piperidines and palmitoleic-acid

The effect of fatty acids on the skin permeation of donepezil base (DPB) and its hydrochloride salt (DPH) were studied in vitro using hairless mouse and human cadaver skin. DPB and DPH were solubilized in propylene glycol (PG) containing 1% (w/v) fatty acid, after which the in vitro permeation through hairless mouse skin and human cadaver skin were evaluated using Keshary-Chien diffusion cells. The optimized formulation obtained from the in vitro study was then tested in rats for an in vivo pharmacokinetic study. The relative in vitro skin permeation rate of donepezil (DP) through the hairless mouse skin showed a parabolic relationship with increased carbon length of the fatty acid enhancers. Among the fatty acids tested, oleic acid for DPB and palmitoleic acid for DPH showed the highest enhancing effect, respectively. Both the permeation rates of DPB and DPH evaluated in human cadaver skin were in good correlation with those in hairless mouse skin, regardless of the presence of fatty acids. This suggests that the mouse skin model serves as a useful in vitro system that satisfactorily represents the characteristics of the human skin. Moreover, based on the in vitro results, the optimal formulation that could maintain the human plasma concentration of 50 ng/mL was determined to be 10mg DP with 1% (w/v) enhancer. When the DP transdermal formulations were applied to the abdominal skin of rats (2.14 cm(2)), the C(ss) was maintained for 48 h, among which the highest value of 52.21 ± 2.09 ng/mL was achieved with the DPB formulation using oleic acid. These results showed that fatty acids could enhance the transdermal delivery of DP and suggested the feasibility of developing a novel transdermal delivery system for clinical use.

Topics: Administration, Cutaneous; Animals; Cadaver; Chemistry, Pharmaceutical; Cholinesterase Inhibitors; Donepezil; Dose-Response Relationship, Drug; Drug Compounding; Fatty Acids, Monounsaturated; Humans; Indans; Male; Mice; Mice, Hairless; Oleic Acid; Permeability; Piperidines; Propylene Glycol; Rats; Rats, Sprague-Dawley; Skin; Skin Absorption; Solubility; Solvents; Technology, Pharmaceutical

Endothelium-dependent responses were assessed in myometrial small arteries isolated from pregnant women, using pressure myography. Responses to bradykinin were unaffected by the combined presence of the nitric oxide synthase (NOS) inhibitor, N-nitro-L-arginine methyl ester (L-NAME, 100 micro M) and the cyclo-oxygenase inhibitor, indomethacin (10 micro M). The additional presence of clotrimazole (50 micro M) attenuated, but did not abolish, vasodilator responses to bradykinin. Raising extracellular [K(+)] (by between 1 and 15 mM) did not evoke a vasodilator response, nor did the cannabinoids, anandamide and methanandamide. Responses to bradykinin were attenuated in the presence of the gap junction inhibitors 18-alpha-glycyrrhetinic acid (18-alpha GA, 100 micro M), carbenoxolone (100 micro M) and palmitoleic acid (50 micro M). SR141716A, the CB(1) receptor antagonist attenuated responses to bradykinin, but only at high concentrations (10 micro M). These results suggest that gap junctional communication is involved in the nitric oxide (NO)- and prostanoid-independent vasodilator responses to bradykinin in myometrial small arteries in normal pregnancy.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Arteries; Biological Factors; Bradykinin; Cannabinoids; Carbenoxolone; Clotrimazole; Cyclooxygenase Inhibitors; Endothelium, Vascular; Fatty Acids, Monounsaturated; Female; Gap Junctions; Glycyrrhetinic Acid; Humans; In Vitro Techniques; Indomethacin; Myometrium; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase; Piperidines; Pregnancy; Pyrazoles; Receptors, Cannabinoid; Receptors, Drug; Rimonabant; Vasoconstrictor Agents; Vasodilation