Endocrine disruptor agent nonyl phenol exerts an estrogen-like transcriptional activity on estrogen receptor positive breast cancer cells.

Several substances widely dispersed in the environment including hormones, industrial by-products and pollutants exert hormone like activity affecting steroid-responsive physiological systems. These compounds, named endocrine disruptors, are suspected to affect the mammalian reproductive system. However it is still unclear whether these substances are able to elicit estrogen like activity at the low concentrations encountered in the environment. Here we compare the effects of the endocrine disruptor nonylphenol with the effects elicited by 17-ß-estradiol on gene transcription in the human breast cancer cell line MCF7. The correlation of the nonylphenol induced gene expression alterations with a reference profile of estradiol treated cells shows that nonylphenol at a concentration of 100 nM exerts a significant effect on estrogen responsive gene transcription in MCF7 cells. Most of the genes regulated by 17-ß-estradiol respond to the nonylphenol in the same direction though to a much lesser extent. Molecular modeling of the potential interaction of nonylphenol with the estrogen receptor α shows that nonylphenol is likely to bind to the estrogen receptor α.

Punch geometry and formulation considerations in reducing tablet friability and their effect on in vitro dissolution.

The tablet friability resulting from formulation variations was studied under controlled granulation moisture content and tablet crushing strength. Tablets made with lactose were more friable than tablets made with microcrystalline cellulose. Replacement of 0.5% magnesium stearate with 0.5% stearic acid in the formula reduced tablet friability, whereas the combination of 0.5% stearic acid and up to 0.25% magnesium stearate did not increase tablet friability, decrease drug dissolution rate, or increase tablet-to-tablet variability in dissolution. Tablets compressed with extra deep concave punches resulted in lower friability compared with tablets compressed with standard concave or deep concave punches. The friabilities of the standard convex and deep convex tablets were similar, indicating that a critical level of punch tip curvature was important in reducing tablet friability. The dissolution rate was not affected by the punch tip geometry, but the tablet-to-tablet dissolution variability at the 0.5% stearic acid level for the extra deep convex tablets was higher compared with the standard convex tablets.

Effect of moisture and crushing strength on tablet friability and in vitro dissolution.

The friability and dissolution of a formulation of compressed tablets were studied by varying the granulation moisture and tablet crushing strength. A general quadratic response surface model was used to analyze the data. The response surface contour plots of tablet friability consisted of a series of ellipsoidal curves. The optimum friability corresponding to a granulation moisture content and a tablet crushing strength was a simple minimum. The in vitro dissolution contour plots showed a stationary ridge system. Along the ridge, a large number of combinations of tablet crushing strength and granulation moisture represented 100% drug dissolution. The contour overlays of friability and dissolution contour plots showed a region where both the friability and dissolution requirement could be met. The analysis of the data by means of multiple linear regression was helpful in understanding the role of granulation moisture and tablet crushing strength on tablet friability and in vitro dissolution.

Blemishes developing on soft contact lenses.

Suspected contamination of soft contact lenses lead to biological, X-ray spectrophotometric, and photographic investigations to attempt identification of substances which could not be cleaned from the lenses and which increased in number with time. All indications point to suspect contaminant not being foreign material but a breakdown of the polymer structure.

Everted rat intestinal sacs as an in vitro model for assessing absorptivity of new drugs.

An in vitro model that utilizes everted rat intestinal sacs was evaluated for assessing the absorptivity of several analogs of potential drug substances prior to formulation work and clinical trials. This model not only is a useful qualitative tool for assessing absorptivity of structurally related compounds but also yields some insight into the process involved in drug absorption. Notwithstanding the complexities involved in the absorption processes, the data support the hypothesis that the absorption of organic electrolytes mainly takes place by the partitioning of the unionized species into the lipoidal membranes and then diffusion.

Pulmonary absorption studies utilizing in situ rat lung model: designing dosage regimen for bronchial delivery of new drug entities.

The absorption of 7-methylsulfinylxanthone-2-carboxylic acid, 7-(methylthio)xanthone-2-carboxylic acid, and their sodium salts from the respiratory tract of anesthetized rats was studied after intratracheal administration of 0.1 ml of a solution or suspension containing the drug. At various times after administration, the lungs and trachea were removed and assayed radiochemically for unabsorbed drug. Sodium 7-(methylthio)xanthone-2-carboxylate from solution was absorbed approximately 20 times faster than sodium 7-methylsulfinylxanthone-2-carboxylate from a solution. The absorption from solutions was three to four times faster than the absorption from suspensions. For inhalation aerosol dosage forms intended for prophylactic use, the drug entity with slower systemic absorption probably would be more desirable than the drug entity with rapid absorption. Rapid systemic absorption following inhalation of powder or liquid aerosols would lead to more frequent dosing if the biological activity is related to the drug concentration in the tracheobronchial tissues. Therefore, the powder or liquid inhalation aerosols of organic acids rather than the corresponding sodium salts may be preferable for designing a dosage regimen. However, if the dosage form is intended for utilizing the bronchodilator activity of the compound, the drug entity with rapid absorption is more desirable. Therefore, in the treatment of asthmatic attacks, liquid or powder inhalation aerosols of the sodium salt of the rapidly absorbing drug entity are preferable. The absorption rates were directly proportional to concentration when the initial concentration of sodium 7-methylsulfinylxanthone-2-carboxylate was varied over a 333-fold range. The effect of the pH of the drug solution administered intratracheally to the rat lung indicated a sharp increase in the pulmonary absorption at a pH near the pKa. The results suggested that structurally related xanthones are absorbed possibly by passive diffusion across the lipoidal region of the pulmonary membranes and that the absorption of organic acids and organic electrolytes is mainly controlled by the lipid solubility of the unionized species.