific mechanisms of action among older people with CV disease was added by this study.

Adverse events following cannabis for medical use in Tuscany: An analysis of the Italian Phytovigilance database.

AIMS: Despite a significant increase in using cannabis for medical purposes, current evidence on its safety in real-world clinical practice is still poorly characterised. By a case-by-case analysis of spontaneous reports of suspected adverse events (AEs) collected in Tuscany within the Italian Phytovigilance database, the aim of the present study was to describe AEs occurred in patients exposed to medical cannabis. METHODS: We evaluated all reports of cannabis-related suspected AEs collected within the Phytovigilance database up to December 2018. Information regarding cannabis therapy, patient's demographic and clinical characteristics, concomitant medications, AE description according to the Medical Dictionary for Regulatory Activities (MedDRA) classification, AE seriousness and AE outcome, were collected. The causality assessment was performed following World Health Organisation-Uppsala Monitoring Centre criteria. RESULTS: Fifty-three cannabis-related AE reports were analysed. The majority of patients were females (77.3%), with a mean age of 61.9 years. Thirty-nine (73.6%) cases were defined as nonserious and the majority of them (86.9%) showed a complete resolution or improvement. Forty-six (86.8%) cases were judged as probably related to cannabis consumption. The most frequently reported system organ class was psychiatric and nervous system disorders, and a potential drug-drug interaction was present in 16 cases. CONCLUSION: Cannabis was generally well tolerated and the majority of AEs were mild and transient. Our analysis highlighted important safety issues for clinical practice, in particular the need for an accurate prescription monitoring during the titration phase, particularly in the presence of concomitant medications.

Blood pressure and long-term mortality in older patients: results of the Fiesole Misurata Follow-up Study.

BACKGROUND: Optimal blood pressure (BP) control can prevent major adverse health events, but target values are still controversial, especially in older patients with comorbidities, frailty and disability. AIMS: To evaluate mortality according to BP values in a cohort of older adults enrolled in the Fiesole Misurata Study, after a 6-year follow-up. METHODS: Living status as of December 31, 2016 was obtained in 385 subjects participating in the Fiesole Misurata Study. Patients' characteristics were analysed to detect predictors of mortality. At baseline, all participants had undergone office BP measurement and a comprehensive geriatric assessment. RESULTS: After a 6-year follow-up, 97 participants had died (25.2%). After adjustment for comorbidities and comprehensive geriatric assessment, mortality was significantly lower for SBP 140-159 mmHg as compared with 120-139 mmHg (HR 0.54, 95% CI 0.33-0.89). This result was also confirmed in patients aged 75 + (HR 0.49, 95% CI 0.29-0.85), and in those with disability (HR 0.36, 95% CI 0.15-0.86) or taking antihypertensive medications (HR 0.49, 95% CI 0.28-0.86). DISCUSSION: An intensive BP control may lead to greater harm than benefit in older adults. Indeed, the European guidelines recommend caution in BP lowering in older patients, especially if functionally compromised, to minimize the risk of hypotension-related adverse events. CONCLUSIONS: After a 6-year follow-up, mortality risk was lower in participants with SBP 140-159 mmHg as compared with SBP 120-139 mmHg, in the overall population and in the subgroups of subjects aged 75 + , with a disability or taking anti-hypertensive medications.

Opioid response in paediatric cancer patients and the Val158Met polymorphism of the human catechol-O-methyltransferase (COMT) gene: an Italian study on 87 cancer children and a systematic review.

BACKGROUND: Genetic polymorphisms in genes involved in pain modulation have been reported to be associated to opioid efficacy and safety in different clinical settings. METHODS: The association between COMT Val158Met polymorphism (rs4680) and the inter-individual differences in the response to opioid analgesic therapy was investigated in a cohort of 87 Italian paediatric patients receiving opioids for cancer pain (STOP Pain study). Furthermore, a systematic review of the association between opioid response in cancer patients and the COMT polymorphism was performed in accordance with the Cochrane Handbook and the Prisma Statement. RESULTS: In the 87 paediatric patients, pain intensity (total time needed to reach the lowest possible level) was significantly higher for G/G than A/G and A/A carriers (p-value = 0.042). In the 60 patients treated only with morphine, the mean of total dose to reach the same pain intensity was significantly higher for G/G than A/G and A/A carriers (p-value = 0.010). Systematic review identified five studies on adults, reporting that opioid dose (mg after 24 h of treatment from the first pain measurement) was higher for G/G compared to A/G and A/A carriers. CONCLUSIONS: Present research suggests that the A allele in COMT polymorphism could be a marker of opioid sensitivity in paediatric cancer patients (STOP Pain), as well as in adults (Systematic Review), indicating that the polymorphism impact could be not age-dependent in the cancer pain context. TRIAL REGISTRATION: Registration number: CRD42017057831 .

Efficacy and safety of pharmacological treatments for patent ductus arteriosus closure: A systematic review and network meta-analysis of clinical trials and observational studies.

Efficacy and safety profiles of different pharmacological interventions used to treat patent ductus arteriosus (PDA) are relatively unexplored. Integrating the findings of randomized clinical trials (RCTs) with those from observational studies may provide key evidence on this important issue. We aimed at estimating the relative likelihood of failure to close the PDA, need for surgical closure, and occurrence of adverse events among preterm and full-term infants treated with indomethacin, ibuprofen, or acetaminophen, placebo, or no treatment including both RCTs and observational studies. We searched PubMed, Embase, and the Register of Controlled Trials from inception to October 30, 2018. We first estimated proportions of subjects with failure to close the PDA, subjects in whom surgical closure was performed after pharmacological treatment, death, and subjects with selected adverse events (AEs). These estimates were obtained using frequentist random-effect meta-analysis of arm-specific proportions. We then compared active drugs with each other and with control (either placebo or no treatment) by summarizing results at the end of treatment reported in the papers, regardless of number of administration(s), dose, route and type of administration, and study design and quality. We also summarized primary outcome results separately at first, second and third cycles of treatment. These estimates were obtained using Bayesian random-effects network meta-analysis for mixed comparisons, and frequentist random-effect pairwise meta-analysis for direct comparisons. We included 64 RCTs and 24 observational studies including 14,568 subjects (5339 in RCTs and 9229 in observational studies, 8292 subjects received indomethacin, 4761 ibuprofen, 574 acetaminophen, and 941 control (including placebo or no intervention).The proportion of subjects with failure to close the PDA was 0.24 (95% Confidence Interval, CI: 0.20, 0.29) for indomethacin, 0.18 (0.14, 0.22) for ibuprofen, 0.19 (0.09, 0.30) for acetaminophen, and 0.59 (0.48, 0.69) for control. At end of treatment, compared to control, we found inverse associations between all active drugs and failure to close PDA (for indomethacin Odds Ratio, OR, was 0.17 [95% Credible Interval, CrI: 0.11-0.24], ibuprofen 0.19 [0.12-0.28], and acetaminophen 0.15 [0.09-0.26]), without differences among active drugs. We showed inverse associations between effective drugs and need for surgical closure, as compared to control (for indomethacin OR was 0.28 [0.15-0.50], ibuprofen 0.30 [0.16-0.54], and acetaminophen 0.19 [0.07-0.46]), without differences among drugs. Indomethacin was directly associated with intraventricular hemorrhage (IVH) (1.27; 1.00, 1.62) compared to ibuprofen, and to oliguria as compared to ibuprofen (3.92; 1.69, 9.82) or acetaminophen (10.8; 1.86, 93.1). In conclusion, active pharmacological treatment, with indomethacin, ibuprofen, or acetaminophen, is inversely associated with failure to close the PDA compared to non-treatment. Ibuprofen should be preferred to indomethacin to avoid occurrence of IVH or oliguria, acetaminophen should be preferred to indomethacin to avoid oliguria.

Angiotensin-II Drives Human Satellite Cells Toward Hypertrophy and Myofibroblast Trans-Differentiation by Two Independent Pathways.

Skeletal muscle regeneration is ensured by satellite cells (SC), which upon activation undergo self-renewal and myogenesis. The correct sequence of healing events may be offset by inflammatory and/or fibrotic factors able to promote fibrosis and consequent muscle wasting. Angiotensin-II (Ang) is an effector peptide of the renin angiotensin system (RAS), of which the direct role in human SCs (hSCs) is still controversial. Based on the hypertrophic and fibrogenic effects of Ang via transient receptor potential canonical (TRPC) channels in cardiac and renal tissues, we hypothesized a similar axis in hSCs. Toward this aim, we demonstrated that hSCs respond to acute Ang stimulation, dose-dependently enhancing p-mTOR, p-AKT, p-ERK1/2 and p-P38. Additionally, sub-acute Ang conditioning increased cell size and promoted trans-differentiation into myofibroblasts. To provide a mechanistic hypothesis on TRPC channel involvement in the processes, we proved that TRPC channels mediate a basal calcium entry into hSCs that is stimulated by acute Ang and strongly amplified by sub-chronic Ang conditioning. Altogether, these findings demonstrate that Ang induces a fate shift of hSCs into myofibroblasts and provide a basis to support a benefit of RAS and TRPC channel blockade to oppose muscle fibrosis.

A systematic review of the risk factors for clinical response to opioids for all-age patients with cancer-related pain and presentation of the paediatric STOP pain study.

BACKGROUND: Inter-patient variability in response to opioids is well known but a comprehensive definition of its pathophysiological mechanism is still lacking and, more importantly, no studies have focused on children. The STOP Pain project aimed to evaluate the risk factors that contribute to clinical response and adverse drug reactions to opioids by means of a systematic review and a clinical investigation on paediatric oncological patients. METHODS: We conducted a systematic literature search in EMBASE and PubMed up to the 24th of November 2016 following Cochrane Handbook and PRISMA guidelines. Two independent reviewers screened titles and abstracts along with full-text papers; disagreements were resolved by discussion with two other independent reviewers. We used a data extraction form to provide details of the included studies, and conducted quality assessment using the Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies. RESULTS: Young age, lung or gastrointestinal cancer, neuropathic or breakthrough pain and anxiety or sleep disturbance were associated to a worse response to opioid analgesia. No clear association was identified in literature regarding gender, ethnicity, weight, presence of metastases, biochemical or hematological factors. Studies in children were lacking. Between June 2011 and April 2014, the Italian STOP Pain project enrolled 87 paediatric cancer patients under treatment with opioids (morphine, codeine, oxycodone, fentanyl and tramadol). CONCLUSIONS: Future studies on cancer pain should be designed with consideration for the highlighted factors to enhance our understanding of opioid non-response and safety. Studies in children are mandatory. TRIAL REGISTRATION: CRD42017057740 .

Comparative efficacy of antiepileptic drugs in children and adolescents: A network meta-analysis.

OBJECTIVE: To estimate the comparative efficacy among antiepileptic drugs in the pediatric population (0-18 years). METHODS: Using the Embase and MEDLINE databases, we updated to February 2017 the search strategy of the National Institute for Health and Care Excellence guidelines for epilepsy. We only included randomized clinical trials conducted in children and mixed-age populations. According to the PRISMA network meta-analysis guideline, the study-level quality assessment was made with the Cochrane risk-of-bias tool. Three investigators independently selected articles. The efficacy outcome was considered to be seizure freedom or ≥50% seizure reduction. RESULTS: We selected 46 randomized clinical trials. A total of 5652 individuals were randomized to 22 antiepileptic drugs and placebo. The point estimates of carbamazepine and lamotrigine efficacy showed their superiority with respect to all comparator antiepileptic drugs for the treatment of newly diagnosed focal epilepsy. In refractory focal epilepsy, levetiracetam (odds ratio [OR] = 3.3, 95% credible interval [CrI] = 1.3-7.6) and perampanel (OR = 2.5, 95% CrI = 1.1-5.8) were more effective compared to placebo. Ethosuximide and valproic acid were both superior to lamotrigine against absence seizures. The OR point estimate showed the superiority of adrenocorticotropic hormone over all comparators in infantile spasms. A wide heterogeneity in the length of follow-up was observed among the studies. SIGNIFICANCE: This network meta-analysis suggests that the quality of studies should be improved through the use of comparative designs, relevant outcomes, appropriate follow-up length, and more reliable inclusion criteria.

The use of complementary and alternative medicines during breastfeeding: results from the Herbal supplements in Breastfeeding InvesTigation (HaBIT) study.

AIMS: The use of complementary and alternative medicines (CAMs) during breastfeeding is increasing, mainly because of their presumed greater safety compared with conventional medications. However, CAMs can cause serious adverse effects, and there is limited high-quality evidence supporting their use during lactation. In Italy, specific investigations on the attitude of lactating women towards CAMs are lacking. The Herbal supplements in Breastfeeding InvesTigation (HaBIT) study aimed to explore attitudes to and knowledge on CAMs among lactating women. METHODS: A web-based survey was conducted over a 6-year period among lactating women resident in Tuscany, Italy. Data on lactating behaviour, CAMs use during pregnancy or breastfeeding, and women's knowledge about the efficacy and safety of CAMs were collected. RESULTS: A total of 388 lactating women answered the questionnaire. The majority of them were primiparae, with a high educational level. Of these, 204 women declared themselves to have used CAMs during breastfeeding. Moreover, 61% and 48% of subjects reported also using CAMs before and during pregnancy, respectively. A significant proportion of subjects were unable to identify correctly the types of CAMs they were using. Seventy-three per cent of women were convinced that CAMs were equally safe or safer than conventional medications; nevertheless, 65% of women admitted to have no scientific information about the potential risks of CAMs, and 14 CAMs users reported that they had experienced side effects. CONCLUSIONS: These results demonstrate the need for healthcare providers to increase the awareness of breastfeeding women about CAMs. Further research is needed to support the evidence base for nonpharmaceutical approaches for symptom control during breastfeeding.

NSAIDs utilization for musculoskeletal indications in elderly patients with cerebro/cardiovascular disease.

OBJECTIVES: To describe NSAID utilization for musculoskeletal conditions in a large cohort of Italian elderly with cerebro/cardiovascular disease, a population in which NSAIDs should be generally avoided due to the prothrombotic potential. METHODS: Administrative data from five Italian geographic areas were analyzed. Patients aged ≥ 65 with a cerebro/cardiovascular event recorded between 2008 and 2011 (cohort entry) were selected. Prescription NSAIDs reimbursed for musculoskeletal conditions and dispensed during 1 year follow-up were retrieved to describe (i) prevalence of use, (ii) average amount of defined daily doses of NSAIDs claimed by users per day of follow-up, and (iii) distribution of the received daily dose (RDD) among patients with ≥ 2 dispensings. Among new users, i.e., patients without NSAID dispensings during 2 years before cohort entry, the first dispensed NSAID molecule was observed. RESULTS: Overall, 511,989 patients were selected. Across the five geographic areas, prevalence of use ranged from 48 to 21% and average consumption ranged between 30 and 67 DDD/1000 users/day. Around 10% of patients in the overall cohort had a RDD > 1. Nimesulide (9.6%) and diclofenac (7.5%) had the highest prevalence of use. The most consumed NSAIDs were nimesulide and coxibs with 10.6 and 7.5 DDD/1000 users/day, respectively. Among new users recruited in 2011, 30% had diclofenac or a coxibs as the first prescription. CONCLUSIONS: NSAID use was common in the study cohort, particularly in central-southern areas. In contrast with current recommendations, coxibs and diclofenac were among the most prescribed active principles, even in new users. Interventions to promote appropriateness of use are warranted.

Bleeding events attributable to concurrent use of warfarin and other medications in high-risk elderly: meta-analysis and Italian population-based investigation.

PURPOSE: The aim of this study was to estimate the proportion of bleedings that occurred among warfarin users attributable to the concomitant use of other medications. A general approach for measuring the impact of the prescriptive inappropriateness on drug adverse outcomes at the population level is described. METHODS: A meta-analysis was conducted to obtain summary relative risks of bleeding associated with concurrent use of warfarin and other medications compared to warfarin use alone. A population-based investigation was performed, in an Italian cohort of cardiopathic patients aged 65 years or older, to estimate the prevalence of concurrent users of warfarin and other medicaments. The population attributable fraction was computed by combining data on summary relative risks and prevalence of concurrent users. RESULTS: Concomitant use of warfarin and cotrimoxazole, amiodarone, quinolones, macrolides, platelet aggregation inhibitors, SSRIs, NSAIDs, and lipid-lowering agents was associated with an increased risk of bleeding. The corresponding attributable fractions were 3% (95% CI 2 to 4%), 21% (1 to 41%), 21% (17 to 25%), 9% (8 to 10%), 14% (12 to 16%), 6% (5 to 8%), 10% (1 to 20%), and 8% (0 to 18%), respectively. CONCLUSIONS: More than half of bleeding events occurring among frail elderly using warfarin are attributable to a concomitant use of warfarin with certain drugs. Because some of these drugs appear to be essential for the treatment/prevention of cardiovascular conditions, and their concomitant use with warfarin could be acceptable in some cases, proper INR-monitoring and warfarin dose adjustments are requested.

Hyperpolarization-activated cyclic-nucleotide-gated channels: pathophysiological, developmental, and pharmacological insights into their function in cellular excitability.

The hyperpolarization-activated cyclic-nucleotide-gated (HCN) proteins are voltage-dependent ion channels, conducting both Na+ and K+, blocked by millimolar concentrations of extracellular Cs+ and modulated by cyclic nucleotides (mainly cAMP) that contribute crucially to the pacemaker activity in cardiac nodal cells and subsidiary pacemakers. Over the last decades, much attention has focused on HCN current, If, in non-pacemaker cardiac cells and its potential role in triggering arrhythmias. In fact, in addition to pacemakers, HCN current is constitutively present in the human atria and has long been proposed to sustain atrial arrhythmias associated to different cardiac pathologies or triggered by various modulatory signals (catecholamines, serotonin, natriuretic peptides). An atypical If occurs in diseased ventricular cardiomyocytes, its amplitude being linearly related to the severity of cardiac hypertrophy. The properties of atrial and ventricular If and its modulation by pharmacological interventions has been object of intense study, including the synthesis and characterization of new compounds able to block preferentially HCN1, HCN2, or HCN4 isoforms. Altogether, clues emerge for opportunities of future pharmacological strategies exploiting the unique properties of this channel family: the prevalence of different HCN subtypes in organs and tissues, the possibility to target HCN gain- or loss-of-function associated with disease, the feasibility of novel isoform-selective drugs, as well as the discovery of HCN-mediated effects for old medicines.

Synthesis of novel benzenesulfamide derivatives with inhibitory activity against human cytosolic carbonic anhydrase I and II and Vibrio cholerae α- and ß-class enzymes.

The synthesis of a new series of sulfamides incorporating ortho-, meta, and para-benzenesulfamide moieties is reported, which were investigated for the inhibition of two human (h) isoforms of the zinc enzyme carbonic anhydrase (CA, EC 4.2.1.1), hCA I and II, and two Vibrio cholerae enzymes, belonging to the α- and ß-CA classes (VchCAα, VchCAß). The compounds were prepared by using the "tail approach", aiming to overcome the scarcity of selective inhibition profiles associated to CA inhibitors belonging to the zinc binders. The built structure-activity relationship showed that the incorporation of benzhydryl piperazine tails on a phenyl sulfamide scaffold determines rather good efficacies against hCA I and VchCAα, with several compounds showing KIs < 100 nM. The activity was lower against hCA II and VchCAß, probably due to the fact that the incorporated tails are quite bulky. The obtained evidences allow us to continue the investigations of different tails/zinc binding groups, with the purpose to increase the effectiveness/selectivity of such inhibitors against bacterial CAs from pathogens, affording thus potential new anti-infectives.

2016 Update of the Italian Pediatric Society Guidelines for Management of Fever in Children.

OBJECTIVE: To review new scientific evidence to update the Italian guidelines for managing fever in children as drafted by the panel of the Italian Pediatric Society. STUDY DESIGN: Relevant publications in English and Italian were identified through search of MEDLINE and the Cochrane Database of Systematic Reviews from May 2012 to November 2015. RESULTS: Previous recommendations are substantially reaffirmed. Antipyretics should be administered with the purpose to control the child's discomfort. Antipyretics should be administered orally; rectal administration is discouraged except in the setting of vomiting. Combined use of paracetamol and ibuprofen is discouraged, considering risk and benefit. Antipyretics are not recommended preemptively to reduce the incidence of fever and local reactions in children undergoing vaccination, or in attempt to prevent febrile convulsions in children. Ibuprofen and paracetamol are not contraindicated in children who are febrile with asthma, with the exception of known cases of paracetamol- or nonsteroidal anti-inflammatory drug-induced asthma. CONCLUSIONS: Recent medical literature leads to reaffirmation of previous recommendations for use of antipyretics in children who are febrile.

Exposure to statins is associated to fracture risk reduction in elderly people with cardiovascular disease: evidence from the AIFA-I-GrADE observational project.

PURPOSE: Conflicting findings were observed from clinical trials and observational studies evaluating the association between the use of statins and the risk of fracture. A case-control study nested into a cohort of elderly patients on treatment with statins for cardiovascular secondary prevention was performed on this issue. METHODS: The cohort was formed by 13 875 individuals aged ≥65 years from several Italian health units receiving statins after hospital discharge for cardiovascular outcomes. From this cohort, 964 patients who experienced fracture were identified (i.e., cases). Up to five controls were randomly selected for each case from the underlying cohort. Conditional logistic regression was used to model the risk of fracture associated with adherence to statins, which was measured from the proportion of days covered (PDC) by treatment. A set of sensitivity analyses was performed in order to account for sources of systematic uncertainty. RESULTS: Compared with patients with low adherence (PDC ≤ 40%), those on intermediate (PDC 41-80%) and high (PDC > 80%) adherence exhibited a risk reduction of 21% (95% confidence interval 6% to 23%) and 25% (7% to 40%). Similar effects were observed among patients younger and older than 80 years, as well as among men, while there was no evidence that adherence to statins affected the risk of fracture among women. Sensitivity analyses revealed that the associations were consistent and robust. CONCLUSIONS: Use of statins for secondary cardiovascular prevention is associated with fracture risk reduction in elderly people. Further studies are required to better clarify the statin-fracture association in postmenopausal women. Copyright © 2017 John Wiley & Sons, Ltd.

ANMCO/ISS/AMD/ANCE/ARCA/FADOI/GICR-IACPR/SICI-GISE/SIBioC/SIC/SICOA/SID/SIF/SIMEU/SIMG/SIMI/SISA Joint Consensus Document on cholesterol and cardiovascular risk: diagnostic-therapeutic pathway in Italy.

Atherosclerotic cardiovascular disease still represents the leading cause of death in Western countries. A wealth of scientific evidence demonstrates that increased blood cholesterol levels have a major impact on the outbreak and progression of atherosclerotic plaques. Moreover, several cholesterol-lowering pharmacological agents, including statins and ezetimibe, have proved effective in improving clinical outcomes. This document focuses on the clinical management of hypercholesterolaemia and has been conceived by 16 Italian medical associations with the support of the Italian National Institute of Health. The authors discuss in detail the role of hypercholesterolaemia in the genesis of atherosclerotic cardiovascular disease. In addition, the implications for high cholesterol levels in the definition of the individual cardiovascular risk profile have been carefully analysed, while all available therapeutic options for blood cholesterol reduction and cardiovascular risk mitigation have been explored. Finally, this document outlines the diagnostic and therapeutic pathways for the clinical management of patients with hypercholesterolaemia.

Novel Sulfamide-Containing Compounds as Selective Carbonic Anhydrase I Inhibitors.

The development of isoform selective inhibitors of the carbonic anhydrase (CA; EC 4.2.1.1) enzymes represents the key approach for the successful development of druggable small molecules. Herein we report a series of new benzenesulfamide derivatives (-NH-SO2NH2) bearing the 1-benzhydrylpiperazine tail and connected by means of a ß-alanyl or nipecotyl spacer. All compounds 6a-l were investigated in vitro for their ability to inhibit the physiological relevant human (h) CA isoforms such as I, II, IV and IX. Molecular modeling provided further structural support to enzyme inhibition data and structure-activity relationship. In conclusion the hCA I resulted the most inhibited isoform, whereas all the remaining ones showed different inhibition profiles.

Clinical research in neonates and infants: Challenges and perspectives.

To date, up to 65% of drugs used in neonates and infants are off-label or unlicensed, as they were implemented in clinical care without the usual regulatory phases of pharmacological drug development. Pharmacotherapy in this age group is still mainly based on the individual clinical expertise of specialized pediatricians. Pharmacological trials involving neonates are indeed more difficult to perform: appropriate dosing is hampered by the rapid physiological changes occurring at this stage of development, and the selection of proper end-points and biomarkers is complicated by the limited knowledge of the pathophysiology of the specific diseases of infancy. Moreover, there are many ethical challenges in planning and conducting drug studies in pediatric patients (especially in newborns and infants). In the current review, we address some challenges and discuss possible perspectives to stimulate scientific and clinical pharmacological research in neonates and infants. We hereby aim to illustrate the add on value of the regulatory framework for model-based neonatal medicinal development currently used in Europe and the United States. We provide several examples of successful recent pharmacological trials performed in neonates and infants. In these examples, success was ensured by the implementation of specific pharmacokinetic assessments, thanks to accurate drug dosing achieved with a combination of dose validation, population pharmacokinetics and mathematical models of drug clearance and distribution; moreover, age-specific pharmacodynamics was considered via appropriate evaluations of drug efficacy with end-points adapted to the peculiar pathophysiology of diseases in this age group. These "pharmacological" challenges add to the ethical challenges that are always present in planning and conducting clinical studies in neonates and infants and support the opinion that clinical research in pediatrics should be evaluated by ad hoc ethical committees with specific expertise.