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Vora J.,University of Liverpool | Caputo S.,UniversitaCattolica | Damci T.,Istanbul University | Orozco-Beltran D.,University Miguel Hernandez | And 4 more authors.
Journal of Clinical Pharmacy and Therapeutics | Year: 2014

Summary What is known and objective There are acknowledged benefits to continuing metformin when initiating insulin, but there appears to be growing concern over the role of sulphonylureas and thiazolidinediones when used in combination with insulin. This analysis investigates the effects of continuing or discontinuing oral antidiabetic drugs (OADs) following the initiation of once-daily insulin detemir. Methods SOLVE is a 24-week, multinational observational study of insulin detemir initiation in patients with type 2 diabetes mellitus treated with one or more OADs. Results In the total cohort (n = 17 374), there were significant improvements in HbA1c (-1·3%, 95% CI -1·34; -1·27%) and weight (-0·6 kg, 95% CI -0·65; -0·47 kg), with an increase in the incidence rate of minor hypoglycaemia (+0·256 events ppy, P < 0·001), but not severe hypoglycaemia (-0·038 events ppy, P < 0·001). Study participants had information on OAD use either prior to (n = 17 086) or during insulin initiation (n = 16 346). HbA1c reductions were significantly greater in patients continuing treatment with metformin (-1·3% vs. -1·1%, P < 0·01), thiazolidinediones (-1·3% vs. -1·0%, P < 0·01) and DPP-IV inhibitors (-1·3% vs. -0·9%, P < 0·001). Final insulin doses were significantly greater in patients discontinuing treatment with sulphonylureas (0·29 vs. 0·26 IU/kg, P < 0·001), glinides (0·28 vs. 0·26 IU/kg, P < 0·01), thiazolidinediones (0·31 vs. 0·26 IU/kg, P < 0·001) and DPP-IV inhibitors (0·35 vs. 0·29 IU/kg, P < 0·001) compared with patients continuing these respective agents. All patient subgroups had a mean weight loss irrespective of OAD continuation, apart from those continuing thiazolidinediones (+0·2 kg). The largest improvements in weight were seen following the withdrawal of sulphonylureas and thiazolidinediones (-1·1 and -1·1 kg, respectively). What is new and conclusion Discontinuation (or switching) of OADs at the time of insulin initiation appears to be governed principally by concerns about hypoglycaemia and weight. HbA1c improvements were smaller in patients discontinuing OADs at the time of insulin initiation and may be associated with insufficient insulin titration. Metabolic and survival benefits of maintaining metformin therapy when initiating insulin are widely acknowledged, but combination of other oral antidiabetic drugs (OADs) with insulin are more controversial. In this study, the discontinuation of specific classes of OAD appeared to be more closely associated with weight and history of hypoglycaemia, rather than the degree of glycaemic control. Improvements in glycaemic contol were smaller in patients discontinuing OADs at the time of insulin initiation, and may be associated with insufficient insulin titration. © 2013 John Wiley & Sons Ltd.

Piludu M.,University of Cagliari | Piras M.,University of Cagliari | Pichiri G.,University of Cagliari | Coni P.,University of Cagliari | And 6 more authors.
PLoS ONE | Year: 2015

Due to its actin-sequestering properties, thymosin beta-4 (Tβ4) is considered to play a significant role in the cellular metabolism. Several physiological properties of Tβ4 have been reported;, however, many questions concerning its cellular function remain to be ascertained. To better understand the role of this small peptide we have analyzed by means of transmission immunoelectron microscopy techniques the ultrastructural localization of Tβ4 in HepG2 cells. Samples of HepG2 cells were fixed in a mixture of 3% formaldehyde and 0.1% glutaraldehyde in 0.1 M cacodylate buffer and processed for standard electron microscopic techniques. The samples were dehydrated in a cold graded methanol series and embedded in LR gold resin. Ultrathin sections were labeled with rabbit antibodies to Tβ4, followed by gold-labeled goat anti-rabbit, stained with uranyl acetate and bismuth subnitrate, observed and photographed in a JEOL 100S transmission electron microscope. Highresolution electron microscopy showed that Tβ4 was mainly restricted to the cytoplasm of HepG2 growing in complete medium. A strong Tβ4 reactivity was detected in the perinuclear region of the cytoplasmic compartment where gold particles appeared strictly associated to the nuclear membrane. In the nucleus specific Tβ4 labeling was observed in the nucleolus. The above electron microscopic results confirm and extend previous observations at light microscopic level, highlighting the subcellular distribution of T β4 in both cytoplasmic and nuclear compartments of HepG2 cells. The meaning of Tβ4 presence in the nucleolus is not on the best of our knowledge clarified yet. It could account for the interaction of Tβ4 with nucleolar actin and according with this hypothesis, Tβ4 could contribute together with the other nucleolar acting binding proteins to modulate the transcription activity of the RNA polymerases. © 2015 Piludu et al.

Khunti K.,University of Leicester | Caputo S.,UniversitaCattolica | Damci T.,Istanbul University | Dzida G.J.,Medical University of Lublin | And 12 more authors.
Diabetes, Obesity and Metabolism | Year: 2012

Aims: Evaluate the safety and efficacy of once-daily insulin detemir initiated in routine clinical practice in patients with type 2 diabetes mellitus inadequately controlled with oral hypoglycaemic agents (OHAs). Methods: This large observational study was conducted in 10 countries. Adverse event data (including hypoglycaemia) and glycaemic control wererecorded before and 24 weeks following insulin initiation while patients continued routine clinical management. Results:In this study, 17 374 patients (53% male) were included. Mean pre-insulin values (±s.d.) were: age 62±12 years; body mass index (BMI) 29.3±5.4 kg/m2; diabetes duration 10±7 years; haemoglobin A1c (HbA1c) 8.9±1.6%. During the study, 27 patients experienced serious adverse drug reaction, severe hypoglycaemic events or both; and there were 31 episodes of severehypoglycaemia in 21 patients. After 24 weeks, HbA1c was 7.5±1.2% (change of -1.3%; p<0.001) and mean weight change was -0.6 kg (confidence interval -0.7, -0.5 kg, p<0.001). Daily insulin dose increased from 13±6 U (0.16±0.09 U/kg) to 22±16 U (0.27±0.17U/kg) by 24 weeks. Multivariate regression analysis identified several independent demographic and treatmentpredictors of end of study HbA1c. Conclusions: Addition of once-daily insulin detemir to patients with type 2 diabetes mellitus on OHA therapy resulted in few adverse events, significant improvements in glycaemic control, small reductions in weight and low rates of hypoglycaemia. On the basis of this study, concerns about hypoglycaemia or weight gain should not preclude initiation of basal insulin analogues in patients with poor glycaemic control on OHAs. © 2012 Blackwell Publishing Ltd.

Gianfagna F.,University Cattolica | Tamburrelli C.,University Cattolica | Vohnout B.,University Cattolica | Vohnout B.,Slovak Medical University | And 16 more authors.
Nutrition, Metabolism and Cardiovascular Diseases | Year: 2013

Background and aims: Variations in mixed platelet-leukocyte conjugate formation in human whole blood could be genetically determined. We quantified platelet and leukocyte activation and interaction in families with or without early myocardial infarction and evaluated their heritability, genetic correlation and linkage to the 9p21.3 region. Methods and results: The study population included 739 subjects (≥15 years old) from 54 large pedigrees, 23 with and 31 without familial myocardial infarction. Mixed platelet-leukocyte conjugates and markers of platelet or leukocyte activation (P-selectin, CD11b and L-selectin surface expression) were measured both before and after invitro blood stimulation with collagen-ADP. All traits had significant genetic components (17.5-65.3% of the phenotypic variability), while shared household effects (0-39.6%) and environmental covariates (0-10.2%) tendedto be smaller. Stimulated platelet-polymorphonuclear leukocyte (PMN) andplatelet-monocyteconjugates showed the highest linkage to the 9p21.3 region (LOD=0.94 and 1.33, respectively; empirical p value=0.017 and 0.009). PMN markers resulted strongly genetically correlated between them in bivariate analysis among pairs of quantitative traits. Conclusion: This study supports a genetic regulation of human mixed platelet-leukocyte conjugates. © 2012 Elsevier B.V.

Chegaev K.,University of Turin | Federico A.,University of Turin | Marini E.,University of Turin | Rolando B.,University of Turin | And 12 more authors.
Bioorganic and Medicinal Chemistry | Year: 2015

Some symmetrical and unsymmetrical thiacarbocyanines bearing NO-donor nitrooxy and furoxan moieties were synthesized and studied as candidate anti-Alzheimer's drugs. All products activated soluble guanylate cyclase (sGC) in a dose-dependent manner, depending on the presence in their structures of NO-donor groups. None displayed toxicity when tested at concentrations below 10 μM on human brain microvascular endothelial cells (hCMEC/D3). Some products were capable of inhibiting amyloid β-protein (Aβ) aggregation, with a potency in the low μM concentration range, and of inhibiting aggregation of human recombinant tau protein in amyloid fibrils when incubated with the protein at 1 μM concentration. Nitrooxy derivative 21 and furoxan derivative 22 were selected to investigate synaptic plasticity. Both products, tested at 2 μM concentration, counteracted the inhibition of long-term potentiation (LTP) induced by Aβ42 in hippocampal brain slices. © 2015 Elsevier Ltd. All rights reserved.

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