Annalisa Capuano

Metabolic syndrome and postmenopausal breast cancer: systematic review and meta-analysis.

ObjectiveThe role of metabolic syndrome (MS) and its individual components in postmenopausal breast cancer (PBC) risk is still unclear. We reviewed and summarized epidemiological studies assessing the association of MS with the risk of PBC. MethodsWe conducted an electronic search, without restrictions, for articles published before October 31, 2012. Every included study was to report risk estimates with 95% CIs for the association between MS and PBC. Study-specific estimates were pooled using random-effects models. ResultsNine articles (with 6,417 cancer cases), all published in English, were included in the meta-analysis. MS was associated with a 52% increase in cancer risk (P < 0.001)—for the most part confined to noncohort studies (109% increased risk); the risk estimates changed little, depending on populations (United States and Europe) and definition of the syndrome (traditional vs nontraditional). The risk estimates for PBC were 1.12 (P = 0.068) for higher values of body mass index/waist circumference, 1.19 (P = 0.005) for hyperglycemia (higher fasting glucose or diabetes), 1.13 (P = 0.027) for higher blood pressure, 1.08 (P = 0.248) for higher triglycerides, and 1.39 (P = 0.008) for lower high-density lipoprotein cholesterol. All these estimates were lower than those associated with MS in the same studies. ConclusionsMS is associated with a moderately increased risk of PBC. No single component explains the risk conveyed by the full syndrome.

Effect of metabolic syndrome and its components on prostate cancer risk: Meta-analysis

Background: Literature data examining the role of metabolic syndrome and its components in prostate cancer risk are limited and contradictory. Aim: We did a meta-analysis of studies that evaluated the association between metabolic syndrome, its components, and risk of prostate cancer. Subjects and methods: We conducted an electronic search for articles published through September 2012 without restrictions. Every included study was to report risk estimates with 95% confidence intervals for the association between metabolic syndrome and prostate cancer. Results: The final number of papers included in the meta-analysis was 14, all published in English, with 4728 prostate cancer cases. Metabolic syndrome was associated with a 12% increase in prostate cancer risk (p=0.231), that was lower in cohort studies (7 studies, RR=1.04, p=0.791) than other studies (RR=1.23, p=0.125). The association was significant in the 8 European studies (RR=1.30, p=0.034), but not in the 4 U.S. or 2 Asiatic studies. The risk estimates of prostate cancer for higher values of body mass index, dysglycemia or dyslipidemia (high triglycerides, low HDL-cholesterol) were not significant; on the contrary, hypertension and waist circumference >102 cm were associated with a significant 15% (p=0.035) and 56% (p=0.007) greater risk of prostate cancer, respectively. Conclusions: Metabolic syndrome is weakly and non significantly associated with prostate cancer risk, but associations vary with geography. Among single components of the syndrome, hypertension and higher waist circumference are significantly associated with increased risk of prostate cancer.

Association between drug and vaccine use and acute immune thrombocytopenia in childhood: a case-control study in Italy.

AbstractBackground: Immune thrombocytopenic purpura (ITP) is an immuno-mediated disease characterized by a decrease in platelet count and, in its more severe forms, by bleeding symptoms. Many drugs have been implicated in the pathogenesis of drug-induced thrombocytopenia in adults; only limited data on drug-related ITP in children have been published. Objective: Our study was set up to evaluate the consistency of the association between drug and vaccine use and ITP in children. Study Design: This study is part of an Italian multicentre study on adverse drug reactions in children, coordinated by the Italian National Institute of Health, which was started in November 1999 and is ongoing. Patients or Other Participants: The study was conducted by enrolling all children aged more than 1 month who were hospitalized through the paediatric emergency department for the following conditions: thrombocytopenia (platelet count <100×103/L); acute neurological disorders; non-infectious mucocutaneous diseases and vasculitis; and endoscopically confirmed gastroduodenal lesions and/or clinically defined haematemesis and melaena. Children with chronic pathologies or concomitant diagnoses of cancer or immunodeficiency were not included in our study. Main Outcome Measure: During hospital admission, a physician interviewed parents using a structured questionnaire. The main aim of the interview was to collect information on drug exposure in a time period of 3 weeks and vaccine exposure in a period of 6 weeks preceding hospitalization. Using a case-control study design, exposure of children with thrombocytopenia (cases) to drugs and vaccines was compared with similar exposure of children with gastroduodenal lesions and neurological disorders (controls); this allowed us to estimate the odds ratios (ORs) of the occurrence of thrombo-cytopenia associated with the use of drugs or vaccines. Results: Up to December 2007, the study population included 387 cases of thrombocytopenia and 1924 controls. Despite the low platelet count, ITP was generally a mild disease, without serious bleeding in the majority of cases and associated with a short length of hospital stay. After adjusting for concurrent use of other drugs, use of the antibacterials was associated with a more than 2-fold increase in the risk of developing ITP (OR 2.4; 95% CI 1.8, 3.1). Mucolytics and NSAIDs were associated with an OR of 1.9; 95% CI 1.2, 2.9 and 1.5; 95% CI 1.0, 2.1 respectively, while paracetamol (acetaminophen) was associated with an OR of 1.5; 95% CI 1.2, 2.0. MMR vaccination was associated with an increased risk of developing ITP (OR 2.4; 95% CI 1.2, 4.7). Conclusions: The results of this study provide evidence for an association between ITP and exposure to selected antibacterials, NSAIDs, paracetamol, mucolytics and MMR vaccination.

Drug‐induced hepatic injury in children: a case/non‐case study of suspected adverse drug reactions in VigiBase

AIM To identify which drugs are associated with reports of suspected hepatic injury in children and adolescents. METHODS Using a worldwide pharmacovigilance database, VigiBase, we conducted a case/non-case study on suspected adverse drug reactions (ADRs) occurring in the population <18 years old. Cases were all the records with hepatic ADRs and non-cases were all the other ADR records. Records regarding topically administered drugs were excluded from both groups. The association between drug and suspected hepatic ADRs was calculated using the reporting odds ratio (ROR) as a measure of disproportionality while adjusting for gender, country, reporter and calendar year. Sub-analyses were performed within therapeutic class and by excluding vaccination-related reports to reduce confounding. RESULTS Overall, 6595 (1%) out of 624 673 ADR records in children and adolescents concerned hepatic injury. Most of the reported hepatic injuries concerned children 12-17 years of age. Drugs that were most frequently reported as suspected cause and were associated with hepatic injury comprised paracetamol, valproic acid, carbamazepine, methotrexate, minocycline, zidovudine, pemoline, ceftriaxone, bosentan, ciclosporin, atomoxetine, olanzapine, basiliximab, erythromycin and voriconazole. The association between hepatotoxicity and all these drugs, except for basiliximab, is already known. CONCLUSIONS Drug-induced hepatic injury is infrequently reported (only 1% of total) as a suspected ADR in children and adolescents. The drugs associated with reported hepatotoxicity (paracetamol, antiepileptic and anti-tuberculosis agents) are known to be hepatotoxic in adults as well, but age related changes in associations were observed. VigiBase is useful as a start to plan further drug safety studies in children.

Glycaemic durability with dipeptidyl peptidase-4 inhibitors in type 2 diabetes: a systematic review and meta-analysis of long-term randomised controlled trials

Objectives To evaluate glycaemic durability with dipeptidyl peptidase-4 (DPP-4) inhibitors in type 2 diabetes. Design A systematic review and meta-analysis of long-term randomised trials of DPP-4 inhibitors on haemoglobin A1c (HbA1c) was conducted. Electronic searches were carried out on the following databases: MEDLINE, EMBASE, Scopus and Web of Knowledge to December 2013. Searches were supplemented by a review of trial registries and references from identified trials. Trials were included if they lasted at least 76 weeks, and had intermediate and final assessments of HbA1c. Citations and full-text articles were screened by two reviewers. A random effect model was used to pool data. Participants Adults with type 2 diabetes. Interventions Any DPP-4 inhibitor (sitagliptin, vildagliptin, saxagliptin, linagliptin and alogliptin). Outcome measures The difference between final and intermediate HbA1c assessment was the primary outcome. Results We screened 461 citations and reviewed 12 articles reporting 12 trials in 14 829 participants. All trials were of 76 weeks duration at least. The difference in HbA1c changes between final and intermediate points averaged 0.22% (95% CI 0.15% to 0.29%), with high heterogeneity (I2=91%, p<0.0001). Estimates of differences were not affected by the analysis of six extension trials (0.24%, 0.02 to 0.46), or five trials in which a DPP-4 inhibitor was added to metformin (0.24%, 0.16 to 0.32). Conclusions There is evidence that the effect of DPP-4 inhibitors on HbA1c in type 2 diabetes significantly declines during the second year of treatment. Future research should focus on the characteristics of patients that benefit most from DPP-4 inhibitors in terms of glycaemic durability.

Pharmacovigilance in Italy: An overview

Introduction: Spontaneous reporting of adverse drug reactions (ADRs) is the basis of pharmacovigilance. In fact, ADRs are associated with a high degree of morbidity and mortality. However, underreporting by all healthcare professionals remains the major problem in Italy and in the rest of the world. The dissemination of pharmacovigilance knowledge among Italian healthcare professionals, and the new pharmacovigilance regulations may promote the early detection and reporting of ADRs. This review examines the legislative framework concerning the pharmacovigilance in Italy. Materials and Methods: The information was collected from scientific articles and the websites of the Italian Ministry of Health and the Italian Medicines Agency (Agenzia Italiana del Farmaco, AIFA). Results: The pharmacovigilance system, both in Italy and Europe, has undergone profound changes. European legislation on pharmacovigilance has been changed in 2010 according to the EU Regulation 1235/2010 and Directive 2010/84/EU. Basically, the changes tend to increase the efficiency, speed and transparency of pharmacovigilance activities. The new Regulation (1235/2010) and the Directive (2010/84/EU) aim to strengthen the system of pharmacovigilance, establish more precisely who is obliged to do what, and allow faster and easier circulation and retrieval of information about ADRs. Conclusion: A greater knowledge on what is the Italian pharmacovigilance legislation will be useful to improve the status of ADRs reporting and spread the culture of spontaneous reporting.

A nomogram to estimate the HbA1c response to different DPP-4 inhibitors in type 2 diabetes: a systematic review and meta-analysis of 98 trials with 24 163 patients

Objectives To develop a nomogram for estimating the glycated haemoglobin (HbA1c) response to different dipeptidyl peptidase-4 (DPP-4) inhibitors in type 2 diabetes. Design A systematic review and meta-analysis of randomised controlled trials (RCTs) of DPP-4 inhibitors (vildagliptin, sitagliptin, saxagliptin, linagliptin and alogliptin) on HbA1c were conducted. Electronic searches were carried out up to December 2013. Trials were included if they were carried out on participants with type 2 diabetes, lasted at least 12 weeks, included at least 30 participants and had a final assessment of HbA1c. A random effect model was used to pool data. A nomogram was used to represent results of the metaregression model. Participants Adults with type 2 diabetes. Interventions Any DPP-4 inhibitor (vildagliptin, sitagliptin, saxagliptin, linagliptin or alogliptin). Outcome measures The HbA1c response to each DPP-4 inhibitor within 1 year of therapy. Results We screened 928 citations and reviewed 98 articles reporting 98 RCTs with 100 arms in 24 163 participants. There were 26 arms with vildagliptin, 37 with sitagliptin, 13 with saxagliptin, 13 with linagliptin and 11 with alogliptin. For all 100 arms, the mean baseline HbA1c value was 8.05% (64 mmol/mol); the decrease of HbA1c from baseline was −0.77% (95% CI −0.82 to −0.72%), with high heterogeneity (I2=96%). Multivariable metaregression model that included baseline HbA1c, type of DPP-4 inhibitor and fasting glucose explained 58% of variance between studies, with no significant interaction between them. Other factors, including age, previous diabetes drugs and duration of treatment added low predictive power (<1%). The nomogram estimates the absolute HbA1c reduction from baseline using the type of DPP-4 inhibitor, baseline values of HbA1c and fasting glucose. Conclusions Baseline HbA1c level and fasting glucose explain most of the variance in HbA1c change in response to DPP-4 inhibitors: each increase of 1.0% units HbA1c provides a 0.4–0.5% units greater fall.

Anti-inflammatory effect of simvastatin in an experimental model of spinal cord trauma: involvement of PPAR-α

BackgroundStatins such as simvastatin are inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase used in the prevention of cardiovascular disease. In addition to their cholesterol-lowering activities, statins exert pleiotropic anti-inflammatory effects, which might contribute to their beneficial effects on lipid-unrelated inflammatory diseases. Recently it has been demonstrated that the peroxisome proliferator-activated receptor (PPAR)-α mediates anti-inflammatory effects of simvastatin in vivo models of acute inflammation. Moreover, previous results suggest that PPAR-α plays a role in control of secondary inflammatory process associated with spinal cord injury (SCI).MethodsWith the aim to characterize the role of PPAR-α in simvastatin activity, we tested the efficacy of simvastatin (10 mg/kg dissolved in saline i.p. 1 h and 6 h after the trauma) in an experimental model of SCI induced in mice by extradural compression of the spinal cord (T6-T7 level) using an aneurysm clip with a closing force of 24 g via a four-level T5-T8 laminectomy, and comparing mice lacking PPAR-α (PPAR-α KO) with wild type (WT) mice. In order to elucidate whether the effects of simvastatin are due to activation of the PPAR-α, we also investigated the effect of a PPAR-α antagonist, GW6471 (1 mg/kg administered i.p. 30 min prior treatment with simvastatin) on the protective effects of on simvastatin.ResultsResults indicate that simvastatin activity is weakened in PPAR-α KO mice, as compared to WT controls. In particular, simvastatin was less effective in PPAR-α KO, compared to WT mice, as evaluated by inhibition of the degree of spinal cord inflammation, neutrophil infiltration, nitrotyrosine formation, pro-inflammmatory cytokine expression, nuclear factor (NF)-κB activation, inducible nitric-oxide synthase (iNOS) expression, and apoptosis. In addition we demonstrated that GW6471 significantly antagonized the effect of the statin and thus abolished the protective effect.ConclusionsThis study indicates that PPAR-α can contribute to the anti-inflammatory activity of simvastatin in SCI.

Dipeptidyl peptidase-4 inhibitors in type 2 diabetes therapy – focus on alogliptin

Type 2 diabetes mellitus is a complex and progressive disease that is showing an apparently unstoppable increase worldwide. Although there is general agreement on the first-line use of metformin in most patients with type 2 diabetes, the ideal drug sequence after metformin failure is an area of increasing uncertainty. New treatment strategies target pancreatic islet dysfunction, in particular gut-derived incretin hormones. Inhibition of the enzyme dipeptidyl peptidase-4 (DPP-4) slows degradation of endogenous glucagon-like peptide-1 (GLP-1) and thereby enhances and prolongs the action of the endogenous incretin hormones. The five available DPP-4 inhibitors, also known as ‘gliptins’ (sitagliptin, vildagliptin, saxagliptin, linagliptin, alogliptin), are small molecules used orally with similar overall clinical efficacy and safety profiles in patients with type 2 diabetes. The main differences between the five gliptins on the market include: potency, target selectivity, oral bioavailability, long or short half-life, high or low binding to plasma proteins, metabolism, presence of active or inactive metabolites, excretion routes, dosage adjustment for renal and liver insufficiency, and potential drug–drug interactions. On average, treatment with gliptins is expected to produce a mean glycated hemoglobin (HbA1c) decrease of 0.5%–0.8%, with about 40% of diabetic subjects at target for the HbA1c goal <7%. There are very few studies comparing DPP-4 inhibitors. Alogliptin as monotherapy or added to metformin, pioglitazone, glibenclamide, voglibose, or insulin therapy significantly improves glycemic control compared with placebo in adult or elderly patients with inadequately controlled type 2 diabetes. In the EXAMINE trial, alogliptin is being compared with placebo on cardiovascular outcomes in approximately 5,400 patients with type 2 diabetes. In clinical studies, DPP-4 inhibitors were generally safe and well tolerated. However, there are limited data on their tolerability, due to their relatively recent marketing approval. Alogliptin will be used most when avoidance of hypoglycemic events is paramount, such as in patients with congestive heart failure, renal failure, and liver disease, and in the elderly.

Protein Prenylation Contributes to the Effects of LPS on EFS-Induced Responses in Human Isolated Bronchi

Rho/Ras signaling pathways may play an important role in the mechanism of LPS-induced inflammation and bronchoconstriction. In this study, we investigated the effect of LPS on the transmural contractile tension induced by electrical field stimulation (EFS) of human isolated bronchi. The possible contribution of Rho/Ras signaling pathways was examined by using geranylgeranyl-pyrophosphate (GGPP) and farnesyl-pyrophosphate (FPP), the selective geranylgeranyl-pyrophosphate-transferase inhibitor GGTI2133, and the selective farnesyl-pyrophosphate transferase inhibitor FTI276, the hydroxy-3-methylglutaryl coenzyme A reductase inhibitor simvastatin and the Rho-associated coiled-coil-forming protein serine/threonine kinase inhibitor Y27632. LPS (300 ng/ml) significantly enhanced the EFS-induced contractile force of human bronchi (P < 0.05). The plateau was reached at 105.0 (±4.1) minutes; the maximal effect (Emax) value was 267.47 (±8.88) %, with a time to evoke a half-maximal contraction (t(1/2)) of 40.5 (±2.0) minutes. Pretreatment with GGPP (5 μM) enhanced the EFS-mediated contractile tension (Emax, 164.56 ± 9.80% and the t(1/2) 23.0 ± 2.5 min). Pretreatment with FPP (5 μM) was effective, as was GGPP, in enhancing the EFS response (Emax, of 189.23 ± 12.98% and a t(1/2) of 17.0 ± 4.5 min). Furthermore, GGTI2133 (500 nM) and FTI276 (10 nM) significantly inhibited the effects of GGPP and FPP on EFS-induced response. Pretreatment with GGPP (5 μM) significantly enhanced the EFS response compared with the control and LPS-treated tissues; GGTI2133 (500 nM) significantly inhibited the EFS-induced contractile tension in LPS (300 ng/ml)-treated tissues, and it was not possible to calculate the t(1/2). In addition, simvastatin and Y27632 (both 1 μM) were effective in abolishing the contracturant effect of LPS. Our results provide mechanistic evidence for the enhanced bronchoconstriction induced by LPS in human isolated airways, the contribution of Rho/Ras pathways in this LPS response, and the protective role of statins.