In vitro bulk/surface erosion pattern of PLGA implant in physiological conditions: a study based on auxiliary microsphere systems

This work investigates the degradation of PLGA implants in an aqueous medium maintained at physiological pH ≈ 7.4. Two limiting systems are also investigated, which involve the degradation of PLGA microspheres in two different media characterized by: (i) a non-regulated pH, for emulating the autocatalyzed degradation in the implant core; and (ii) a regulated physiological pH, for emulating the uncatalyzed degradation at the implant surface. The degradation experiments were carried out along 40?50 days, and samples withdrawn during this period were characterized by gravimetry, electronic microscopy, and size exclusion chromatography. Experimental results suggest that PLGA implants are degraded according to a time-variant spatial pattern, which depends on the pH of the surrounding medium. Initially, the implants suffered a typically bulk erosion process, governed by the acidification of the implant core; and after breakage of the implant wall, the regulated physiological pH induces a surface erosion process. The two auxiliary microsphere-based experiments were useful to elucidate the degradation phenomena occurring in the PLGA implants. The evolution of the mass loss and the weight-average molecular weight along the degradation can be successfully predicted by simple mathematical models based on first-order kinetics.Fil: Boimvaser, Sonia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Santa Fe. Instituto de Desarrollo Tecnológico para la Industria Química. Universidad Nacional del Litoral. Instituto de Desarrollo Tecnológico para la Industria Química; ArgentinaFil: Mariano, Rodolfo Nicolás. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Santa Fe. Instituto de Desarrollo Tecnológico para la Industria Química. Universidad Nacional del Litoral. Instituto de Desarrollo Tecnológico para la Industria Química; ArgentinaFil: Turino, Ludmila Noelia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Santa Fe. Instituto de Desarrollo Tecnológico para la Industria Química. Universidad Nacional del Litoral. Instituto de Desarrollo Tecnológico para la Industria Química; ArgentinaFil: Vega, Jorge Ruben. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Santa Fe. Instituto de Desarrollo Tecnológico para la Industria Química. Universidad Nacional del Litoral. Instituto de Desarrollo Tecnológico para la Industria Química; Argentin

In situ formed microparticles of PLGA from O/W emulsions stabilized with PVA: Encapsulation and controlled release of progesterone

In situ-formed microspheres are an alternative to expensive and complex manufactured preformed systems for the controlled release of drugs. The aim of this study was to evaluate the potential of stable O/W emulsions to entrap progesterone after in vitro precipitation of poly(d,l-lactide-co-glycolide) (PLGA) microparticles. This was achieved by a solvent selection based on their miscibility and capability to solubilize the drug and PLGA. Stability assays, size distribution studies, and progesterone encapsulation efficiency evaluation were carried out for the candidate formulations. After selection of the most suitable formulations, in vitro-controlled release test of progesterone were done. Results demonstrate that emulsions based on triacetin and polyvinyl alcohol (PVA) aqueous solutions were useful solvent systems to obtain microspheres capable to deliver the hormone in a controlled release manner. In addition, for the first time, for these authors, PVA was successfully implemented into a continuous phase to increase the stability of in situ-formed O/W formulations.Fil: Turino, Ludmila Noelia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Santa Fe. Instituto de Desarrollo Tecnológico Para la Industria Química (i); ArgentinaFil: Mariano, Rodolfo Nicolás. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Santa Fe. Instituto de Desarrollo Tecnológico Para la Industria Química (i); ArgentinaFil: Boimvaser, Sonia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Santa Fe. Instituto de Desarrollo Tecnológico Para la Industria Química (i); ArgentinaFil: Luna, Julio Alberto. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Santa Fe. Instituto de Desarrollo Tecnológico Para la Industria Química (i); Argentin

Metabolic level recognition of progesterone in dairy Holstein cows using probabilistic models

Administration of exogenous progesterone is widely used in hormonal protocols for estrous (re)synchronization of dairy cattle without regarding pharmacological issues for dose calculation. This happens because it is difficult to estimate the metabolic level of progesterone for each individual cow before administration. In the present contribution, progesterone pharmacokinetics has been determined in lactating Holstein cows with different milk production yields. A Bayesian approach has been implemented to build two probabilistic progesterone pharmacokinetic models for high and low yield dairy cows. Such models are based on a one-compartment Hill structure. Posterior probabilistic models have been structurally set up and parametric probability density functions have been empirically estimated. Moreover, a global sensitivity analysis has been done to know sensitivity profile of each model. Finally, posterior probabilistic models have adequately recognized cow�s progesterone metabolic level in a validation set when Kullback-Leibler based indices were used. These results suggest that milk yield may be a good index for estimating pharmacokinetic level of progesteron

Neuregulin-1 attenuates development of nephropathy in a type 1 diabetes mouse model with high cardiovascular risk

Neuregulin-1 (NRG-1) is an endothelium-derived growth factor with cardioprotective and antiatherosclerotic properties and is currently being tested in clinical trials as a treatment for systolic heart failure. In clinical practice, heart failure often coexists with renal failure, sharing an overlapping pathophysiological background. In this study, we hypothesized that NRG-1 might protect against cardiomyopathy, atherosclerosis, and nephropathy within one disease process. We tested this hypothesis in a hypercholesterolemic apolipoprotein E-deficient (apoE(−/−)) type 1 diabetes mouse model prone to the development of cardiomyopathy, atherosclerosis, and nephropathy and compared the effects of NRG-1 with insulin. Upon onset of hyperglycemia induced by streptozotocin, apoE(−/−) mice were treated with vehicle, insulin, or recombinant human (rh)NRG-1 for 14 wk and were compared with nondiabetic apoE(−/−) littermates. Vehicle-treated diabetic apoE(−/−) mice developed left ventricular (LV) dilatation and dysfunction, dense atherosclerotic plaques, and signs of nephropathy. Nephropathy was characterized by abnormalities including hyperfiltration, albuminuria, increased urinary neutrophil gelatinase-associated lipocalin (NGAL), upregulation of renal fibrotic markers, and glomerulosclerosis. rhNRG-1 treatment induced systemic activation of ErbB2 and ErbB4 receptors in both heart and kidneys and prevented LV dilatation, improved LV contractile function, and reduced atherosclerotic plaque size. rhNRG-1 also significantly reduced albuminuria, NGALuria, glomerular fibrosis, and expression of fibrotic markers. Regarding the renal effects of rhNRG-1, further analysis showed that rhNRG-1 inhibited collagen synthesis of glomerular mesangial cells in vitro but did not affect AngII-induced vasoconstriction of glomerular arterioles. In conclusion, systemic administration of rhNRG-1 in hypercholesterolemic type 1 diabetic mice simultaneously protects against complications in the heart, arteries and kidneys