The penetration, permeation, and resorption of radioactively labelled 8-Methoxypsoralen was investigated in human skin. Siultaneously, the effects to time and ointment carrier on the penetration kinetics were ascertained. The carriers tested were: vaseline, aqueous wool-wax alcohol ointment, aqueous hydrophilic ointment and polyethylene glycol ointment. The absolute concentrations of 8-Methoxypsoralen were estimated in the horny layer, epidermis and dermis. With the most advantageous carrier, aqueous wool-wax alcohol ointment, 4-6X10(-5) M and 10(-5) M were attained in the epidermis and dermis, respectively. Moreover, it was shown that the substance penetrates rapidly (10 min) into the epidermis and dermis and the high concentrations reached constant over a period of 16 h. Only with a formulation of aqueous wool-wax alcohols is any accumulation at all achieved in the deeper areas of the horny layer. A uniform decrease in drug concentration with increasing depth of the horny layer is found with the other 3 vehicles, whereby slight variations in concentrations pertain from carrier to carrier. 4 h after local application, 8-Methoxypsoralen can be detected in the urine. Regardless of the ointment base employed, 8-Methoxypsoralen is no longer detectable in the urine 40 h after application. In comparison to the oral therapy, the same magnitude of percutaneous resorption into the central compartment is to be derived from the data, if half the body surface is treated locally.
The influence of cyproterone acetate (CPA) containing drugs on the endometrium has not yet been investigated. Therefore, endometrial biopsies were obtained in 22 hirsute patients between day 14 and 28 of the cycle after 7-18 months of oral antiandrogen therapy. The effects of various regimens consisting of different doses of CPA in combination with ethinylestradiol (EE) were evaluated. The low-dose standard regimen (50 micrograms of EE plus 2 mg of CPA daily from day 5 to 25) caused regressive changes in the endometrium, i.e., sparse atrophic glands, relatively compact stroma, islands of stromal edema. These alterations correspond to those induced by conventional balanced low-dose combined oral contraceptives. High-dose reversed sequential regimen (40 micrograms of EE daily from day 5 to 25 plus 100 mg of CPA daily from day 5 to 14) resulted in pseudodeciduation and massive stromal edema. Pseudodeciduation during the early secretory phase is taken as a sign of the progestational depot effect of CPA, while the stromal edema is regarded as a result of the relatively unopposed estrogen intake during the second half of the treatment cycle. Thus, the effects of CPA containing drug on the endometrium depend essentially on their type, dosage and mode of administration.
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