New potential application of hydroxypropyl-ß-cyclodextrin in solid self-nanoemulsifying drug delivery system and solid dispersion.

The purpose of this study was to use hydroxypropyl-ß-cyclodextrin (HP-ß-CD) as a novel carrier in solid SNEDDS and solid dispersions to enhance the solubility and oral bioavailability of poorly water-soluble dexibuprofen. The novel dexibuprofen-loaded solid SNEDDS was composed of dexibuprofen, corn oil, polysorbate 80, Cremophor® EL, and HP-ß-CD at a weight ratio of 45/35/50/15/100. This solid SNEDDS spontaneously formed a nano-emulsion with a size of approximately 120 nm. Unlike the conventional solid SNEDDS prepared with colloidal silica as a carrier, this dexibuprofen-loaded solid SNEDDS exhibited a spherical structure. Similar to the dexibuprofen-loaded solid dispersion prepared with HP-ß-CD, the transformation of the crystalline drug to an amorphous state with no molecular interactions were observed in the solid SNEDDS. Compared to the solid dispersion and dexibuprofen powder, solid SNEDDS significantly enhanced drug solubility and AUC. Therefore, HP-ß-CD is a novel potential carrier in SNEDDS for improving the oral bioavailability of dexibuprofen.

Estrogenicidad de los aceites de maíz y de almendras en modelos roedores / Estrogenicity of corn and almond oils in rodent models

En este estudio se utilizaron los modelos Allen-Doisy y uterotrópico para estudiar la estrogenicidad de aceites de coco, hígado de bacalao, maíz, pepita de uva y de almendras, en ratas. En el ensayo Allen-Doisy, la actividad estrogénica fue evidenciada por cornificación del epitelio vaginal en ratas adultas ovariectomizadas a las que se administró 300 μl de aceite por tres días consecutivos y por vía subcutánea. La cornificación vaginal se estudió a través de observaciones microscópicas diarias de frotis vaginales. En el ensayo uterotrópico, la estrogenicidad fue evaluada por un incremento en el peso uterino en ratas de 18 días postnatales a las que se administró 300 μl de aceite, subcutaneo, por tres días consecutivos. En el día cuarto, los úteros fueron recolectados y pesados. En ambos ensayos se utilizaron controles negativos (sin tratamiento y suero fisiológico, 300 μl) y controles positivos (estradiol 50 μg/kg y bisfenol A 20 mg/kg). Tanto el aceite de almendras como el de maíz demostraron una respuesta estrogénica estadísticamente significativa, aunque con una potencia bastante menor a la del estradiol y bisfenol A, mientras que los aceites de coco, hígado de bacalao y pepita de uva no indujeron la respuesta. Proponemos que la estrogenicidad del aceite de almendras puede deberse a su contenido relativo en ácidos oleico y linoleico, mientras que la del aceite de maíz a su contenido de factores mitogénicos. El impacto potencial en humanos de estas respuestas en roedores debe ser investigado (AU)

Here we report the use of the Allen-Doisy and the uterotrophic assay in rats to study the estrogenicity of coconut, cod liver, corn, grapeseed and almond oil. In the Allen-Doisy assay, estrogenic activity was evidenced by vaginal epithelium cornification in adult female ovarioctemized rats which were subcutaneously administered 300 μl of oil for three consecutive days. Vaginal cornification was studied by daily observation under a microscope of vaginal smears. In the uterotrophic assay, estrogenicity was evaluated by the increase of uterine weight in 18 day rats administered 300 μl of oil subcutaneously for three consecutive days. On the fourth day, uteri were collected and weighed. An untreated group as well as a saline solution (300 μl subcutaneous) treatment group was included as negative controls while bisphenol A (20 mg/kg) and estradiol (50 􀈝g/kg) were used as positive control in both assays. Our data shows that both corn and almond oil have a strong and statistically significant estrogenic response in the assays although their potency was several orders of magnitude lower tan estradiol, while cod, coconut and grapeseed oils did not induce a response. The potential health impacts of estrogenic components in food oil deserve further attention (AU)

TCDD administered on activated carbon eliminates bioavailability and subsequent shifts to a key murine gut commensal.

Activated carbon (AC) is an increasingly attractive remediation alternative for the sequestration of dioxins at contaminated sites globally. However, the potential for AC to reduce the bioavailability of dioxins in mammals and the residing gut microbiota has received less attention. This question was partially answered in a recent study examining 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced hallmark toxic responses in mice administered with TCDD sequestered by AC or freely available in corn oil by oral gavage. Results from that study support the use of AC to significantly reduce the bioavailability of TCDD to the host. Herein, we examined the bioavailability of TCDD sequestered to AC on a key murine gut commensal and the influence of AC on the community structure of the gut microbiota. The analysis included qPCR to quantify the expression of segmented filamentous bacteria (SFB) in the mouse ileum, which has responded to TCDD-induced host toxicity in previous studies and community structure via sequencing the 16S ribosomal RNA (rRNA) gene. The expression of SFB 16S rRNA gene and functional genes significantly increased with TCDD administered with corn oil vehicle. Such a response was absent when TCDD was sequestered by AC. In addition, AC appeared to have a minimal influence on murine gut community structure and diversity, affecting only the relative abundance of Lactobacillaceae and two other groups. Results of this study further support the remedial use of AC for eliminating bioavailability of TCDD to host and subsequent influence on the gut microbiome.

The effect of plasma lipids on the pharmacokinetics of chlorpyrifos and the impact on interpretation of blood biomonitoring data.

Lipophilic molecules, like chlorpyrifos (CPF), present a special problem for interpretation of biomonitoring data because both the environmental dose of CPF and the physiological (pregnancy, diet, etc.) or pathological levels of blood lipids will affect the concentrations of CPF measured in blood. The objective of this study was to investigate the distribution of CPF between plasma and tissues when lipid levels are altered in late pregnancy. CPF was sequestered more in the low-density lipid fraction of the blood during the late stages of gestation in the rat and returned to nonpregnant patterns in the dam after birth. Plasma partitioning of CPF increased with increases in plasma lipid levels and the increased partitioning of CPF into plasma lipids resulted in less CPF in other tissue compartments. Gavage dosing with corn oil also increased plasma lipids that led to a moderate increase of CPF partitioning into the plasma. To mechanistically investigate the potential pharmacokinetic effects of blood lipid changes, an existing CPF physiologically based pharmacokinetic/pharmacodynamic model for rats and humans was modified to account for altered lipid-tissue partition coefficients and for major physiological and biochemical changes of pregnancy. The model indicated that plasma CPF levels are expected to be proportional to the well-known changes in plasma lipids during gestation. There is a rapidly growing literature on the relationship of lipid profiles with different disease conditions and on birth outcomes. Increased blood concentrations of lipophilic chemicals like CPF may point to altered lipid status, as well as possibly higher levels of exposure. Thus, proper interpretation of blood biomonitoring data of lipophilic chemicals requires a careful consideration of blood lipids.

Influence of the fatty acid composition of lipids in chylomicron remnants derived from fish or corn oil on the lipid profile of cultured rat hepatocytes.

The aim of this work was to characterise the lipid and fatty acid composition of chylomicron remnants enriched in n-3 or n-6 polyunsaturated fatty acids (PUFA) and to investigate their influence on the fatty acid profiles of the lipids of rat hepatocytes cultured in monolayers. Chylomicrons were prepared from the lymph collected from the thoracic duct of rats given an oral dose of fish or corn oil (high in n-3 and n-6 PUFA, respectively), and remnants were prepared in vitro from such chylomicrons using rat plasma containing lipoprotein lipase. The fatty acids predominating in the oils abounded also in their respective chylomicrons and remnants, especially in triacylglycerols. Chylomicrons as well as remnants contained small amounts of phospholipids and long-chain PUFA that were minor in, or absent from, the dietary oils, evidently provided by the intestinal epithelium. The incubation of hepatocytes for 6 h, with either n-3 or n-6 PUFA-rich remnants (0.25-0.75 mM triacylglycerol) resulted in a dose-dependent increase in the amount of triacylglycerols and phospholipids in the cells, which was not affected further by increasing the incubation time to 19 h. Whereas hepatocyte triacylglycerols mostly incorporated the PUFA predominating in each remnant type, the fatty acid profile of cell phospholipids was virtually unchanged. In addition, irrespective of whether they were enriched in n-3 or n-6 PUFA, remnants promoted a relative decrease in the amount of cholesteryl esters, a minor hepatocyte lipid class poor in PUFA. The results demonstrate that the hepatocyte fatty acid profile is modulated in a lipid-class specific way by the amount and type of dietary PUFA delivered to cells in chylomicron remnants.

Pharmacokinetics of parenteral 13-cis-retinoic acid formulations in rats.

The pharmacokinetics of three 13-cis-retinoic acid formulations were studied after intraperitoneal (ip) administration to rats. Rats were given ip injections of 2.5 mg of 13-cis-retinoic acid per 360 g of body weight; the drug was administered as an alkaline solution, suspended in corn oil, or as a mixture with polysorbate 80. The alkaline solution was also given intravenously (iv) via the tail vein as a control. The mean elimination rate constant, calculated from data from iv administration, was 0.72 +/- 0.088 h-1 (r = 0.988). The peak concentration in plasma and the time to reach this maximum were 14 mg/L and 0.5 h, 22 mg/L and 2 h, and 10 mg/L and 1 h for the drug administered as an alkaline solution, suspended in corn oil, and as a mixture with polysorbate 80, respectively. The areas under the concentration-time curve (concentration in plasma versus time) were 34.9 +/- 8.78 mg.h/L for the iv dose and 34.1 +/- 9.97, 62.4 +/- 32.3, and 25.9 +/- 12.0 mg.h/L for the ip doses of alkaline solution, suspension in oil, and mixture with polysorbate 80, respectively. Because of the rapid increase of concentration in plasma, which is identical to that of the iv profile, and the ease of its handling and preparation, the ip administered alkaline solution is the preferable formulation.

Fat absorption in dogs with demodicosis or zinc-responsive dermatosis.

Quantitative absorption of long-chain triglycerides was studied in normal dogs, dogs with demodicosis and dogs which had been successfully treated for zinc-responsive dermatosis. The mean serum triglyceride concentration of dogs treated for zinc-responsive dermatosis was significantly lower than that of normal dogs before (P less than 0.01) and at one hour (P less than 0.01) and two, three and four hours (P less than 0.001) after feeding vegetable oil. No significant difference was detected in the mean serum triglyceride concentration of dogs with demodicosis and normal dogs at any of the sampling times.