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Biomedical subjects

G D Weinstein

Publications and source records attributed to G D Weinstein.

At least 55 records · Page 3Linked to original sources
PubMed1986

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 [3H]dThd 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 24 h 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 48 h. These studies establish the rationale for using topical delivery of [3H]dThd for the in vivo measurement of epidermal GF.

1-Propanol↗
PubMed1986

Characterization of cutaneous phototoxicity induced by topical alpha-terthienyl and ultraviolet A radiation.

Alpha-terthienyl (alpha-T), a phototoxic thiophene compound isolated from marigolds (Tagetes species), affects cell membranes and does not appear to induce cytogenetic damage. This study was undertaken to investigate topical delivery of alpha-T and characterize its cutaneous phototoxicity in combination with long-wave UV radiation (UVA) in comparison with locally (intradermal) administered alpha-T. Percutaneous penetration (PC) of 0.1% and 1% alpha-T in a 3% Azone gel vehicle was studied in guinea pig skin in vitro and quantitated by UV fluorescence microscopy. Dose-dependent PC of epidermis, adnexae, and superficial dermis was demonstrated in vitro. Alpha-terthienyl (0.1% and 1%) in this vehicle was applied topically in vivo and irradiated with 30 J/cm2 UVA at intervals of 10 min-24 h. Maximum sensitization was achieved with irradiation 1 h following drug application. The clinical response was dose-dependent consisting of erythema, edema, crusting, erosion, and inhibition of hair growth and was observed 72 h to 7 days postirradiation. A comparable dose-dependent phototoxic response was observed when 5-500 micrograms alpha-T were injected intradermally and irradiated with UVA. These results indicated that low-dose topical alpha-T in a nonirritating vehicle can rapidly produce cutaneous photosensitization. Topical alpha-T/UVA may provide a selective and safer alternative approach for the photochemotherapy of psoriasis and other cutaneous diseases.

Administration, Oral↗
PubMed1985

Regulation of epidermal proliferation in mouse epidermis by combination of difluoromethyl ornithine (DFMO) and methylglyoxal bis(guanylhydrazone) (MGBG).

Topical methylglyoxal bis(guanylhydrazone) (MGBG) and alpha-difluoromethylornithine (DFMO) individually have been shown to produce partial clinical improvement in psoriasis. In an effort to further enhance therapeutic activity, studies were designed to optimize percutaneous penetraton of DFMO in vitro and to determine the effects of the combination of DFMO and MGBG on DNA synthesis and polyamine levels in hairless mouse skin. MGBG was shown to be more effective than DFMO in inhibiting DNA synthesis in vitro and in vivo. Maximum in vitro percutaneous penetration of DFMO (5%) was obtained in Vehicle N containing 10% Azone (297 micrograms/h/cm2). Topical administration of the combination of 5% DFMO and 0.1% MGBG in this vehicle produced a greater inhibition of DNA synthesis and depletion of polyamine levels than either drug individually. The simultaneous topical administration of DFMO and MGBG, allowing the use of lower concentrations of the more toxic MGBG, may be useful for therapy of psoriasis and other cutaneous disorders associated with abnormalities in polyamine metabolism.

Animals↗
PubMed1985

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.

Cell Division↗
PubMed1984

Psoriasis.

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Adolescent↗
PubMed1984

Cell proliferation in normal epidermis.

A detailed examination of cell proliferation kinetics in normal human epidermis is presented. Using tritiated thymidine with autoradiographic techniques, proliferative and differentiated cell kinetics are defined and interrelated. The proliferative compartment of normal epidermis has a cell cycle duration (Tc) of 311 h derived from 3 components: the germinative labeling index (LI), the duration of DNA synthesis (ts), and the growth fraction (GF). The germinative LI is 2.7% +/- 1.2 and ts is 14 h, the latter obtained from a composite fraction of labeled mitoses curve obtained from 11 normal subjects. The GF obtained from the literature and from human skin xenografts to nude mice is estimated to be 60%. Normal-appearing epidermis from patients with psoriasis appears to have a higher proliferation rate. The mean LI is 4.2% +/- 0.9, approximately 50% greater than in normal epidermis. Absolute cell kinetic values for this tissue, however, cannot yet be calculated for lack of other information on ts and GF. A kinetic model for epidermal cell renewal in normal epidermis is described that interrelates the rate of birth/entry, transit, and/or loss of keratinocytes in the 3 epidermal compartments: proliferative, viable differentiated (stratum malpighii ), and stratum corneum. Expected kinetic homeostasis in the epidermis is confirmed by the very similar "turnover" rates in each of the compartments that are, respectively, 1246, 1417, and 1490 cells/day/mm2 surface area. The mean epidermal turnover time of the entire tissue is 39 days. The Tc of 311 h in normal cells in 8-fold longer than the psoriatic Tc of 36 h and is necessary for understanding the hyperproliferative pathophysiologic process in psoriasis.

Adult↗
PubMed1983

Percutaneous penetration of methylglyoxal bis(guanylhydrazone): effects on hairless mouse epidermis in vivo.

Topical methylglyoxal bis(guanylhydrazone) (MGBG) previously has been shown to produce partial clinical improvement in psoriasis. To enhance therapeutic activity, studies were undertaken to optimize MGBG percutaneous penetration in vitro and to study biochemical changes related to epidermal proliferation in vivo. MGBG penetration in saline, Vehicle N, decylmethylsulfoxide, and N-methylpyrrolidone was determined in normal human skin in vitro. Maximum penetration was obtained with 10% MGBG in Vehicle N (3 micrograms/h/cm2). Both topical and systemic MGBG resulted in increased levels of S-adenosyl-L-methionine decarboxylase, suggesting an extended half-life as a consequence of MGBG binding. Topical treatment with 10% MGBG in Vehicle N also resulted in decreased epidermal polyamine levels. The changes in polyamine metabolism were also associated with inhibition of epidermal DNA synthesis. These studies suggest that this topical MGBG formulation may be a candidate for use in the treatment of psoriasis and other hyperproliferative cutaneous diseases associated with increased polyamine synthesis.

Administration, Topical↗
PubMed1983

Development of a topical hematoporphyrin derivative formulation: characterization of photosensitizing effects in vivo.

Photochemotherapy offers a unique approach for the selective therapy of skin diseases. Hematoporphyrin derivative (HPD) in combination with visible light exhibits cytocidal activity in vitro and systemically has demonstrated applicability to the treatment of experimental and human tumors. This study was undertaken to investigate the phototoxic effects in guinea pig skin of systemic HPD in comparison with locally (intradermal) and topically administered HPD. Maximum erythema was obtained by irradiation with red light or UVA 6 h postsystemic HPD (10 mg/kg). Erythema response was dependent upon the dose of irradiation. Systemic HPD produced complete inhibition of epidermal DNA, RNA, and protein synthesis 6-12 h postirradiation with red light, with a lesser degree of inhibition in the deeper hair roots. Local (intradermal) HPD (5-500 micrograms) in combination with red light or UVA produced a dose-dependent erythema and inhibition of epidermal DNA synthesis. Effective in vitro percutaneous penetration of HPD was demonstrated in vehicles containing Azone and N-methylpyrrolidone. Topical application of these HPD formulations in vivo in combination with red light or UVA produced significant erythema and inhibition of epidermal DNA synthesis. These results suggest that HPD can cause photosensitization of the skin. It may therefore be reasonable to explore topical applications as an alternative approach for the photochemotherapy of psoriasis and other cutaneous diseases.

Administration, Topical↗
PubMed1982

Treatment of ichthyosis with isotretinoin.

A multicenter study of the effectiveness of 13-cis-retinoic acid (isotretinoin) in lamellar ichthyosis and epidermolytic hyperkeratosis has been conducted. A dose of the drug which produced maximum clearing with minimum side effects was chosen; this varied among different patients, the mean dose being about 2 mg/kg/day. Almost all of the patients in both groups were clearly improved, as evaluated both by the physicians and the patients. The degree of improvement seemed higher in the group of patients with lamellar ichthyosis.

Adolescent↗
PubMed1982

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.

Administration, Topical↗
PubMed1981

A clinical screening program for topical chemotherapeutic drugs in psoriasis.

In this national, multicenter cooperative study, a standardized drug screening program was designed and evaluated to test the clinical effectiveness of 30 topically applied chemotherapeutic drugs to psoriasis. Appropriate concentrations and vehicles for topical administration were selected with regard to clinical testing consisted of a double-blind application of test agents to psoriatic plaques under occlusion daily for up to nine days. Drugs known to be topically active in psoriasis, eg, thiotepa, fluorouracil, and betamethasone valerate, were easily detected in the clinical protocol, confirming the validity of this topical drug screening program. Seven drugs produced substantial clinical improvement with evidence of clearing; nine drugs produced slight improvement; 14 drugs had no effect. No systemic toxid reactions occurred. This screen should be useful to test other potential antipsoriatic drugs and to evaluate potential animal model screens for their predictive values with the same drugs.

Adult↗