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Biomedical subjects

G D Weinstein

Publications and source records attributed to G D Weinstein.

At least 73 records · Page 4Linked to original sources
PubMed1981

Topical drug effects on normal and proliferating epidermal cell models.

The effects of 28 different antiproliferative agents applied topically to normal and hyperproliferative hairless mouse skin were studied. Epidermal cell hyperproliferation was induced by an essential fatty acid-deficient diet or by irradiation with short-wavelength ultraviolet (UV) energy. Epidermal DNA synthesis was measured by hydroxyapatite column chromatography. We compared the effects of these drugs used on normal and hyperproliferative hairless mouse skin with clinical responses in patients with psoriasis treated using the same topical preparations. For most of the drugs tested, the normal and essential fatty acid-deficient mouse model effects showed a good correlation with clinical responses seen in treated patients with psoriasis. The short-wavelength UV energy-treated mouse model effects showed a poorer clinical correlation, perhaps partially caused by wide variations in DNA synthetic rates encountered in the epidermis in this model.

Animals↗
PubMed1981

Mechanism of chemotherapeutic drug action in mouse vaginal epithelium.

The mouse vaginal assay was modified to study mechanisms of drug action in epithelial cells in relation to the cell cycle. An evaluation of the labeling index, mitotic index, and the percent labeled mitoses in the vaginal epithelium was used to determine the site of drug action in the cell cycle. Systemic absorption from the vaginal epithelium was also monitored by these same measurements in rectal mucosa. Thirty drugs was tested; 17 showed cell kinetic perturbations in the vaginal mucosa and four of these had both vaginal (local) and rectal (systemic) effects. Thirteen drugs had no effect, suggesting inadequate concentration, penetration, duration of drugs exposure, or lack of biochemical action. These 30 drugs were tested in concentrations and vehicles also used for topical screening in psoriatic patients. Only 15 of the 30 drugs tested in this model predicted the clinical results.

Animals↗
PubMed1980

Cell proliferation kinetics in the human hair root.

The kinetics of cell proliferation in the matrix cells of human scalp hair were determined in vivo. Autoradiographic analysis was employed on biopsy specimens taken at specific time intervals after intradermal injection of tritiated thymidine (3H-TdR) into the scalps of volunteer subjects. The durations of the S and G2 phases (Ts and Tg2) were 11.1 and 3.6 hr respectively, obtained from the composite percent labeled mitosis curve. The labeling index of the hari matrix cells was 28.6% +/- 2.2%. The durations of mitosis and of the total cell cycle (Tm and Tgc) were calculated to be 0.8 hr and 38.8 hr respectively. The growth fraction of hair root germinative cells was estimated as 75-100% on the basis of "continuous" 3H-TdR exposure over the duration of the cell cycle. It is noted that the kinetics of human hair root cells are quite similar to the kinetics of psoriatic epidermal cells, suggesting that both tissues are approaching the maximum proliferative rate of keratinogenic epithelial cells.

Autoradiography↗
PubMed1979

Ro 20-1724: an agent that significantly improves psoriatic lesions in double-blind clinical trials.

Two double-blind studies comparing the effectiveness of the cyclic nucleotide-altering agent (4-[3-butoxy-4-methoxybenzyl]-2-imidazolidinone) (Ro 20-1724) vs vehicle have demonstrated that this compound can improve psoriatic lesions. Although Ro 20-1724 was not as effective as intensive occlusive treatment of psoriatic lesions with 0.025% triamcinolone acetonide, Ro 20-1724 had no adverse systemic or cutaneous effects. Ro 20-1724 and other cyclic nucleotide-altering agents may have therapeutic potential in the future treatment of psoriasis.

4-(3-Butoxy-4-methoxybenzyl)-2-imidazolidinone↗
PubMed1979

Abnormal proliferation of uninvolved psoriatic epidermis: differential induction by saline, propranolol, and tape stripping in vivo.

Cell proliferation of the uninvolved psoriatic skin was compared with normal skin of volunteers following stimulation by the intradermal injections of saline or propranolol, or stripping of the stratum corneum with pressure-sensitive tape. Initially, no significant in vivo difference in tritiated thymidine labeling indices were observed between normal and uninvolved epidermal cells. However, 48 hr after each stimulus more DNA synthesizing cells were found in the uninvolved psoriatic than in normal epidermis. Of these 3 stimuli, propranolol was the most effective in distinguishing between uninvolved psoriatic skin and skin from normal control subjects. Thus, uninvolved psoriatic skin appears to possess an abnormal regulation of epidermopoiesis that may be amplified by propranolol injection.

Bandages↗
PubMed1977

Cell proliferation in human cutaneous squamous cell carcinoma.

Squamous cell carcinoma (SCC) of the skin, a fairly slow-growing locally invasive tumor that occasionally matastasizes, was studied in 12 patients in vivo with the use of intralesional tritiated thymidine as a marker for cell proliferation kinetics. Analysis of the cell cycle of the germinative population revealed that the duration of S-phase was 12.5 hours; G1-phase, 28.8 hours; mitotic period (M-phase), 2 hours; G-pahse, 6.9 hours; and the total germinative cell cycle, 50.2 hours. The application of cell kinetics to programming chemotherapy for skin cancer with phase-specific cytotoxins was discussed.

Antineoplastic Agents↗
PubMed1977

In vitro screening of biochemical activity of folic acid antagonists in skin.

Dihydrofolate reductase (DHFR) inhibitors, which differ from the classical folate antagonists in physicochemical and pharmacologic parameters such as lipid solubility and mechanisms of cellular transport, were screened for DHFR inhibitory activity and biologic activity in newborn rat skin. The most effective drugs from this screen were tested for their effects on de novo DNA synthesis in psoriatic epidermis in vitro. Of the 24 compounds studied, methotrexate (MTX) was the most potent inhibitor of rat skin DHFR (I50=8.6 X 10(-9) M). Methotrexate-dimethylester, methasquin-diethylester, DDEP (2,4-diamino-5-(3',4'-dichlorophenyl)-6-ethylprimidine), and Baker's triazine antifolate (NSC 139105), while less effective than MTX as DHFR inhibitors, were more effective than MTX as inhibitors of de novo DNA synthesis in rat skin in vitro. Baker's antifolate was the only compound tested which was considerably more effective than MTX as an inhibitor of de novo DNA synthesis in psoriatic epidermis in vitro.

Animals↗
PubMed1977

Decreased thymidine incorporation in circulating leukocytes after treatment of psoriasis with psoralen and long-wave ultraviolet light.

Tritiated thymidine incorporation, a measure of DNA synthesis, was studied in circulating leukocytes from patients with widespread psoriasis who were being treated with photochemotherapy using oral 8-methoxypsoralen (8-MOP) and high-intensity, long-wave ultraviolet light (UVA). Seven of 13 psoriasis patients treated with photochemotherapy demonstrated a significant (p less than 0.05) reduction in leukocyte incorporation of tritiated thymidine immediately after UVA in comparison to incorporation before UVA. None of 10 control subjects treated with UVA alone demonstrated such reduction in leukocyte tritiated thymidine incorporation. Photochemotherapy thus affects circulating blood cells in some patients with psoriasis in addition to its therapeutic effect on epidermal cells. Further investigations are needed to determine the reasons for the differences in susceptibility to inhibition of leukocyte DNA synthesis among patients and the possible long-term consequences of such inhibition.

Coumarins↗
PubMed1977

Methotrexate.

The folic acid antagonists, aminopterin and then methotrexate, have been the primary systemically administered drugs for the treatment of severe psoriasis for 25 years. Methotrexate was finally approved by the FDA 5 years ago and was recently estimated to be used for approximately 25,000 psoriatic patients annually. With the small but chronic doses used for psoriasis, methotrexate has been relatively safe, except for a limited occurrence of significant hepatotoxicity. The good to excellent results obtained in most patients must, therefore, be weighted against the small risk of liver damage. Methotrexate has also been used with some effectiveness in several other dermatologic conditions, including mycosis fungoides, dermatomyositis, pityriasis rubra pilaris, and others, although they are not yet FDA-approved indications. The recent successful introduction of photochemotherapy (psoralen and ultraviolet light) for moderate and severely affected psoriatics will probably lead to a substantial decrease in the number of patients requiring methotrexate.

Chemical and Drug Induced Liver Injury↗
PubMed1976

Cell kinetics and programmed chemotherapy for gynecologic cancer. I. Squamous-cell carcinoma.

The results of current investigation into cellular kinetics of both normal and abnormal human genital tissue have stimulated interest in programming chemotherapeutic drug regimens for the treatment of genital cancer. This report outlines the results of cell kinetic studies of normal and abnormal squamous epithelium of the female genital tract and presents preliminary results of a regimen utilizing methotrexate, hydroxyurea, and vincristine in patients with far-advanced squamous-cell cancer of the vulva, vagina, and cervix. A total of 92 patients have received 444 courses of programmed chemotherapy by either pelvic intra-arterial infusion or systemic administration of the drugs. Our results are presented and the theoretical basis of the research is discussed.

Carcinoma, Squamous Cell↗
PubMed1976

Factors affecting human percutaneous penetration of methotrexate and its analogues in vitro.

Factors affecting the percutaneous penetration of methotrexate (MTX) and its analogues through excised human skin were studied. With application of 0.05% MTX solution to the epidermis, 0.07% of the applied dose was recovered in the epidermis and less than 0.005% penetrated completely through the skin. The percent of drug which penetrated remained constant from 0.05% to 2.0% MTX and was also unchanged by increasing incubation temperature from 28 degrees C to 37 degrees C. Cellophane tape stripping of stratum corneum following drug incubation removed essentially all the MTX that had been measured in whole epidermis. Binding of MTX was localized to the outermost layers of the stratum corneum. With removal of the stratum corneum prior to drug incubation, 25% of the applied MTX penetrated through the skin. Various vehicles were tested to determine their effect on MTX percutaneous absorption. Dimethylsulfoxide (80%), dimethylacetamide (25%), or retinoic acid (0.1%) had no effect on penetration. Maximum enhancement of penetration by 25-fold and 143-fold was obtained with retinoic acid (saturated solution in aqueous ethanol) and C-10-methylsulfoxide (2.5%), respectively. The penetration of lipid-soluble derivatives of MTX was also tested. The compound that penetrated best was the dimethyl ester of dichloro-MTX with a 3-fold increase in penetration over MTX.

Acetamides↗
PubMed1976

Cytokinetics and chemotherapy of psoriasis.

The successful treatment of psoriasis with folic acid antagonists during the past 25 years has led to extensive research in the areas of cytokinetics and chemotherapy. In this paper we shall review selected aspects of these topics relevant to the treatment of psoriasis. The effectiveness of methotrexate treatment of psoriasis can be related to both the hyperproliferative cytokinetics of psoriasis and an increased biochemical sensitivity of psoriatic epidermal cells to this drug. Future research goals in chemotherapy of psoriasis include (a) optimizing drug schedules for available drugs; (b) identifying other susceptible biochemical points of selective drug attack; (c) identifying secondary advantages in order to facilitate selective drug action in psoriasis, such as ultraviolet light therapy in combination with a systemic drug; and (d) developing topically effective chemotherapeutic agents. Approaches to research on topical therapy are reviewed with specific reference to animal testing models for psoriasis and percutaneous penetration of topically applied agents.

Administration, Topical↗
PubMed1976

Epidermal activity in annular dermatophytosis.

In five patients with annular tinea corporis, the tritated thymidine labeling indexes were determined in the rim, center, and intermediate areas of the lesion and compared with normal skin. Labeling indexes at the rim were much higher than those of normal skin (mean, 4.2 times). Labeling indexes elsewhere in the lesion were not significantly different from those of normal skin. Histologic examination showed epidermal thickening in all areas of the lesion as compared with normal skin. This study suggests that there is an increased epidermal turnover at the rim of annular dermatophytosis that may be important in the pathophysiology and morphogenesis of such lesions.

Adult↗
PubMed1976

Ultraviolet light and tar in the Goeckerman treatment of psoriasis.

In an attempt to evaluate and improve the Goeckerman treatment of psoriasis, combinations of tar and ultraviolet (UV) light were studied. The effects of UV irradiation alone, of curde coal tar (CCT) ointment alone, and of UV irradiation with 1% CCT ointment and with 6% CCT ointment on psoriatic lesions were compared. The combinations of 1% CCT ointment with UV irradiation and of 6% CCT ointment with UV irradiation were found to be equally effective. The combination of UV irradiation with ointment had little effect on psoriatic lesions. In most cases, the combination of 1% CCT ointment and UV irradiation was superior to high-concentration (6%) tar ointment without UV irradiation. This study suggests that UV light is an important component of the Goeckerman treatment ant that tar and UV irradiation are superior to tar alone.

Adolescent↗