Bioavailability assessment of topical delivery systems: in vitro delivery of minoxidil from prototypical semi-solid formulations

An in vitro technique has been developed for evaluating the delivery performance of topical semi-solid formulations. A thin and uniform layer of formulation was applied in facsimile to actual usage conditions by troweling the vehicle across a thin. circular copper template (200 [mu]m in thickness). Approximately 30-45 mg of an oil-in-water cream, a water-in-oil cream or an ointment, each containing a range of concentrations of minoxidil, were applied over human cadaver skin within a defined circular area of 1.54 cm2. The rates of permeation of minoxidil from these formulations were determined by finite dose diffusion experiments. For formulations containing 2% minoxidil, the flux from the w/o cream tested was about 4 times higher than fluxes from the o/w cream and the ointment. Even though all w/o formulations were initially saturated with drug, the flux of minoxidil from these creams increased as the concentration of minoxidil was increased from 0.5% to 2%. In contrast, the delivery rates from the o/w cream and the ointment did not appear to be dependent on the minoxidil concentration applied (0.5-2%). Under the operative experimental conditions, the percent coefficients of variation of flux of minoxidil from these formulations were less than 20%. To achieve this low level of variability, the skin samples were all obtained from the same cadaver abdomen. If one assumes that the efficacy of a particular formulation is dependent on the ability of the drug to be released from the vehicle and diffuse through the skin, the studies show that the nature of the vehicle can profoundly affect delivery even when excess solid drug is present. They also indicate that reliable in vitro comparisons of drug delivery are possible as long as one performs the studies on skin samples taken from the same section of skin.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/28086/1/0000532.pd

GCN5 maintains muscle integrity by acetylating YY1 to promote dystrophin expression

Protein lysine acetylation is a post-translational modification that regulates protein structure and function. It is targeted to proteins by lysine acetyltransferases (KATs) or removed by lysine deacetylases. This work identifies a role for the KAT enzyme general control of amino acid synthesis protein 5 (GCN5; KAT2A) in regulating muscle integrity by inhibiting DNA binding of the transcription factor/repressor Yin Yang 1 (YY1). Here we report that a muscle-specific mouse knockout of GCN5 (Gcn5(skm)(−/−)) reduces the expression of key structural muscle proteins, including dystrophin, resulting in myopathy. GCN5 was found to acetylate YY1 at two residues (K392 and K393), disrupting the interaction between the YY1 zinc finger region and DNA. These findings were supported by human data, including an observed negative correlation between YY1 gene expression and muscle fiber diameter. Collectively, GCN5 positively regulates muscle integrity through maintenance of structural protein expression via acetylation-dependent inhibition of YY1. This work implicates the role of protein acetylation in the regulation of muscle health and for consideration in the design of novel therapeutic strategies to support healthy muscle during myopathy or aging