Prostaglandin and Dna Synthesis in Human Skin: Possible Relationship to ultraviolet light effects

The effect of prostaglandin E2 (PGE2) on DNA synthesis in human skin was evaluated. PGE2 (1μg) was injected intradermally into normal buttock skin of 15 volunteers followed by tritiated thymidine for autoradiographic quanitation of DNA sythesizing cells. Controls of normal saline, histamine (50μg), and lower doses of PGE2 were also injected into 8 of the volunteers. Forty-eight hours after injection of 1μg and 0.1μg PGE2 there was a 264% and 62% increase, respectively, in the number of DNA synthesizing epidermal cells/high-power field as compared to saline controls. These differences were statistically significant (p<0.01). Histamine (50μg) produced a statistically significant 36% higher labeling index compared to its saline controls (p<0.05). Many types of skin injury, including ultraviolet light (UVL) irradiation, produce an increase in the number of DNA synthesizing cells about 48 hr after the stimulus. Our findings suggest the PGE, a putative mediator of UVL-induced inflammation, may be one of the chemical mediators for the UVL-induced increase in DNA sythesizing cells. Histamine may also contribute to the increase in DNA synthesizing cells following UVL-induced inflammation

Cell Kinetic Basis for Pathophysiology of Psoriasis

Studies on the cell proliferation kinetics of psoriatic epidermal cells are presented and the results compared to similar studies for normal epidermis. The short 36-h duration of the psoriatic cell cycle (Tc) is confirmed with the first double-peaked fraction of labeled mitoses (FLM) curve in human subjects. The growth fraction of psoriasis using two experimental techniques approximates 100% within 36 h, confirming the rapid Tc found by the FLM method. The cell kinetic basis for the pathophysiology of psoriasis consists of at least 3 proliferative abnormalities in comparison to normal epidermis. By far the largest alteration is the shortening of the Tc from 311 to 36 h. There is also a doubling of the proliferative cell population in psoriasis from 27,000 to 52,000 cells/mm and an increase in the growth fraction from 60% to 100%. As a consequence of these abnormalities the psoriatic epidermis produces 35,000 cells/day from a proliferative compartment of 52,000 cells/mm2 surface area. This is a 28-fold greater production of cells than the 1,246 cells/day produced in normal epidermis. The biochemical or control factors leading to these kinetic differences continue to remain elusive

Topical Tritiated Thymidine for Epidermal Growth Fraction Determination

Direct autoradiographic identification of the epidermal growth fraction (GF) requires the delivery of tritiated thymidine ([3H]dThd) to the skin during the time interval of an entire cell cycle. The GF in normal human epidermis has not been directly measured using this technique because the systemic infusion of radioactive [3H]dThd in benign skin conditions is precluded by ethical considerations. Studies were undertaken to assess the feasibility of measuring the epidermal GF in vivo by the topical delivery of [3H]dThd. The percutaneous penetration of [3dThd in various vehicles was evaluated to select an effective topical delivery system. A vehicle consisting of Azone, isopropanol, and water (2:49:49) was the best of 4 different vehicles tested. The optimal penetration of [3H]dThd, with respect to the concentration of Azone over a range of 0–4%, was achieved at 2%. During the initial 24h following a single topical application of [3H]dThd to hairless mice the labeling increased linearly with time. In vivo studies in hairless mice produced a GF of 95% by both continuous systemic [3H]dThd infusion, and by twice daily topical [3H]dThd. Azone vehicles induced epidermal hyperplasia which was minimized by lowering the Azone concentration and by decreasing the frequency of applications from 24 to 48h. These studies establish the rationale for using topical delivery of [3H]dThd for the in vivo measurement of epidermal GF

Cell Kinetic Basis for Pathophysiology of Psoriasis

Studies on the cell proliferation kinetics of psoriatic epidermal cells are presented and the results compared to similar studies for normal epidermis. The short 36-h duration of the psoriatic cell cycle (Tc) is confirmed with the first double-peaked fraction of labeled mitoses (FLM) curve in human subjects. The growth fraction of psoriasis using two experimental techniques approximates 100% within 36 h, confirming the rapid Tc found by the FLM method. The cell kinetic basis for the pathophysiology of psoriasis consists of at least 3 proliferative abnormalities in comparison to normal epidermis. By far the largest alteration is the shortening of the Tc from 311 to 36 h. There is also a doubling of the proliferative cell population in psoriasis from 27,000 to 52,000 cells/mm and an increase in the growth fraction from 60% to 100%. As a consequence of these abnormalities the psoriatic epidermis produces 35,000 cells/day from a proliferative compartment of 52,000 cells/mm2 surface area. This is a 28-fold greater production of cells than the 1,246 cells/day produced in normal epidermis. The biochemical or control factors leading to these kinetic differences continue to remain elusive

Percutaneous Absorption of Methotrexate: Effect on Epidermal DNA Synthesis in Hairless Mice

One of the presumed reasons for the lack of clinical activity of topical methotrexate in psoriasis is insufficient percutaneous penetration necessary to inhibit epidermal DNA synthesis. The present study was undertaken to select a vehicle to optimize penetration of methotrexate in vitro and to determine the effects of this topical formulation on epidermal DNA synthesis in vivo in hairless mouse skin.Increased penetration of methotrexate was obtained in human skin in vitro with Vehicle N compared to water and n-decylmethylsulfoxide vehicles. Repeated topical application of this methotrexate/Vehicle N preparation produced marked epidermal atrophy in treated sites in both normal and hyperproliferative essential fatty acid deficient hairless mouse skin without similar effects at a distant skin site. Local inhibition of epidermal DNA synthesis was also obtained without systemic effects at a distant site. These studies demonstrate that methotrexate in Vehicle N may produce a direct effect on epidermis which may be useful for the topical therapy of psoriasis

Biodynamic Studies of Hamster Flank Organ Growth: Hormonal Influences

The biodynamic response of flank organs of male and female hamsters to androgenic stimulation has been studied by autoradiographic and electron microscopic techniques, as well as by routine histology and gross observation. Intraperitoneal administration of 2.5mg of testosterone on alternate days resulted in bilateral increase in palpable bulk, and pigmentation of flank organs of females, males, and castrated males. Topical application of testosterone, dihydrotestosterone (DHT), methyltestosterone, or androstenedione to one flank organ of females resulted in unilateral stimulation of sebaceous gland growth and pigmentation. Androsterone, epiandrosterone, and progesterone did not cause flank organ growth or increased pigmentation when applied topically. Histologic changes in flank organs of castrated males following testosterone administration are described. Auto0radiographic studies indicate a decrease in the labeling index of flank organ sebaceous gland cells within 20 hours after castration and a subsequent significant increase in the labeling index within 10 hours after a single intraperitoneal administration of 2.5mg of testosterone. Pigmentation of flank organs is due to the presence of dendritic cells in the dermis which contain dense structures resembling stage IV melanosomes

Recommendations for selecting drug-drug interactions for clinical decision support

To recommend principles for including drug-drug interactions (DDIs) in clinical decision support