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To develop and validate a model for predicting 5-year eGFR-loss in type 2 diabetes mellitus (T2DM) patients with preserved renal function at baseline.A cohort of 504.532 T2DM outpatients participating to the Medical Associations of Diabetologists (AMD) Annals Initiative was splitted into the Learning and Validation cohorts, in which the predictive model was respectively developed and validated. A multivariate Cox proportional hazard regression model including all baseline characteristics was performed to identify predictors of eGFR-loss. A weight derived from regression coefficients was assigned to each variable and the overall sum of weights determined the 0 to 8-risk score.A set of demographic, clinical and laboratory parameters entered the final model. The eGFR-loss score showed a good performance in the Validation cohort. Increasing score values progressively identified a higher risk of GFR loss: a score ≥ 8 was associated with a HR of 13.48 (12.96-14.01) in the Learning and a HR of 13.45 (12.93-13.99) in the Validation cohort. The 5 years-probability of developing the study outcome was 55.9% higher in subjects with a score ≥ 8.In the large AMD Annals Initiative cohort, we developed and validated an eGFR-loss prediction model to identify T2DM patients at risk of developing clinically meaningful renal complications within a 5-years time frame.

Aims Diabetic kidney disease (DKD) and retinopathy (DR) develop in a considerable number of subjects with Type 2 Diabetes (T2D) despite the achievement of the recommended targets for glycaemia and blood pressure. Atherogenic dyslipidemia may play a relevant role, especially in T2DM women. Methods We report our findings on the effect of diabetic dyslipidaemia, the HDL subclasses distribution and the common cholesteryl ester transfer protein (CETP)TaqIB variant on the incidence or the progression of DKD and DR in 97 T2D women, after a ∼9 years of follow-up. Results At baseline, T2D women presented with low HDL-C levels and higher levels of large lipid rich α-1 (16.34 mg/dl), α-2 (33.39 mg/dl) and pre- α1 (4.81 mg/dl) HDL subparticles. The CETP TaqIB polymorphism and baseline HbA1c, triglycerides, and HDL-C levels as well as specific HDL subpopulations were associated to the occurrence of RD after ∼9 years of follow-up. At stepwise regression analysis, HbA1c, triglycerides and the less atheroprotective α-3 HDL particles were the only factors independently associated to the incidence of RD. These same variables were also associated with the progression from background to proliferative RD. BMI, LDL/HDL ratio and low levels of α-1 HDL particles were associated to the occurrence of DKD at univariate analysis, although BMI was the only significant predictor at stepwise multivariate regression analysis. Conclusions In T2D women, atherogenic dyslipidemia as well as subtle modifications in lipoprotein particles profile are associated with incidence and progression of microvascular disease.

The aptitude of ropinirole to permeate the buccal tissue was tested using porcine mucosa mounted on Franz-type diffusion cells as ex vivo model. Drug permeation was also evaluated in presence of various penetration enhancers and in iontophoretic conditions. Ropinirole, widely used in treatment of motor fluctuations of Parkinson's disease, passes the buccal mucosa. Flux and permeability coefficient values suggested that the membrane does not appear a limiting step to the drug absorption. Nevertheless, an initial lag time is observed but the input rate can be modulated by permeation enhancement using limonene or by application of electric fields. Absorption improvement was accompanied by the important reduction of the lag time; at once the time required to reach the steady state plasma concentration was drastically decreased. On the basis of these results we could assume that clinical application of ropinirole by buccal delivery is feasible.

Transbuccal drug delivery has got several well-known advantages especially with respect to peroral way. Since a major limitation in buccal drug delivery could be the low permeability of the epithelium, the aptitude of NLX to penetrate the mucosal barrier was assessed. Ex vivo permeation across porcine buccal mucosa 800 microm thick was investigated using Franz type diffusion cells and compared with in vitro data previously obtained by reconstituted human oral epithelium 100 microm thick. Both fluxes (Js) and permeability coefficients (K(p)) are in accordance, using either buffer solution simulating saliva or natural human saliva. Permeation was evaluated also in presence of chemical enhancers or iontophoresis. No significant differences in penetration rate were observed using chemical enhancers; in contrast, Js and K(p) were extensively affected by application of electric fields. Tablets, designed for Naltrexone hydrochloride (NLX) administration on buccal mucosa, were developed and prepared by direct compression of drug loaded (56%) poly-octylcyanocrylate (poly-OCA) matrices. NLX is slowly discharged from buccal tablets following Higuchian kinetic. Histologically, no signs of flogosis ascribable to NLX and/or poly-OCA were observed, while cytoarchitectural changes due to iontophoresis were detected. Buccal tablets containing NLX may represent a potential alternative dosage form in addiction management.

Ionizing radiation can be used as a drug sterilization technique, provided that the drug itself is not modified and that no toxic products are produced; moreover, if the irradiated product is a drug delivery system, the drug release characteristics must not be significantly altered by radiation. The aim of this work was to study the effects of sterilization by ionizing radiation on hydroxyethylcellulose/trehalose spherical micromatrices, containing the antibiotic vancomycin. Our experimental results showed that gamma-rays did not alter the chromophore groups of vancomycin (UV measurements), and did not modify the kinetic behavior of drug release from microspheres. Moreover, no significant changes in the shape and in the size distribution of microspheres were found after irradiation. The electron spin resonance (ESR) spectroscopy was proven to be a valid identification method of the executed radiation treatment, even after 5 years. The experimental results showed that the therapeutic application of the pharmacological system investigated was not compromised by irradiation, and that ESR spectroscopy can be used to distinguish irradiated from non-irradiated products.

The common TaqIB variant in the gene coding for cholesteryl ester transfer protein (CETP), a key enzyme in reverse cholesterol transport, has been associated with higher HDL-C levels and with a more atheroprotective HDL subpopulations profile. Similar information are lacking in women with diabetes. The effect of menopause and the CETP polymorphism on lipid, lipoprotein profile, as well as on apoA-I-containing HDL subclasses distribution, as determined by two-dimensional gel electrophoresis, was examined in a group of women with and without type 2 diabetes. Diabetic women showed a less atheroprotective lipid and HDL subpopulations profile, with lower levels of the large α-1 (P = 0.006), α-2 (P = 0.005), and preα-1 (P = 0.02), and higher concentration of the small α-3 HDL particles (P = 0.02) as compared to controls, independently from menopause, HDL-C and triglycerides concentrations. CETP TaqIB genotype distribution was in the Hardy–Weinberg equilibrium and comparable in the two groups, but the effect of CETP polymorphism was limited to diabetic women. In this group, the CETP variant showed significant interactions with HOMAIR (P

Background and aims Atherosclerosis is a blood vessel inflammatory disease. Besides their role in reverse cholesterol transport (RCT), HDL particles may affect the atherosclerotic process through the modulation of subclinical inflammation. Notably, HDL are a heterogeneous class of particles, differing in size, composition and, probably, in their anti-inflammatory properties. The potential relationships between HDL sub-particles and inflammatory markers have never been explored in diabetic women, who typically shows dysfunctional HDL. In this work, we investigated the relationship between different HDL subclasses and major inflammatory markers in a group of women with and without type 2 diabetes. Materials and Methods Eighty type 2 diabetic and 80 control CHD-free women, not taking any hypolipidemic or hormonal drug, and matched for age and menopausal status, participated to the study. Clinical, lifestyle, common laboratory parameters, as well as inflammatory markers and HDL ApoAI-containing subpopulations with two gradient gel electrophoresis technique were measured in all participants. Results When comparing HDL subpopulations profile in women with and without diabetes, diabetic women showed a decrease of the larger alfa-1(P=0.006), alfa-2 (P=0.005), and pre alfa-1 HDL (P=0.02), and higher levels of the smaller, lipid poor alfa-3 HDL particles (P=0.02). Diabetic women also had higher hsCRP and IL-6 serum levels than non diabetic ones (age- and BMI-adjusted P Overall, inflammatory markers showed significant inverse correlations with the larger ApoAI containing HDL subclasses, and positive correlations with the smaller, less atheroprotective HDL particles. In particular, hsCRP inversely correlated with alfa-1 (P=0.01), pre alfa-1 (P Conclusions Our data show that the larger, more atheroprotective HDL subclasses were associated with lower hsCRP and IL-6 levels, whereas the smaller, lipid poor alfa-3 HDL particles were associated with an increase of these inflammatory markers. These associations were more pronounced in type 2 diabetic women, who typically show dysfunctional HDL. These data suggest that different HDL subclasses may influence CHD risk also through altered anti-inflammatory properties.