Copper biodistribution after acute systemic administration of copper gluconate to rats.

Neurodegenerative disorders have been linked to the decrease of copper concentrations in different regions of the brain. Therefore, intake of micronutrient supplements could be a therapeutic alternative. Since the copper distribution profile has not been elucidated yet, the aim of this study was to characterize and to analyze the concentration profile of a single administration of copper gluconate to rats by two routes of administration. Male Wistar rats were divided into three groups. The control group received vehicle (n = 5), and the experimental groups received 79.5 mg/kg of copper orally (n = 4-6) or 0.64 mg/kg of copper intravenously. (n = 3-4). Blood, striatum, midbrain and liver samples were collected at different times. Copper concentrations were assessed using atomic absorption spectrophotometry. Copper concentration in samples from the control group were considered as baseline. The highest copper concentration in plasma was observed at 1.5 h after oral administration, while copper was quickly compartmentalized within the first hour after intravenous administration. The striatum evidenced a maximum metal concentration at 0.25 h for both routes of administration, however, the midbrain did not show any change. The highest concentration of the metal was held by the liver. The use of copper salts as replacement therapy should consider its rapid and discrete accumulation into the brain and the rapid and massive distribution of the metal into the liver for both oral and intravenous routes. Development of controlled-release pharmaceutical formulations may overcome the problems that the liver accumulation may imply, particularly, for hepatic copper toxicity.

Vaginal Bifidobacterium breve for preventing urogenital infections: Development of delayed release mucoadhesive oral tablets.

Bifidobacteria are predominant microorganisms in the intestinal flora, but at the same time represent a subdominant group of the vaginal microbiota. For this reason, oral administration of these probiotic bacteria can provide beneficial effect for both intestinal and urogenital ecosystems. The first aim of this study was to test the strain Bifidobacterium breve BC204, isolated from a vaginal swab of a healthy woman, for its capability to adhere to human cells, to survive to gastric acids and bile salts and to exert antimicrobial activities. The second aim of the work was to develop an oral formulation able to guarantee bacterial survival during storage and administration, thus favouring intestinal and vaginal colonization. B. breve BC204 was encapsulated by spray-drying and subsequently formulated in time-dependent erodible tablets. B. breve BC204 showed good ability to adhere to Caco-2 cells and moderate ability to resist to gastrointestinal stress. Moreover, it exerted a strong antimicrobial activity against urogenital and enteric pathogens. Microencapsulation followed by tablet production allowed high loading and survival of B. breve BC204, associated to a delayed release and mucoadhesive ability. These characteristics are required to achieve appropriate amount and persistence of viable microbial cells in the treatment site.

Microneedles as Enhancer of Drug Absorption Through the Skin and Applications in Medicine and Cosmetology.

The microneedles technology has found applications in many health-related fields. For example, their application in drugs and vaccines delivery as well, as the determination of biomarkers, has been reported. They also have a place in the dermatology and cosmetic areas such as the treatment of wounds from burns, scars, acne, depigmentation, and alopecia will be shown. Microneedles are used in therapeutic applications and are manufactured using materials such as metal (steel, titanium, nickel), polymer (oly-glycolic acid (PGA), poly-lactide-co-glycolide acid (PLGA), poly-L-lactic acid (PLA), chitosan), glass, silicon, ceramic, carbohydrates (trehalose, sucrose, mannitol). Examples of application of microneedles and their advantages and disadvantages are discussed. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.

Supplementation with rumen-protected L-arginine-HCl increased fertility in sheep with synchronized estrus.

The aim of the present study was to evaluate the effects of L-arginine-HCl supplementation on ovulation rate, fertility, prolificacy, and serum VEGF concentrations in ewes with synchronized oestrus. Thirty Suffolk ewes with a mean body weight of 45 ± 3 kg and a mean body condition score (BCS) of 2.4 ± 0.28 were synchronized for estrus presentation with a progestin-containing sponge (20 mg Chronogest® CR) for 9 days plus PGF2-α (Lutalyse; Pfizer, USA) on day 7 after the insertion of the sponge. The ewes were divided into two groups; i.e., a control group (n = 15) that was fed on the native pasture (basal diet) and an L-arginine-HCl group (n = 15) that received 7.8 g of rumen-protected L-arginine-HCl from day 5 of the sponge insertion until day 25 after mating plus the basal diet. The L-arginine-HCl was administered daily via an esophageal probe between days 5 and 9 of the synchronization protocol and every third day subsequently. Blood samples were drawn from the jugular vein every 6 days throughout the entire experimental period. The results revealed that the L-arginine-HCl supplementation increased fertility during the synchronized estrus (P = 0.05). However, no effects were observed on the final BCS (P = 0.78), estrus presentation (P = 0.33), multiple ovulations (P = 0.24), prolificacy (P = 0.63), or serum VEGF concentration. In conclusion, L-arginine-HCl supplementation during the period used in this study increased fertility in sheep with synchronized estrus possibly due to improved embryo-fetal survival during early pregnancy.

Correlation between compactibility values and excipient cluster size using an in silico approach.

BACKGROUND: In silico simulation and percolation theory are important tools in the study of physical and mechanical behavior of pharmaceutical compacts. The aim was to generate a new in silico simulation program that describes the mechanical structure of binary compacts formed from an excipient with excellent compactibility and a drug with null compactibility. MATERIALS AND METHODS: Paracetamol and microcrystalline cellulose powders were compressed under different pressures. Values for the indentation hardness and tensile strength were measured and fitted to the Leuenberger's model. On the other hand, compacts with different composition were in silico simulated. In each system, the biggest excipient cluster was identified and quantified using the Hoshen-Kopelman algorithm. Then, the size of the biggest in silico cluster was correlated with experimental compactibility values. RESULTS AND DISCUSSION: The Leuenberger's model resulted in good fit to the experimental data for all formulations over 40% of excipient load. Formulations with high drug load (≥0.8) had reduced range for forming compacts and gave low compactibility values. The excipient percolation threshold for the simulated system was 0.3395, indicating that over this excipient fraction, a compact with defined mechanical properties will be formed. The compactibility values presented a change in the range of 0.3-0.4 of excipient fraction load, just where the in silico excipient percolation threshold was found. CONCLUSION: Physical measurements of the binary compacts showed good agreement with computational measurements. Subsequently, this in silico approach may be used for the optimization of pharmaceutical powder formulations used in tablet compression.

Parameters affecting drug release from inert matrices. 1: Monte Carlo simulation.

This study investigates the use of Monte Carlo simulation for the determination of release properties from cubic inert matrices. Specifically, the study has focused on factors including porosity, surface area and tortuosity. The release platform was formed by simulating matrices with different ratios of drug and excipient, which undergo drug release in a uni-directional (two-face) or omni-directional (six-face) process. Upon completion of each simulation the matrix 'carcass' was examined and porosity and tortuosity of the medium evaluated. The tortuosity of the medium was evaluated directly by a blind random walk algorithm. These parameters as well as the release profile were then studied with respect to common mathematical models describing drug diffusion (the square-root, power and Weibull models). It was found that, depending on their composition, the matrices systems were either homogeneous or heterogeneous in nature. Furthermore, it was found that the physical parameters could be successfully fitted to the a and b constants of the Weibull model. This approach allows the prediction of drug release from an inert matrix system with the knowledge of a few physical parameters.

Monte Carlo simulations for the study of drug release from cylindrical matrix systems with an inert nucleus.

In this work, drug release from matrices with an inert nucleus using Monte Carlo simulation was studied. Drug-excipient systems were simulated, where the drug is a soluble material while the excipient is a non-soluble material. In the center of these devices, an inert nucleus was placed. The release of the drug was unidirectional and the results were fitted to the square root of time law (Higuchi law), the power law and the Weibull equation. The percolation threshold of the drug was found to be near 0.35 close to the expected value for the cubic lattice, the difference is due to the finite and rather small size of the systems in study as well as to the fact that the lattice in use is not exactly cubic. Near the percolation threshold, the parameters of the different release models presented a drastic change; this was due to a phase transition of the system. On the other hand, it was found that the size of the matrix system modifies the transport properties of the release platform. In general, the release kinetics was adequately described by the Weibull equation.

Comparison of different mathematical models for the tensile strength-relative density profiles of binary tablets.

During the last decade the evolution of the pharmaceutical dosage form design has been important. In controlled release matrix tablets, the tensile strength is an essential parameter to consider, because a minimal mechanical strength is needed for tablet production, handling and avoidance of any dose dumping during its use. Recent developments in percolation theory led to the theoretical proposal of lattice strength that was applied to the tensile strength of tablets. This mechanical property was described as a power law of the relative density involving a critical value that corresponds to the percolation threshold. The objective of the present work is to estimate these mechanical thresholds in KCl-Ethocel100 tablets that were manufactured from different sieve fractions (100-150, 150-200, 250-300 microm). Three power law models are compared regarding the best fit of the tensile strength-relative density profiles. The main criteria for this choice are the Akaike's Information Criterion (AIC), the analysis of the residuals in conjunction with the soundest physical meaning of the models. Accordingly, a power law model was chosen that assumes an initial strength parameter. No correlation could be established between the different mixture ratios or sieve fractions with the critical relative densities. The study showed that an equation based on percolation theory can adequately model tablet strength-density profiles from matrix tablets.