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Alberto Migliore,1 Emanuele Bizzi,1 Colin Gerard Egan,2 Mauro Bernardi,3 Lea Petrella4 1Rheumatology Unit, San Pietro Fatebenefratelli Hospital, Rome, 2Primula Multimedia SRL, Pisa, 3Department of Statistical Sciences, University of Padova, Padova, 4MEMOTEF Department, Sapienza University of Rome, Rome, Italy Background: Biological agents provide an important therapeutic alternative for rheumatoid arthritis patients refractory to conventional disease-modifying antirheumatic drugs. Few head-to-head comparative trials are available.Purpose: The aim of this meta-analysis was to compare the relative efficacy of different biologic agents indicated for use as monotherapy in rheumatoid arthritis.Methods: A systemic literature search was performed on electronic databases to identify articles reporting double-blind randomized controlled trials investigating the efficacy of biologic agents indicated for monotherapy. Efficacy was assessed using American College of Rheumatology (ACR) 20, 50, and 70 criteria at 16–24 weeks. Relative efficacy was estimated using Bayesian mixed-treatment comparison models. Outcome measures were expressed as odds ratio and 95% credible intervals.Results: Ten randomized controlled trials were selected for data extraction and analysis. Mixed-treatment comparison analysis revealed that tocilizumab offered 100% probability of being the best treatment for inducing an ACR20 response versus placebo, methotrexate, adalimumab, or etanercept. Likewise, for ACR50 and ACR70 outcome responses, tocilizumab had a 99.8% or 98.7% probability of being the best treatment, respectively, compared to other treatments or placebo. Tocilizumab increased the relative probability of being the best treatment (vs methotrexate) by 3.2-fold (odds ratio: 2.1–3.89) for all ACR outcomes.Conclusion: Tocilizumab offered the greatest possibility of obtaining an ACR20, ACR50, and ACR70 outcome vs other monotherapies or placebo. Keywords: biologics, meta-analysis, mixed-treatment comparison, monotherapy, rheumatoid arthritis, tocilizumab

Lidia Savi,1 Selene Mogavero,2 Colin Gerard Egan21Department of Neuroscience, University of Turin, Turin, Italy; 2Primula Multimedia SRL, Pisa, ItalyBackground: Migraine is a painful neurological disorder that affects over 10% of the general population. Frovatriptan and rizatriptan are antimigraine agents belonging to the triptan class. Although previous studies have independently compared the efficacy of these agents, contemporaneous data examining both pharmacokinetic (PK) properties and efficacy in parallel have not previously been available.Materials and methods: In this single-center double-blind study, 18 subjects (ten female) were treated for a single migraine attack with frovatriptan 2.5 mg or rizatriptan 10 mg. Plasma concentrations were measured predose and at 2, 4, 6, 12, 24, 48, and 72 hours after drug administration. The primary end point of this study was to evaluate the association between PK parameters and efficacy measures and recurrence rate. Secondary end points were pain-free and pain-relief episodes at 2 and 4 hours, recurrent episodes within 48 hours, and cumulative hazard of recurrence within 72 hours.Results: At baseline, approximately 17% of patients had mild migraine, while 83% had moderate–severe migraine. Although the time to maximum concentration was similar for both drugs (2.7 versus 2.3 hours), the terminal half-life for frovatriptan was longer than rizatriptan (29.3 versus 3.2 hours, P

Massimo Morosetti,1 Antonio Gorini,2 Anna Maria Costanzo,2 Silvia Cipriani,1 Sara Dominijanni,1 Colin G Egan,3 Laura Zappalà,1 Umberto di Luzio Paparatti21Nephrology and Dialysis Department, ‘G.B. Grassi’ Hospital, Ostia Lido, Rome, Italy; 2Abbott S.r.l., Campoverde (LT), Rome, Italy; 3Primula Multimedia S.r.l., Pisa, ItalyBackground: A lack of awareness of chronic kidney disease (CKD) often results in delayed diagnosis and inadequate treatment.Purpose: The objective of this study was to assess the therapeutic management and outcome of nondialysis CKD patients.Methods: Three hundred ninety-seven patients (54.9% males aged 67.5 ± 14.6 years) were retrospectively screened at the Nephrology Department, GB Grassi Hospital, Rome, Italy. After a baseline visit, patient data were collected every 6 months for a total of 24 months. Clinical characteristics were measured at baseline, then the following outcomes were measured every 6 months: staging of CKD, presence of concomitant diseases, treatment and adherence to Kidney Disease Outcomes Quality Initiative (K/DOQI) guidelines for anemia management.Results: Three hundred sixty-eight (92.7%) patients attended at least one visit and 92 (23.2%) patients attended all four visits. Patients were mainly referred to a nephrologist for chronic renal failure (61.7%) or hypertension (42.8%). At baseline, 79.6% of patients had previous hospitalization and 79.1% were receiving antihypertensive medication. Serum creatinine and/or glomerular filtration rate was examined in >90% of patients, whereas parathyroid hormone was rarely examined (5.5%). Vitamin D supplementation was received by 6.5% of patients. The majority of patients were staged at 3 or 4 CKD (32% and 23.9%, respectively) and did not significantly change over time. The use of antithrombotic, antilipidemic and erythropoietin medication increased over the four surveys. The majority of patients (86.8%) achieved hemoglobin K/DOQI target levels.Conclusion: These findings demonstrate a current lack of attention of CKD and related disorders (mineral metabolism, electrolyte balance, and anemia) at the level of the general practitioner (GP) and non-nephrology specialist, which can result in both delayed referral and inadequate treatment. By increasing both awareness of CKD and the coordinated relationship between GPs and nephrologists, patient clinical and therapeutic outcome may be improved.Keywords: chronic kidney disease, metabolic bone disorders, predialysis, renal failure

Maria Circelli,1 Gabriele Nicolini,1 Colin G Egan,2 Giovanni Cremonesi11Chiesi Farmaceutici, Direzione Medica, Parma, Italy; 2Primula Multimedia, Pisa, ItalyAbstract: The main objective of this meta-analysis was to compare the efficacy of the combination of delapril and indapamide (D+I) to different angiotensin-converting enzyme inhibitor (ACEi) plus hydrochlorothiazide (HCTZ) combinations for the treatment of mild-to-moderate hypertension. A secondary objective was to examine the safety of these two combinations. Studies comparing the efficacy of D+I to ACEi+HCTZ combinations in hypertensive patients and published on computerized databases (1974–2010) were considered. Endpoints included percentage of normalized patients, of responders, change in diastolic and systolic blood pressure (DBP/SBP) at different time-points, percentage of adverse events (AEs), and percentage of withdrawal. Four head-to-head randomized controlled trials (D+I-treated, n = 643; ACEi+HCTZ-treated, n = 629) were included. Meta-analysis indicated that D+I-treated patients had a higher proportion with normalized blood pressure (P = 0.024) or responders (P = 0.002) compared to ACEi+HCTZ-treated patients. No difference was observed between treatments on absolute values of DBP and SBP at different time-points. Although the rate of patients reporting at least one AE was similar in both groups (10.4% versus 9.9%), events leading to study withdrawal were lower in the D+I group versus the ACEi+HCTZ group (2.3% versus 4.8%, respectively; P = 0.018). This meta-analysis suggests that treatment with D+I could provide a higher proportion of normalized or responder patients with good tolerability compared to ACEi+HCTZ combinations.Keywords: meta-analysis, hypertension, ACE inhibitor, diuretic, delapril, indapamide

Gastone Leonetti,1 Colin G Egan21Istituto Auxologico Italiano, Ospedale San Luca, Milan, Italy; 2Primula Multimedia SRL, Pisa, ItalyAbstract: β-blockers are effective antihypertensive agents and, together with diuretics, have been the cornerstone of pioneering studies showing their benefits on cardiovascular morbidity and mortality as a consequence of blood pressure reduction in patients with hypertension. However, evidence from recent meta-analyses have demonstrated no benefit afforded by atenolol compared with placebo in risk of mortality, myocardial infarction, or stroke, and a higher risk of mortality and stroke with atenolol/propranolol compared with other antihypertensive drug classes. Thus, the effect of these agents on cardiovascular morbidity and mortality in hypertensive patients, especially their use in uncomplicated hypertension, has remained largely controversial. However, it is recognized that the clinical studies used in these meta-analyses were mainly based on the older second-generation β-blockers, such as atenolol and metoprolol. Actually, considerable heterogeneity in, eg, pharmacokinetic, pharmacological, and physicochemical properties exists across the different classes of β-blockers, particularly between the second-generation and newer third-generation agents. Carvedilol is a vasodilating noncardioselective third-generation β-blocker, without the negative hemodynamic and metabolic effects of traditional β-blockers, which can be used as a cardioprotective agent. Compared with conventional β-blockers, carvedilol maintains cardiac output, has a reduced prolonged effect on heart rate, and reduces blood pressure by decreasing vascular resistance. Studies have also shown that carvedilol exhibits favorable effects on metabolic parameters, eg, glycemic control, insulin sensitivity, and lipid metabolism, suggesting that it could be considered in the treatment of patients with metabolic syndrome or diabetes. The present report provides an overview of the main clinical studies concerning carvedilol administered as either monotherapy or in combination with another antihypertensive or more frequently a diuretic agent, with particular focus on the additional benefits beyond blood pressure reduction.Keywords: carvedilol, β-blocker, hypertension, diabetes, atherosclerosis

Few studies have evaluated the association between circulating levels of 25-hydroxyvitamin D (25(OH)D), 1,25-dihydroxyvitamin D (1,25(OH) 2 D), and the endocrine disruptor bisphenol A (BPA), with risk of cardiovascular (CV) disease in elderly individuals. This was a cross-sectional study in a subgroup of elderly people from the InCHIANTI Biobank in Italy. We examined the association between circulating serum vitamin D metabolites, 1,25(OH) 2 D, 25(OH)D, and the endocrine disrupting agent BPA, with an arbitrary CV risk score and the European Society of Cardiology-based 10-year CV risk (SCORE2/SCORE2-OP) using univariate and multiple regression. In 299 individuals, blood samples were tested for serum values of 25(OH)D, 1,25(OH) 2 D and urinary BPA levels. One hundred eighty individuals (60.2%) were deficient (< 20 ng/ml) in 25(OH)D. Levels of 25(OH)D and 1,25(OH) 2 D were negatively correlated with CV risk score (p < 0.0001 for both) as well as SCORE2/SCORE2-OP (p < 0.0001 for both) while BPA levels were positively correlated with both CV risk scores (p < 0.0001 for both). In a logistic regression model, male gender (odds ratio; OR: 2.1, 95% CI:1.1-3.8, p = 0.022), obesity (OR:2.8, 95% CI:1.2-6.5, p = 0.016) and BPA levels ≥ 110 ng/dl (OR:20.9, 95% CI:9.4-46.8, p < 0.0001) were associated with deficient levels of 25(OH)D. 1,25(OH)2D levels < 41 ng/dl and 25(OH)D levels < 20 ng/ml were associated with CV risk score ≥ 3 (OR: 4.16, 95% CI: 2.32-7.4, p < 0.0001 and OR: 1.86, 95% CI: 1.02-3.39, p = 0.044) respectively and 1,25(OH)2D levels < 41 ng/dl were associated with SCORE2/SCORE2-OP of ≥ 20% (OR:2.98, 95% CI: 1.7-5.2, p = 0.0001). In this cross-sectional analysis, BPA exposure was associated with significantly reduced levels of vitamin D that in turn were significantly associated with increased CV risk., (© 2024. The Author(s).)

Hypophosphatasia (HPP) is a rare disorder of the bone metabolism, characterized by genetically-determined low alkaline phosphatase (ALP) activity. Low ALP may also be observed in some common causes of bone fragility, such as in osteoporosis treated with antiresorptive drugs. This study aimed to verify whether differences in bone turnover markers (BTMs) could help differentiate adult patients with HPP from those with osteoporosis undergoing antiresorptive treatment. In this multicenter study, we enrolled 23 adult patients with a diagnosis of HPP and compared them with 46 osteoporotic subjects previously treated with zoledronic acid or denosumab. BTMs such as C-terminal telopeptide of type I collagen (CTX), N-terminal propeptide of type I procollagen (P1NP), total ALP, and bone ALP (bALP) were measured, and ratios between BTMs were also calculated. Considering that the control group included only females, in the primary analysis we compared their characteristics with that of the 16 female patients with HPP. Both individual BTMs (CTX and P1NP) and four BTM ratios (ALP/P1NP, bALP/P1NP, ALP/CTX, and bALP/CTX) showed satisfactory discriminatory power, outperforming ALP alone. P1NP, in particular, had an AUC of 0.962 with a cut-off of 32 μg/L, while as for the BTMs ratios, the ALP/P1NP ratio had an AUC of 0.964 with a cut-off of 1.114. Similar results were confirmed when including male HPP patients, when adjusting for age and sex, and finally when performing a sensitivity analysis only in patients with ALP less than or equal to 32 U/L (i.e., the median of the distribution of the entire population). In cases of low ALP and bone fragility, BTM and their ratios could help distinguish HPP patients from osteoporotic individuals treated with antiresorptive drugs, aiding in accurate diagnosis and reducing the risk of inappropriate treatment., (© The Author(s) 2024. Published by Oxford University Press on behalf of the American Society for Bone and Mineral Research. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

A retrospective analysis was performed to evaluate the frequency of vitamin D blood testing in individuals from the Padua province, Veneto, Italy from 2005 to 2016. A significant increase in the frequency of vitamin D blood tests, particularly in females was observed and in individuals with severe vitamin D deficiency (Class I)., Purpose: Vitamin D deficiency has been linked to negative health outcomes that extend beyond bone-related conditions. The frequency of vitamin D blood testing in residents from the Padua province, (Veneto, Italy) from 2005 to 2016 was evaluated., Methods: Data were retrospectively retrieved from blood test databases (Laboratory Medicine Unit, Padua University Hospital) and information on number of vitamin D blood tests performed on residents from 2005 to 2016 was collected. Data were stratified by sex and ten birth cohorts from 1901 to 2016. Blood tests were classified into five vitamin D classes: I < 50 nmol/L, II 50-74.9 nmol/L, III 75-149 nmol/L, IV 150-250 nmol/L, and V > 250-1000 nmol/L. Blood test trends were analyzed as blood test rate and vitamin D class rate/resident population. Population analysis was analyzed by incidence rates and stratified by vitamin D class., Results: 293,013 vitamin D blood tests were conducted between 2005 and 2016 across 10 birth cohorts. Females accounted for 75% of tests and fewer were conducted in the youngest and oldest birth cohorts. Sex differences in vitamin D blood test frequency were observed; adjusted rates ranging from 1.7 to 35.6% for males and 8 to 81% for females from 2005 to 2016. Crude incidence rates (per 1000 from 2005 to 2016) varied from 1.5 to 10.8‰ for males and 7 to 19.4‰ for females. Crude blood test rates for vitamin D deficiency (Class I) increased from 1.1 to 9.9‰ in 2016 for males and 5 to 17.3‰ for females. Crude incidence rates (from 2005 to 2016) for Class I were 9.7-57.1‰ in males and 43.6-92.4‰ in females., Conclusions: These findings highlight sex-related differences in vitamin D testing, providing valuable insight for healthcare planning., (© 2024. The Author(s).)

Background: Undifferentiated shock is recognized as a criticality state that is transitional in immune-mediated topology for casual risk of lethal microcirculatory dysfunction. This was a sensitivity analysis of a drug (tetracosactide; TCS10) targeting melanocortin receptors (MCRs) in a phase 3 randomized controlled trial to improve cardiovascular surgical rescue outcome by reversing mortality and hemostatic disorders., Methods: Sensitivity analysis was based on a randomized, two-arm, multicenter, double-blind, controlled trial. The Naïve Bayes classifier was performed by density-based sensitivity index for principal strata as proportional hazard model of 30-day surgical risk mortality according to European System for Cardiac Operative Risk Evaluation inputs-outputs in 100 consecutive cases (from August to September 2013 from Emilia Romagna region, Italy). Patients included an agent-based TCS10 group (10 mg, single intravenous bolus before surgery; n = 56) and control group (n = 44) and the association with cytokines, lactate, and bleeding-blood transfusion episodes with the prior-risk log-odds for mortality rate in time-to-event was analyzed., Results: Thirty-day mortality was significantly improved in the TCS10 group vs. control group (0 vs. 8 deaths, P < 0.0001). Baseline levels of interleukin (IL)-6, IL-10, and lactate were associated with bleeding episodes, independent of TCS10 treatment [odds ratio (OR) = 1.90, 95% confidence interval (CI) 1.39-2.79; OR = 1.53, 95%CI 1.17-2.12; and OR = 2.92, 95%CI 1.40-6.66, respectively], while baseline level of Fms-like tyrosine kinase 3 ligand (Flt3L) was associated with lower bleeding rates in TCS10-treated patients (OR = 0.31, 95%CI 0.11-0.90, P = 0.03). For every 8 TCS10-treated patients, 1 bleeding case was avoided. Blood transfusion episodes were significantly reduced in the TCS10 group compared to the control group (OR = 0.32, 95%CI 0.14-0.73, P = 0.01). For every 4 TCS10-treated patients, 1 transfusion case was avoided., Conclusions: Sensitivity index underlines the quality target product profile of TCS10 in the runway of emergency casualty care. To introduce the technology readiness level in real-life critically ill patients, further large-scale studies are required., Trial Registration: European Union Drug Regulating Authorities Clinical Trials Database (EudraCT Number: 2007-006445-41 )., (© 2024. The Author(s).)

Introduction: Few studies have explored the intricate connections between vitamin D receptor (VDR) gene polymorphisms, VDR, tight junction (TJ) protein expression and clinical features of atopic dermatitis (AD)., Methods: From 43 adult AD patients, VDR polymorphisms were genotyped from peripheral blood samples using polymerase chain reaction-restriction fragment length polymorphism. VDR, occludin, claudin-1 and ZO-1 protein expression from skin lesion biopsies were assessed by immunohistochemistry., Results: The A1012G heterozygous VDR polymorphism exhibited a lower odds ratio (OR) for juvenile AD onset (OR: 0.046, 95% CI 0.004-0.51, p=0.012). In contrast, the presence of ≥2 homozygous VDR polymorphisms were significantly associated with positive skin prick test (SPT) (10/20, 50%) vs. negative SPT (1/23, 4.3%; p=0.0003). The most highly expressed TJ proteins in lesions of AD patients were claudin-1 and zonulin-1 (ZO-1), while VDR and occludin were less prevalent. A significant correlation was observed between ZO-1 expression and a body mass index ≥30 kg/m 2 (OR: 12.1, 95% CI 1.06-137.9, p=0.045). Claudin-1 expression was associated with a positive SPT (OR: 8.23, 95% CI 1.04-65.5, p=0.046) and serum 25(OH)D levels were negatively correlated with ZO-1 expression (rho= -0.43, p=0.0058)., Conclusion: This study provides novel insights into the relationship between VDR gene polymorphisms, VDR, TJ protein expression, and clinical features in adult AD patients, highlighting a significant role of vitamin D in the pathophysiology of this disease.

Few studies have evaluated the effect of bovine lactoferrin (bLf) on reducing respiratory infections in preschool children. This randomized controlled trial evaluated the effect of bLf in preschool children with recurrent respiratory infections. Participants were randomly assigned bLf (n = 25) or control ( n = 25). Outcomes included respiratory infection episodes (RIEs), symptom duration, school absence and medication. Fifty children aged 4.2 ± 0.1 years were included. During the active 4-month phase, median number of RIEs was reduced by 50% in the bLf group [1-episode, interquartile range (IQR): 0-2] vs. control (2, IQR: 1-3; p = 0.02). The proportion of participants with >3 RIEs was significantly lower in bLf ( n = 1, 4%) vs. control ( n = 7, 28%) with 80% lower odds of upper RIEs in the bLf arm (odds ratio: 0.20, 95% CI:0.06-0.74, p = 0.015). The duration of symptoms (3 vs. 6, p = 0.009) and days absent from school (3 vs. 6, p = 0.15) were lower in the active arm. Over the 2-month follow-up, no significant differences were observed between groups for infection episodes, symptom duration or school absence. However, bLf-treated children received significantly less corticosteroids over the entire 6-month study period (32% vs. 60%; p = 0.047). bLf supplementation significantly reduced the frequency and duration of RIEs in children with decreased corticosteroid use.

Patients undergoing hemodialysis with iron deficiency anemia (IDA) receiving treatment with erythropoiesis-stimulating agents (ESAs) who were intolerant or non-responsive to intravenous (i.v.) ferric gluconate (FG) (hemoglobin; Hb values < 10.5 g/dL or increase in <1 g/dL) or % transferrin saturation; TSAT of <20%) in the previous 6 months were switched to i.v. ferric carboxymaltose (FCM). Changes in iron status parameters, economic and safety measures were also assessed. Seventy-seven hemodialysis patients aged 68 ± 15 years were included. Erythropoietin resistance index decreased from 24.2 ± 14.6 at pre-switch to 20.4 ± 14.6 after 6 months of FCM treatment and Hb levels ≥10.5 g/dL improved from 61% to 75.3% patients (p = 0.042). A 1 g/dL increase in Hb levels was also seen in 26% of patients as well as a 37.7% increase in patients achieving >20% increase in TSAT after FCM. Levels of Hb, TSAT and ferritin parameters increased during FCM treatment with a concomitant decrease in ESA. A mixed-model analysis, which also considered gender, confirmed these trends. Safety variables remained stable, no hypersensitivity reaction was recorded and only one patient reported an adverse event after FCM. FCM treatment was associated with a cost saving of 11.11 EUR/patient/month. These results confirm the efficacy, safety and cost-effectiveness of FCM in correcting IDA in hemodialysis patients.

Previous studies have shown a relationship between vitamin D and celiac disease (CD), however little evidence is available examining the direct effects of vitamin D on pathological features of this disease. In this study we evaluated the effect of oral administration of different doses of native vitamin D3 (cholecalciferol) in enteropathic mice. Female non-obese diabetic (NOD)/ShiLt.J mice were fed standard or gluten-free diet and administered gliadin (5 μg/kg) to induce a celiac pathology. Healthy control (gluten-free diet, without gliadin) and control for pathology (standard diet, with gliadin) were administered olive oil. All other experimental groups received gliadin and standard diet plus oral cholecalciferol (5, 10, 20, 50 and 130 μg/kg). Serum levels of 25(OH)D3, calcium and zonulin and expression of vitamin D receptor (VDR), CD3 and zonula occludens-1 (ZO-1) by immunohistochemistry as well as intestinal histological and histomorphometric analyses were undertaken. Although no difference in serum levels of 25(OH)D3, calcium or zonulin was observed in cholecalciferol-treated mice vs. healthy controls, a significant improvement in intestinal mucosa pathological features in mice administered cholecalciferol was observed by histological analysis. Villi length was also significantly increased by cholecalciferol in a dose-dependent manner. Immunohistochemical staining revealed increased expression of CD3 and ZO-1 in celiac mice compared to mice receiving high dose (130 μg/kg) cholecalciferol. These findings show the effect of oral cholecalciferol on signature features of CD in a mouse model of CD. Further dose-ranging studies to investigate the efficacy of cholecalciferol for the treatment of CD are warranted., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: This study aimed to evaluate the association between the endocrine-disrupting chemical, bisphenol A (BPA) on circulating levels of 25-hydroxy vitamin D (25(OD)D) and other vitamin D metabolites in an elderly population in Italy., Methods: This was a retrospective analysis of the InCHIANTI Biobank in Italy. The association between vitamin D metabolites namely 1,25(OH)D, 25(OH)D, parathyroid hormone (PTH) and BPA levels were evaluated. Multiple regression models were used to examine the association between predictor variables with 1,25(OH)D or 25(OH)D levels., Results: Samples from 299 individuals aged 72.8 ± 15.7 years were examined. Mean levels of BPA, 1,25(OH)D and 25(OH)D were 351.2 ± 511.6 ng/dL, 43.7 ± 16.9 pg/mL and 20.2 ± 12.1 ng/mL, respectively. One hundred eighty individuals (60.2%) were deficient (<20 ng/mL) in 25(OH)D and this population also presented higher BPA levels (527.9 ± 1289.5 ng/dL vs 86.9 ± 116.8 ng/dL, P < 0.0001). Univariate analysis revealed that BPA levels were negatively correlated with both 1,25(OH)D (r= -0.67, P < 0.0001) and 25(OH)D (r= -0.69, P < 0.0001). Multivariate regression revealed that PTH (β: -0.23, 95% CI: -0.34, -0.13, P < 0.0001) and BPA (β: -0.25, 95% CI: -0.3, -0.19, P < 0.0001) remained significantly associated with 25(OH)D levels while BPA was also associated with 1,25(OH)D levels (β: -0.19, 95% CI: -0.22, -0.15, P < 0.0001). Receiver operating characteristic curve analysis showed that a BPA concentration of >113 ng/dL was the best cut-off to predict individuals deficient in 25(OH)D (area under the curve: 0.87, 95% CI: 0.82-0.90, P < 0.0001)., Conclusion: The strong negative association between BPA and vitamin D in this elderly population warrants further investigation, particularly since this population is already at greatest risk of hypovitaminosis and fracture.

Background: Transplantation (Tx) is an effective therapeutic option in patients with end-stage organ failure and osteoporosis and related fractures are a recognized complication in these patients. Aim of this study was to evaluate the efficacy of neridronate in patients with reduced bone mass after Tx of the heart, liver or lung., Methods: In this multicenter randomized double-blind controlled trial (RCT), 22 patients were treated with neridronate (25 mg i.m./month) and 17 received placebo. All patients received daily oral calcium (500 mg) and vitamin D (400 IU). Dual-energy X-ray absorptiometry (DXA) was evaluated at 0, 6 and 12 months and markers of bone turnover at 0, 3, 6, 9 and 12 months., Results: Thirty-nine patients (11 heart Tx, 21 liver Tx, 7 lung Tx), aged 49.3±9.1 years, with a T-score <-2.0 SD at lumbar spine or femoral level were included. In neridronate-treated patients, a significant increase in lumbar bone mineral density (BMD) was observed after 12 months vs. placebo control (0.92±0.13 g/cm 2 vs. 0.84±0.08 g/cm 2 ; P=0.005). Femur and hip BMD remained unchanged between groups. Total alkaline phosphatase, bone alkaline phosphatase and beta-cross-laps significantly decreased over the 12 months in neridronate-treated patients vs. placebo, respectively (107.4±74 U/L vs. 157.6±107.1 U/L, P=0.002; 5.7±3.3 µg/L vs. 11.7±4.3 µg/L, P<0.001 and 0.25±0.13 ng/mL vs. 0.73±0.57 ng/mL, P<0.001). No difference was observed between neridronate and placebo groups regarding safety profile., Conclusions: This is the first RCT that demonstrates the efficacy of neridronate in increasing bone density and reducing bone turnover in organ Tx recipients with significant skeletal morbidity.

Hyperphosphatemia is a risk factor for vascular calcifications (VCs), which are part of the chronic kidney disease-mineral and bone disorders (CKD-MBD). Vitamin K-dependent proteins such as matrix Gla protein (MGP) and bone Gla proteins (BGP, or osteocalcin) can inhibit VCs and regulate bone mineralization. In this analysis of the Vitamin K Italian (VIKI) study, the relationship between vitamin K status, vertebral fractures (VFs) and VCs in 387 hemodialysis (HD) patients with (N = 163; 42.1%) or without N = 224; 57.9%) sevelamer was evaluated. Levels of vitamin K vitamers K1 and K2 or menaquinones (MK; MK4-7), total and undercarboxylated (uc) forms for both BGP and MGP were determined. Although no differences in clinical characteristics were noted, lower levels of MK4 (0.45 versus 0.6 ng/mL, p = .01) and a greater MK4 deficiency was observed in sevelamer-treated patients (13.5% versus 5.4%, p = .005). Multivariate logistic regression revealed that MK4 deficiency was associated with sevelamer use (odds ratio [OR] = 2.64, 95% confidence interval [CI] 1.25-5.58, p = .011) and aortic calcification (OR = 8.04, 95% CI 1.07-60.26, p = .04). In the same logistic model, sevelamer amplified the effect of total BGP levels on the odds of VFs in patients with total BGP <150 μg/L compared with those with total BGP ≥150 μg/L (OR = 3.15, 95% CI 1.46-6.76, p = .003). In contrast, there was no such effect in those untreated (total BGP <150 μg/L versus total BGP ≥150 μg/L: OR = 1.21, 95% CI 0.66-2.23, p = .54]; p = .049 for effect modification by sevelamer). Sevelamer may interfere with MK4 levels in HD patients and interact with low BGP levels to increase bone fractures in CKD patients. © 2020 American Society for Bone and Mineral Research (ASBMR)., (© 2020 American Society for Bone and Mineral Research (ASBMR).)

Little information is available on the beneficial effects of cholecalciferol treatment in comorbid patients hospitalized for COVID-19. The aim of this study was to retrospectively examine the clinical outcome of patients receiving in-hospital high-dose bolus cholecalciferol. Patients with a positive diagnosis of SARS-CoV-2 and overt COVID-19, hospitalized from 15 March to 20 April 2020, were considered. Based on clinical characteristics, they were supplemented (or not) with 400,000 IU bolus oral cholecalciferol (200,000 IU administered in two consecutive days) and the composite outcome (transfer to intensive care unit; ICU and/or death) was recorded. Ninety-one patients (aged 74 ± 13 years) with COVID-19 were included in this retrospective study. Fifty (54.9%) patients presented with two or more comorbid diseases. Based on the decision of the referring physician, 36 (39.6%) patients were treated with vitamin D. Receiver operating characteristic curve analysis revealed a significant predictive power of the four variables: (a) low (<50 nmol/L) 25(OH) vitamin D levels, (b) current cigarette smoking, (c) elevated D-dimer levels (d) and the presence of comorbid diseases, to explain the decision to administer vitamin D (area under the curve = 0.77, 95% CI: 0.67-0.87, p < 0.0001). Over the follow-up period (14 ± 10 days), 27 (29.7%) patients were transferred to the ICU and 22 (24.2%) died (16 prior to ICU and six in ICU). Overall, 43 (47.3%) patients experienced the combined endpoint of transfer to ICU and/or death. Logistic regression analyses revealed that the comorbidity burden significantly modified the effect of vitamin D treatment on the study outcome, both in crude ( p = 0.033) and propensity score-adjusted analyses ( p = 0.039), so the positive effect of high-dose cholecalciferol on the combined endpoint was significantly amplified with increasing comorbidity burden. This hypothesis-generating study warrants the formal evaluation (i.e., clinical trial) of the potential benefit that cholecalciferol can offer in these comorbid COVID-19 patients.

Little information is available from real-life studies evaluating the efficacy of guselkumab in moderate-to-severe psoriasis. In this real-life study, we retrospectively examined a database of 52 patients with moderate-to-severe psoriasis treated with guselkumab (100 mg, s.c.) and followed for 1 year. Disease severity and treatment response was assessed by the Psoriasis Area and Severity Index (PASI) at baseline and after 4, 12, 20, 28, 36, 44, and 52 weeks. Predictors of a PASI response were evaluated by univariate and multivariate regression. After 12 months, 84.2% of patients (mean age 51.3 ± 14.1 years) treated with guselkumab achieved a PASI score of <3. Furthermore, PASI score decreased from 20 ± 13.3 at baseline to 4.4 ± 4.7 and 2.7 ± 3.9 at 12 and 20 weeks, and PASI 75, 90, and 100 response was achieved in 84.2%, 78.9%, and 63.2% of patients respectively at 12 months. Stepwise multivariate regression analysis revealed that previous biological treatment and the presence of comorbidities were associated with poorer response between 28-44 weeks, however the presence of obesity per se was not associated with poorer response. Difficult-to-treat areas were also improved as early as 12 weeks following guselkumab. Guselkumab was observed to be effective and safe in patients with moderate-severe chronic psoriasis in a real world-setting.

Background: The analgesic efficacy of oxycodone prolonged-release (PR) combined with naloxone PR (OXN) in postoperative pain management is recognized, however, few studies have examined the efficacy of OXN on pain relief and bowel function following hysterectomy. This study compared the effect of OXN vs. standard treatment for post-operative pain management and bowel function following hysterectomy., Methods: This randomized prospective study included 83 women who underwent laparoscopic/laparotomic hysterectomy. General anesthesia was induced by propofol (1.5-2 mg/kg), fentanyl (50-100 μg) and rocuronium (0.6-1 mg/kg) and maintained with sevoflurane (MAC 0.8-1) and fentanyl (1-2 μg/kg). Intraoperative analgesia was performed with ketorolac (30 mg), paracetamol (1 g) and morphine (0.1 mg/kg). Postoperative analgesia in the control group (N.=41) included morphine (0.2-0.4 mg/kg/day), whereas the OXN (N.=42) group only received oxycodone (10 mg)/naloxone (5 mg) for the first 48 hours. As rescue analgesic, both groups received paracetamol (3 mg). Bowel Function Index (BFI) and pain numeric rating scales (NRS) were measured at day 0, 1, 2, 3, 5 and 7, whereas vital parameters, rescue medication and side effects were recorded for the first three days only., Results: Bowel function indices were significantly improved in OXN-treated patients at all time points compared to morphine-treated patients. Mean static pain NRS was significantly decreased at day 2 and day 3 and dynamic pain NRS at day 3 in the OXN group. Side effects, rescue analgesic and antiemetics were more frequent in the control group., Conclusions: Improved pain control, bowel function and reduced side effects were observed with OXN compared to morphine in patients who underwent hysterectomy.

Few studies have compared the efficacy of switching from etanercept to adalimumab in the real-life setting in rheumatoid arthritis (RA) and psoriatic arthritis (PsA). This study evaluated the 2-year retention rate and 12-month efficacy of adalimumab in RA and PsA patients, previously treated with etanercept. RA and PsA patients from 11 Italian Rheumatology Units received adalimumab after first-line etanercept failure. Two-year adalimumab retention rate was calculated by the Kaplan-Meier method and Cox proportional hazard models were developed to examine predictors of drug persistence. Univariate and multivariate logistic regression analyses were developed to examine potential predictors of 12-month DAS-28 remission. The study population included 117 RA (disease duration of 10.1 ± 7.7 years and baseline DAS28-ESR of 4.97 ± 1.3) and 102 PsA (disease duration of 7.1 ± 5.1 years and baseline DAPSA of 24.6 ± 11.8). The 2-year retention rate was 48.2% in RA and 56.5% in PsA patients. Concomitant methotrexate treatment was not associated with increased drug survival in both groups. Similarly, cause of etanercept discontinuation or treatment duration was not associated with retention rate. 12-month remission and low disease activity were achieved, respectively, in 27.3% and 23.9% of RA patients and 27.4% and 23.5% PsA of patients. In multivariate models, etanercept discontinuation due to inefficacy (OR 0.27, 95% CI 1.03-0.73; p = 0.009) and baseline DAS-28 (OR 0.45, 95% CI 0.29-0.69; p < 0.001) remained significant negative predictors of remission in RA patients. No variable was associated with remission in PsA patients. Adalimumab after etanercept failure was highly effective and safe in both RA and PsA patients.

Anxiety and depression impact dramatically on public health, underlying the importance of alternative cost-effective treatments. Previous studies have shown that biophysical treatment can significantly reduce anxiety symptoms and recently, salivary alpha-amylase (SAA) has been identified as an objective correlate of the sympathetic-parasympathetic imbalance related to increased stress burden, defined as allostatic load. The aim of this study was to evaluate the effect of biophysical therapy on SAA levels, in addition to the Depression Anxiety Stress Scale (DASS)-21 questionnaire. Twenty-four workers (sales representatives) presenting with mild anxiety/stress symptoms (Generalized Anxiety Disorder 7-item scale of > 5) were randomized to biophysical treatment ( N = 12) or placebo control ( N = 12). The biophysical group underwent electromagnetic information transfer through an aqueous system procedure, with daily self-administration for one month. SAA collection and the DASS-21 questionnaire were undertaken at baseline and after one month in all patients. Clinical characteristics and baseline DASS-21 subscale scores were similar between placebo and biophysical group at baseline. After one month, patients receiving biophysical therapy had significantly reduced SAA levels compared to the placebo group (27.8 ± 39.4 vs. 116.8 ± 114.9 U/mL, p = 0.019). All three DASS-21 subscales, depression (9.3 ± 5.1 vs. 5.7 ± 5.5, p = 0.1), anxiety (6.7 ± 25 vs. 3.7 ± 2.2, p = 0.0049) and stress (10.8 ± 4.2 vs. 7.3 ± 3.7, p = 0.041) were also decreased after biophysical treatment compared to placebo after one month. Our findings suggest that biophysical therapy can benefit workers with mild (subclinical) anxiety/stress. These results were also validated by the concomitant reduction of SAA levels and an improvement in DASS-21 subscales. The underlying molecular mechanisms of this therapy remain to be characterized.

Background : Limited information is available from real-life studies evaluating the long-term efficacy and drug retention of ustekinumab. Research design and methods : Data from 378 patients with moderate-severe psoriasis were retrospectively analyzed. Over 8 years, disease severity and treatment response were evaluated using the PASI score. Predictors of PASI response were evaluated by logistic regression. Ustekinumab retention rate was calculated by the Kaplan-Meier method. Results : Over the 8 years, >80% of patients achieved a PASI score of <3 and PASI 75, 90 and 100 response was achieved in 76.2%, 61.9% and 57.1% of patients, respectively. Predictor variables for improved PASI response (after 2 years) were HLA-C*06-POS patients, female gender and BMI <30 Kg/M 2 . The 2-year retention rate was 81% and 59% after 8 years with mean retention rate of 5.4 years. Improved retention rate was observed in patients positive for the HLA-C*06 allele (3.7 vs. 2.5 years, p = 0.005) and female gender (3.7 vs. 3.3 years, p = 0.06), with no significant difference observed in other patient groups. Ustekinumab was generally well tolerated without evidence of cumulative toxicity or organ toxicity. Conclusion : The long-term use of ustekinumab was observed to be effective and safe in patients with moderate-severe chronic psoriasis in a real world-setting.

Objectives: The aim of this study was to develop a Delphi consensus statement between rheumatologists and radiologists for the diagnosis and monitoring of axial spondyloarthritis (axial-SpA)., Methods: Following an extensive literature search to identify unmet needs and potential goals for a multidisciplinary approach, a scientific board comprising 28 Italian hospital-based rheumatologists (n=19) and radiologists (n=9) identified 8 "starting points", resulting in the development of 23 consensus statements covering issues from current practice guidelines to specific MRI protocols for the assessment of axial-SpA. Each participant anonymously expressed a level of agreement for each statement using a 5-point Likert scale (1="strongly disagree"; 5="strongly agree") via an online Delphi method.Total cumulative agreement (TCA) was defined as the sum of the percentage of response to items 4 ("agree") and 5 ("absolutely agree"). Consensus was defined as ≥80% total cumulative agreement for each statement., Results: After the first round of voting (28 participants), positive consensus was reached for 28/31 (90.3%) statements. Statements without consensus (n=3) were discussed in a face-to-face plenary session prior to the second vote (28 participants). After the second round voting, positive consensus was attained for all 31 statements, with mean final TCA of 95.5% (range 82.1-100%)., Conclusions: This Delphi consensus statement provides an aid to rheumatologists and radiologists for the diagnosis and monitoring of axial-SpA.

The clinical characteristics associated with hidradenitis suppurativa (HS) severity are poorly understood. In this study, 124 patients with HS from 6 Italian dermatology centres participated in this study. Disease severity was assessed using the Hidradenitis Suppurativa Physician's Global Assessment score (HS-PGA) and Hurley score. The impact of clinical characteristics on disease severity was assessed by logistic regression. Clinical characteristics were similar between men (n = 53) and women (n = 71). Disease severity was also similar; 75% of the patients had Hurley stage II or III disease, and > 60% had moderate, severe or very severe HS as judged by HS-PGA. Lesions were more frequent in the gluteal region in men (32.3% in men vs. 8.7% in women, P < 0.001) and more frequent on the breast in women (16.3% in women vs. 4.6% in men, P = 0.02). Obesity was associated with increased disease severity as measured by HS-PGA (OR: 3.28, 95% CI 1.55-6.95, P < 0.01) and Hurley classification (OR: 3.22, 95% CI 1.34-7.31, P < 0.01). Although severity of HS is similar between the sexes, the localization of lesions is different., (© 2018 British Association of Dermatologists.)

Background: Few studies have compared the efficacy of switching to adalimumab in the real-life setting in plaque psoriasis patients., Objective: To evaluate the effect of adalimumab in psoriasis patients previously treated with other biologics., Methods: In this multicentre study, psoriasis patients (N = 262) treated with an anti-TNF-alpha agent, ustekinumab or naïve to biologics then switched to adalimumab were included. Disease severity was assessed by the Psoriasis Area and Severity Index (PASI) at baseline and after 3, 6, 12, 24 and 36 months. The association between clinical risk factors and achievement of PASI response was evaluated by logistic regression., Results: Adalimumab treatment resulted in a decrease in PASI (15.1 ± 6.2 at baseline vs. 2.7 ± 4.8 at 6 months, P < 0.0001), regardless of previous biologic treatment. Furthermore, adalimumab allowed 92.5%, 79% and 56% of patients to achieve PASI response (PASI 50, 75 and 90, respectively) and complete remission (PASI 100 response) in 48.4% of patients, by 6 months and maintained over 3 years, independent of prior biologic treatment. The absence of metabolic syndrome, dyslipidemia, hypertension and lower PASI and lower age at baseline was associated with achievement of PASI response at 3, 6 and 12 months, whereas at later time points (24 and 36 months), PASI 90 and PASI 100 response was associated with diagnosis of psoriasis/psoriatic arthritis., Conclusion: Adalimumab was effective at reducing PASI score over 3 years, irrespective of whether patients were biologic naïve or previously treated with a TNF-alpha or IL-12/23 inhibitor., (© 2018 European Academy of Dermatology and Venereology.)

Background: Few studies have compared the use of different biologics in a real-life setting in plaque psoriasis patients., Objective: To compare the efficacy of biologics in psoriasis/psoriatic arthritis patients., Methods: Patients treated with adalimumab, etanercept and ustekinumab for at least 16 weeks were included. Achievement of Psoriasis Area Severity Index (PASI), PASI 90/100 response and time taken to achieve PASI 90/100 response were measured. Logistic regression was used to evaluate the effect of psoriasis localization on achievement of PASI 100 response., Results: Two hundred and fifty five patients were included. No difference was observed in PASI 90 response between etanercept and ustekinumab (65.5 vs. 55.4%), while adalimumab-treated patients had a higher response versusustekinumab (71.6 vs. 55.4%, p = .02). More patients achieved complete remission (PASI 100 response) with adalimumab versus etanercept (65.7 vs. 23%, p < .001) or ustekinumab (65.7 vs. 44.6%, p = .003). Adalimumab-treated patients achieving PASI 90 responded more quickly (by three and six months) versus ustekinumab or etanercept. PASI100 response was achieved in ∼43% of adalimumab and ustekinumab treated-patients by three months versus etanercept (14.3%), increasing to 92.5, 85.4 and 35.7%, respectively by six months. PASI100 response was associated with psoriasis nail involvement or genital psoriasis., Conclusion: In the real-life setting, adalimumab was the most effective biological agent for the treatment of plaque psoriasis.

Background: The genetic basis of predisposition to psoriasis is recognised; however, the response to psoriasis treatment in patients with different genetic predisposition is poorly understood., Objective: To analyse the presence of the HLA-C*06:02 polymorphism in psoriatic patients treated with adalimumab., Methods: Genomic DNA was extracted from whole blood of 122 patients with moderate-to-severe psoriasis treated with adalimumab for 3 years. Genotyping was performed using PCR. Disease severity was assessed by the Psoriasis Area and Severity Index (PASI) at day 0 and after 1, 3, 6, 12, 24 and 36 months. Logistic regression was used to evaluate the association between dependent variables (including HLA-C*06:02 status) and achievement of PASI 50, 75 and 90., Results: No difference was observed after adalimumab treatment between C*06:02 positive (HLA-C*06:02-POS) patients (n = 46) and C*06:02 negative (HLA-C*06:02-NEG) patients (n = 76) over the 3-year follow-up period in terms of PASI response or time-course when PASI response was achieved. However, a small, but non-statistically significant difference was noted between genotypes for PASI 50 at 1 month (HLA-C*06:02-NEG: 44.7% vs. HLA-C*06:02-POS: 56.5%) and at 3 months (HLA-C*06:02-NEG: 71.1% vs. HLA-C*06:02-POS: 80.4%). Simple logistic regression analysis did not reveal an association between independent variables (including C*06:02 status) and PASI response; however, multivariate regression revealed that gender (females better than males) was associated with achievement of PASI 50 at month 1 (OR 0.34, 95% CI 0.16-0.72, p = 0.005) and of PASI 75 at 3 months (OR 0.36, 95% CI 0.16-0.8, p = 0.012)., Conclusion: Adalimumab reduced long-term severity in patients with moderate-severe psoriasis, independent of their HLA-C*06:02 status.

Changes in ultraviolet light radiation can act as a selective force on the genetic and physiological traits of a microbial community. Two strains of the common soil bacterium Pseudomonas stutzeri, isolated from aquifer cores and from human spinal fluid were exposed to ultraviolet light. Amplification length polymorphism analysis (AFLP) was used to genotype this bacterial species and evaluate the effect of UVA-exposure on genomic DNA extracted from 18 survival colonies of the two strains compared to unexposed controls. AFLP showed a high discriminatory power, confirming the existence of different genotypes within the species and presence of DNA polymorphisms in UVA-exposed colonies.

Background and Purpose: Effective non-invasive techniques to monitor plaque psoriasis progression and treatment are desirable. The aim of the study was to evaluate changes in vascular pattern using videodermatoscopy (VD) and in skin thickness by ultrasound (US), along with clinical observation, during treatment with biologicals., Methods: Forty-two patients with moderate-to-severe plaque psoriasis treated with adalimumab, etanercept, or ustekinumab were evaluated. Following the identification of a 'target' plaque at baseline, lesion changes were monitored at 15, 30 and 60 days by clinical observation using a Target Lesion Score (TLS), and by VD and US., Results: After 60 days, a significant improvement in all three parameters was observed. In adalimumab-treated patients mean values of TLS, VD, and US were reduced by 83.9%, 73.5%, and 90%, respectively; in etanercept-treated patients by 67.9%, 49.7%, and 79.3%; in ustekinumab-treated patients by 80.9%, 66.4%, and 80.1%. Skin thickness was the first parameter to improve. Vascular improvement was slower compared to clinical and US responses., Conclusion: VD and US may be useful to monitor psoriasis treatment. Further investigations are warranted to assess if the persistence of an altered vascular pattern despite clinical and US normalization, as observed in 22% of patients, may influence disease progression and/or correlate with rate and severity degree of relapse., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Diabetic macular edema (DME) is a serious condition that can cause blindness in diabetic patients suffering from diabetic retinopathy (DR). Although vascular endothelial growth factor (VEGF) is known to play a role in the development of DME, the pathological processes leading to the onset of this disease are highly complex and the exact sequence in which they occur is still not completely understood. Angiogenesis and inflammation have been shown to be involved in the pathogenesis of this disease. However, it still remains to be clarified whether angiogenesis following VEGF over-expression is a cause or a consequence of inflammation. Here, we provide an overview of the current data available in the literature focusing on VEGF, angiogenesis, inflammation, DR and DME. Our analysis suggests that angiogenesis and inflammation act interdependently during the development of DME. VEGF is a critical player in the molecular crosstalk occurring between these two processes, reinforcing the use of anti-VEGF agents for the treatment of DME., (Copyright © 2015. Published by Elsevier Ltd.)

Background: Recent estimates indicate an increase in the prevalence of skin diseases in children. Few large epidemiologic studies have examined prevalence trends in Europe. This study evaluated the incidence and prevalence of frequently occurring pediatric skin diseases (PSDs) in Italy as seen by family pediatricians (FPs)., Methods: Data were retrospectively extracted from the Pedianet database (2006-2012) in children ages 0 to 14 years presenting with a skin disease at their FP. The incidence and prevalence estimates were calculated per year and stratified according to sex, age, and geographic area., Results: A mean of 145,233 children (52.1% male) across five Italian regions were registered with their participating FP for a total of 913,253 person-years of follow-up. The majority of patients were from the northeast (44.6%) and 37.7% were ages 5-9 years. Incidence estimates (new cases/1,000 person-years) for most PSDs increased from 2006 to 2012, the highest being for atopic dermatitis (AD) (14.1 vs 16.5), acute urticaria (10.1 vs 11.6), and contact dermatitis (9.3 vs 10.8), whereas psoriasis remained unchanged over the 7 years (0.61 vs 0.57). In contrast, prevalence estimates (cases/100 patients) increased two to three times for several PSDs, including AD (2.7% vs 8.5%), seborrheic dermatitis (0.5% vs 1.6%), chronic urticaria (0.4% vs 0.8%), and psoriasis (0.09% vs 0.22%). Differences in prevalence according to age range and geographic area were observed for psoriasis, AD, and urticaria., Conclusion: This study provides comprehensive evidence of the increasing prevalence and incidence of PSDs across Italy. Additional causality studies to address this important clinical and psychosocial problem are recommended., (© 2015 Wiley Periodicals, Inc.)

Background: Persistent dry cough is a well known unwanted effect of Angiotensin-Converting Enzyme inhibitors (ACE-i). Animal studies have shown that the ACE-i zofenopril has a less tussigenic effect compared to the widely used ACE-i ramipril. The aim of this study was to compare cough sensitivity to inhaled tussigens, as well as spontaneous cough in response to the administration of zofenopril and ramipril in healthy volunteers; pharmacokinetic (PK) data of both zofenopril and ramipril, as well as their respective active forms, zofenoprilat and ramiprilat, was also collected., Methods: Forty healthy volunteers were enrolled in a randomized crossover study. Patients were administered zofenopril calcium salt (test drug) coated tablets, 30 mg daily dose or ramipril (reference drug) tablets, 10 mg daily dose, for 7 consecutive days in two periods separated by a 21-day wash-out period. Cough sensitivity to capsaicin and citric acid was assessed as the concentration of each tussigenic agent causing at least 2 (C2) or 5 coughs (C5); spontaneous cough was also monitored throughout the study. PK parameters of zofenopril, ramipril and their active forms, were collected for each of the two study periods. Airway inflammation, as assessed by fractional exhaled nitric oxide (FeNO) and bradykinin (BK) levels, were measured prior to and following each treatment period., Results: Ramipril, but not zofenopril, increased (p < 0.01) cough sensitivity to both tussigenic agents as assessed by C2. With citric acid, C5 values calculated after both ramipril and zofenopril administration were significantly (p < 0.05 and p < 0.01, respectively) lower than corresponding control values. With both ACE-i drugs, spontaneous cough was infrequently reported by subjects. Zofenopril/zofenoprilat PK analysis showed higher area under the curve of plasma concentration, τ values (ng/ml x h) than ramipril/ramiprilat (zofenopril vs. ramipril, 84.25 ± 34.47 vs. 47.40 ± 21.30; and zofenoprilat vs. ramiprilat, 653.67 ± 174.91 vs. 182.26 ± 61.28). Both ACE-i drugs did not affect BK plasma levels; in contrast, ramipril, but not zofenopril, significantly increased control FeNO values (from 24 ± 9.6 parts per billion [PPB] to 33 ± 16 PPB; p < 0.01)., Conclusions: Zofenopril has a more favourable profile when compared to ramipril as shown by a reduced pro-inflammatory activity and less impact on the cough reflex.

Aim: To examine the efficacy and safety of otilonium bromide (OB) in treatment-sensitive functional irritable bowel syndrome (IBS) clinical parameters., Methods: Ninety-three patients (44.8 ± 12.6 years, 69% female) with IBS symptoms complying with Rome II criteria participated in this double-blind, placebo-controlled, randomised, dose-ranging phase I/II study. Patients were administered OB 20 mg (n = 24), 40 mg (n = 23) and 80 mg (n = 23) tid or placebo (n = 23) in 4 parallel groups for 4 wk. Primary efficacy variables included abdominal discomfort, intestinal habits, number of daily evacuations and stool consistency. Secondary efficacy measures included return to regular intestinal habits and global discomfort. Safety was also assessed., Results: Baseline clinical characteristics were similar among the 4 groups. Although individual parameters such as intensity and frequency of abdominal discomfort, bloating or pain were reduced by OB over the 4 wk, no significant differences were observed between groups. Similarly, no difference was observed between OB treatment or placebo for mucus in stool and incomplete or difficulty of evacuation. However, evacuation frequency was significantly reduced after 4 wk by 80 mg OB compared to placebo (-8.36% for placebo vs -41.9% for 80 mg OB, P < 0.01). While 21.7% of patients in the placebo group experienced regular intestinal habits after 4 wk, this improvement was greater for patients treated with 40 mg OB (P < 0.01 vs placebo). Furthermore, a dose-dependent reduction in frequency of diarrhoea (χ(2)-test for trend = 11.5, P < 0.001) and an increase in normal stool frequency was observed. Combining individual variables into a global discomfort index revealed significant improvement among increasing OB doses, favouring 40 mg (P = 0.013) and 80 mg OB (P = 0.001) over placebo. No difference was observed between frequency of adverse events for placebo vs OB., Conclusion: This dose-ranging study demonstrates that OB at 40 and 80 mg can improve individual and global clinical symptoms of IBS compared to placebo over a 4-wk period.

Background: Previous evidence indicates that pioglitazone may improve dyslipidemia in patients with Type 2 diabetes mellitus (T2DM)., Aim: The primary objective of this study was to evaluate the effect of either pioglitazone or placebo with metformin on levels of serum HDL cholesterol (HDL-C) in patients with T2DM. A secondary objective evaluated changes in metabolic syndrome (MS)-specific parameters., Subjects and Methods: This multicenter, double-blind, randomized study was performed in patients with T2DM treated with metformin and hemoglobin A1c (HbA1c) levels between 6-8%, central obesity and reduced HDL-C. MS was evaluated from global changes in parameter values and expressed as a single factorial score following multivariate analysis of each parameter. 213 patients (110 in the pioglitazone group and 103 in the placebo group) were available for intention-to-treat analysis., Results: Pioglitazone-treated patients showed a significant increase in HDL-C compared to placebo group (6.3 mg/dl vs 3.0 mg/dl; p<0.01) in addition to a greater reduction in the extent of MS (-13.2 vs -4.9; p=0.0055). Upon study completion, patients treated with pioglitazone had lower levels of HbA1c (6.41±0.65 vs 6.96±0.74%; p<0.001) and homeostasis model assessment-insulin resistance (HOMA-IR) (2.88±1.95 vs 4.68±3.63; p=0.013) and a reduction of the atherogenic LDL subfraction (pattern B) (-5.7%)., Conclusions: The beneficial effects observed in pioglitazone-treated patients in the present study, (i.e. the increase in HDL-C and the reduction of insulin resistance and atherogenic LDL subfractions), support findings from the PROactive trial, where pioglitazone showed pleiotropic effects and reduced death, fatal myocardial infarction (MI) and non-fatal MI in T2DM patients with MS. Furthermore, medication used in this study showed good tolerability.

Background: Chronic kidney disease (CKD) is a major worldwide problem. A lack of CKD awareness and knowledge of associated risk factors may delay diagnosis and treatment. The purpose of this epidemiological study was to assess the presence and awareness of CKD, in addition to evaluating associated clinical characteristics., Methods: This cross-sectional observational study included 573 healthy volunteers (aged 21-62 years) based in central Italy. All participants underwent a nephrological visit, providing data on medical history, anamnesis and CKD awareness. Blood and urine samples were also collected., Results: Estimated glomerular filtration rate (eGFR) calculated by the abbreviated Modification of Diet in Renal Disease (MDRD) study formula revealed that 55% of participants had an eGFR of <90 ml/min per 1.73 m2 compared with 24.6% by the Cockcroft-Gault formula (C-G; p<0.0001). Approximately 45% of participants showed an awareness of CKD, these subjects also having a significantly lower Framingham score (p<0.046). Approximately half of participants (51%) had insufficient levels (<30 ng/mL) of serum 25-hydroxyvitamin D (25(OH)D), with a higher proportion observed in female (58.3%) than male participants (45.6%, p=0.0016). Levels of 25(OH)D were negatively correlated with eGFR, measured by either MDRD or C-G (r=-0.12, p=0.0039 and r=-0.09, p=0.029 respectively). Logistic regression analysis revealed that male sex and increased serum creatinine levels were predictors associated with study outcomes (clinical risk factors)., Conclusions: This study suggests that screening for CKD in the general population by eGFR calculations (MDRD or C-G) is unreliable; therefore, the monitoring of serum creatinine and other risk factors may be more appropriate. The presence of vitamin D insufficiency in apparently healthy individuals warrants further investigation.

This study aims to examine the effect of pioglitazone on potential progression of autonomic damage in addition to changes in control of cardiovascular function in patients with type 2 diabetes (T2DM). Thirty patients with T2DM and 32 healthy subjects participated in the study. Sympathovagal activity, assessed by power spectral analysis (PSA) of R-R intervals variability, and blood pressure (BP) were studied during clinostatism and orthostatism in controls and patients. We have assessed blood pressure control by 24-hour monitoring of ambulatory blood pressure. Patients were treated with pioglitazone (30 mg/day) for 6 months, and then re-evaluated by PSA for heart rate variability (HRV). Reduced levels of HbA1c (P < 0.0001) and urinary albumin (P = 0.008) were observed in pioglitazone-treated patients compared to untreated baseline levels. Arterial BP remained unchanged following pioglitazone treatment. T2DM patients had reduced HRV (low-frequency power; LF; P < 0.0001 and LF/HF; LF/HF; P < 0.0001) at baseline (clinostatism) compared to controls. Baseline clinostatic differences between groups persisted after pioglitazone treatment and no effect of treatment on basal HRV variables was observed. In controls, HF decreased and LF and LF/HF ratio increased in the orthostatic position. A similar effect for HF was observed in patients, but LF and LF/HF did not increase. The normal difference between HF-power in clinostatism versus orthostatism observed for controls (P < 0.0001) was restored in patients following pioglitazone treatment (P = 0.028). A significant decrease from lying to standing position in orthostatic LF-power (P < 0.0001) and LF/HF (P < 0.0001) was also observed between patients and controls. Although no differences in autonomic control of HRV were observed between controls and patients with T2DM, significant differences were observed in sympathovagal balance following either clinostatic or orthostatic challenge. These findings provide initial evidence of a potential additional benefit afforded by pioglitazone for the improvement of cardiac sympathovagal balance in T2DM.

Even with the availability of novel and efficacious antihypertensive agents, an insufficient number of hypertensive patients achieve their desired blood pressure (BP) target. This failure is partly due to the fact that many patients do not strictly adhere to their drug therapy and/or they report the presence of adverse effects. Traditionally, monotherapy is used as first-line treatment to achieve BP targets; however, when this fails, combination therapy is then required. In light of the need to attain BP goals, combination therapy (especially fixed-dose) is currently recommended. The main advantages of combination therapy over monotherapy are not only that of reduced dose, improved efficacy and reduced adverse effects, but also of target protection and reduced cardiovascular (CV) risk. Therefore, the development of single-administration drug combinations should also improve patient adherence to therapy and therefore help in achieving BP control. Among the various combinations available, calcium channel blockers (CCBs) and angiotensin-converting enzyme (ACE) inhibitors have been proven to be extremely effective, while also displaying good tolerability. Individually, both the third-generation CCB lercanidipine and the ACE inhibitor enalapril are effective antihypertensive agents. In addition, both of these agents also show other beneficial effects when administered as monotherapy. Of particular importance is the fact that when lercanidipine plus enalapril are administered in combination, they show synergism, thus providing added efficacy with reduced side effects. The present report provides an overview of the main clinical studies examining lercanidipine and enalapril administered as monotherapy, with particular focus on the potential renoprotective effects afforded by the fixed-dose combination lercanidipine-enalapril.

The association between levels of circulating endothelial progenitor cells (EPCs) and heart transplant recipients (HTX) with cardiac allograft vasculopathy (CAV) is under debate. The chemokine receptor CXCR4 plays an important role in the mobilization of progenitor cells and is implicated in pathological conditions, including cardiovascular disease. This study aims to evaluate the association between EPCs and CXCR4-positive cells in HTX patients. Peripheral blood mononuclear cells (PBMCs) from 34 HTX patients and 25 control participants were analyzed by flow cytometry for CXCR4-positive cells and EPCs. Endothelial progenitor cells were defined by the expression of a range of hematopoietic and endothelial lineage markers in different combinations. The ability to form endothelial cell colonies in vitro was also assessed by colony-forming unit (CFU) assay. Phenotypic analysis of EPCs by flow cytometry revealed similar levels in HTX patients compared to controls. In addition, no difference was observed between levels of EPCs or CFU number in patients with and without CAV. By contrast, CFU assay revealed a reduced number of CFUs in HTX patients compared to controls (3.3% ± 0.95 and 13.3% ± 4.5%, respectively, P = 0.014). Likewise, levels of CXCR4-positive cells were significantly reduced (15.9 ± 1.4 in patients vs 24.8 ± 3.3% in controls, P < 0.01), negatively correlated with Framingham risk score (rho = -0.4, P = 0.02) and the number of risk factors (rho = -0.3, P = 0.049). Levels of CXCR4-positive cells were also correlated with CFU number (r = 0.65, P = 0.0005). These findings further develop our understanding of the role of EPCs and endothelial CFUs in cardiovascular disease, in addition to highlighting the potential importance of CXCR4 in heart transplantation.

For the past 25 years, cyclosporine A (CyA) has played a pivotal role in transplant immunosuppressant therapy. From the availability of the 2 primary marketed formulations (Sandimmun® and Sandimmun Neoral®, Novartis), confusion has existed with regard to whether these two formulations are bioequivalent. Due to the underlying clinical relevance of this information, we therefore conducted a meta-analysis of all available comparative pharmacokinetic studies to assess whether the two different CyA formulations, Sandimmun® and Sandimmun Neoral®, can be considered bioequivalent. All clinical studies that compared the bioavailability of the 2 formulations in organ transplant recipients were considered for analysis. We searched computerised databases (Embase/Excerpta Medica and Medline/PubMed) from their inception to May 2010. Only studies with AUC values determined at 12 hours were considered for analysis. Relative bioavailability was calculated with 90 percent confidence intervals (CI) for Sandimmun® (test substance) versus Sandimmun Neoral® (reference substance) according to Schuirmann?s Two One-Sided Tests Procedure and the Classical Shortest CI. Homogeneity of data was tested using the Χ(2) test. Fifteen studies were considered for meta-analysis and none of these studies reported AUC values in the 80-125 percent range required for the bioequivalence of two formulations. The overall bioavailability for Sandimmun® versus the microemulsion formulation Sandimmun Neoral® was 76 percent, with upper CI limits lower than 80 percent in some cases. Mean AUC values for Sandimmun® were significantly lower than those for Sandimmun Neoral® (p<0.01). This study demonstrates that the 2 main cyclosporine formulations, Sandimmun® and Sandimmun Neoral®, cannot be considered bioequivalent.

Mucus hypersecretion is a clinical feature of severe respiratory diseases such as asthma, cystic fibrosis and chronic obstructive pulmonary disease. Airway mucosal infection and/or inflammation associated with these diseases often gives rise to inflammatory products, including neutrophil-derived DNA and filamentous actin, in addition to bacteria, apoptotic cells and cellular debris, that may collectively increase mucus production and viscosity. Mucoactive agents have been the medication of choice for the treatment of respiratory diseases in which mucus hypersecretion is a clinical complication. The main purpose of mucoactive drugs is to increase the ability to expectorate sputum and/or decrease mucus hypersecretion. Many mucoactive drugs are currently available and can be classified according to their putative mechanism of action. Mucoactive medications include expectorants, mucoregulators, mucolytics and mucokinetics. By developing our understanding of the specific effects of mucoactive agents, we may result in improved therapeutic use of these drugs. The present review provides a summary of the most clinically relevant mucoactive drugs in addition to their potential mechanism of action.

The aim of this systematic review was to evaluate the efficacy of isoxsuprine (1-(4-hydroxyphenyl)-2-(1-methyl-2-phe-noxyethylamino)-1-propanol, CAS 395-28-8), a tocolytic agent used in both preterm labour and risk of abortion. Two analyses were conducted on data reporting the use of isoxsuprine in the prevention of preterm delivery. The first analysis examined two double-blind studies to determine the effect of isoxsuprine compared to placebo. The second analysis reviewed data from 25 publications containing individual and general patient data. Main outcome measures included delay of pregnancy and patient outcome. Analysis of double-blind studies demonstrated a positive outcome with isoxsuprine in 92% of cases compared to placebo control (44.4%, p < 0.001). This beneficial effect was maintained when either risk of abortion (92.5% in isoxsuprine treated compared to 46.4% in placebo, p < 0.001) or risk of premature delivery (89.5% in isoxsuprine treated compared to 29.4% in placebo, p < 0.001) was examined. Secondary analysis of individual patient data also revealed a beneficial effect of isoxsuprine in prolonging pregnancy in 54.5% of women at risk of abortion and in 82.3% of women at risk of premature delivery. Combination of individual and general data revealed a beneficial effect of isoxsuprine in 77.3% of cases at risk of abortion and 89% for risk of premature delivery. These findings provide preliminary evidence in favour of the effectiveness of isoxsuprine in prolonging pregnancy in women at risk of abortion or premature delivery.