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Biomedical subjects

G D Weinstein

Publications and source records attributed to G D Weinstein.

At least 37 records · Page 2Linked to original sources

Safety, efficacy and duration of therapeutic effect of tazarotene used in the treatment of plaque psoriasis.

Topical therapies are first-line treatment for mild/limited stable plaque psoriasis. Disadvantages of currently available therapies include lack of short-term efficacy and long-term maintenance, adverse effects, and cosmetic problems. Tazarotene is a new topical retinoid which has proven to be efficacious in the treatment of mild-to-moderate plaque psoriasis. Results from a large, multicentre, pivotal study show that a once-daily application is as effective as a first-line monotherapy, providing rapid resolution of signs and symptoms and sustained therapeutic effects in some patients. Tazarotene gel is cosmetically acceptable, and is minimally absorbed systemically, with adverse events limited to local irritation.

Administration, Cutaneous↗

Preoperative infusional chemoradiation and surgery with or without an electron beam intraoperative boost for advanced primary rectal cancer.

PURPOSE: To compare the multimodality treatment results of surgical resection plus preoperative radiotherapy with concomitant protracted infusion chemotherapy (preop-chemoXRT), with or without an electron beam intraoperative radiotherapy (EB-IORT) boost, in 37 patients having advanced primary rectal cancer, with the results of a protocol using only preoperative radiotherapy (preop-XRT) plus surgical resection in a historic control group of 36 patients. METHODS AND MATERIALS: Thirty-eight patients with tethered T3 or T4 primary rectal cancer were treated with 45 Gy delivered in 25 fractions over 5 weeks plus infusional chemotherapy. Thirty-seven patients underwent surgical resection: 13 (35%) had restorative operations, and the remainder had either abdomino-perineal resection (APR) or pelvic exenteration (PE). Electron beam intraoperative radiotherapy (EB-IORT) was used in doses of 10-20 Gy for 11 patients with adherent pelvic tumor. In the 36 historic control patients, the preop-XRT dose was 45 Gy, and 93% of them had APR or PE. RESULTS: The local recurrence rate was 3% for the preop-chemoXRT group and 33% for the historic control group. The 3-year survival rate for patients treated with preop-chemoXRT plus resection was 82% compared with 62% for the historic control group. Distant metastases occurred more frequently in patients treated with an EB-IORT boost than in patients who were not (64% vs. 19%, p < 0.05), and the overall 3-year survival rate was lower for the former (67% vs. 96%, p < 0.05). Acute and late toxicities were acceptable. CONCLUSIONS: Preop-chemoXRT for advanced primary rectal cancer results in better control of pelvic disease and better overall survival rates than does preop-XRT alone. With preop-chemoXRT, acute chemoradiation toxicity is increased whereas late morbidity is unchanged compared with preop-XRT alone. Local control in patients with areas of residual or clinically adherent disease is improved by the use of EB-IORT; however, patients treated with EB-IORT had poorer survival rates than those treated without EB-IORT.

Adult↗

Effectiveness of topical therapy for psoriasis: results of a national survey.

Topical therapy is the major treatment approach for patients with psoriasis. However, the effectiveness of available drugs (response rates and long-term maintenance) is not well known. This study investigated the current perceptions of American dermatologists on the effectiveness of topical medications for patients with mild or limited psoriasis. In a survey of 225 American dermatologists, class I to II topical steroids were regarded as most effective: 29 percent of dermatologists expected most of their patients to experience clearing of lesions when treated with these agents. Much lower response rates were found with medium and low-potency steroids, anthralin, or tars. The percentage of patients whose skin remained clear of lesions decreased to 50 percent while receiving maintenance corticosteroid therapy by three months and to 29 percent after one year. Topical corticosteroids were considered less effective than the available photo/systemic therapies by 79 percent of physicians. More effective topical modalities need to be developed to treat patients with mild/limited psoriasis.

Administration, Topical↗

Methotrexate and other chemotherapeutic agents used to treat psoriasis.

The oral chemotherapy agent methotrexate remains a mainstay for the treatment of moderate to severe psoriasis after 40 years experience. Extensive usage, both for psoriasis and rheumatoid arthritis patients, has continued the reasonable safety profile for this drug when appropriate precautions are taken. The availability of other treatment modalities for severe psoriasis permits a rotational system with periods of time when methotrexate is not used, thereby lessening the risk of long-term side effects. Other chemotherapeutic agents for psoriasis are described, but they are used infrequently.

Administration, Oral↗

An approach to the treatment of moderate to severe psoriasis with rotational therapy.

BACKGROUND: There are four standard approaches for treating moderate to severe psoriasis: UVB plus tar, PUVA, methotrexate, and etretinate. Although patients with psoriasis receive these therapies for many years, there is no commonly accepted approach for the initial and subsequent selection of the alternatives. OBJECTIVE: Our purpose was to develop a theoretical and practical basis for using these treatments that will minimize the risks of their long-term toxicities and prolong their safe long-term use. METHODS: A review of the published side effects of the treatments and cumulative clinical experience are used to develop an approach for the treatment of severe psoriasis. RESULTS: It is proposed that patients receive each form of therapy for 1 to 2 years and then switch to the next form of treatment. By rotating each of the three or four treatments at these time intervals, it may well be 4 or 5 years before needing to return to the first therapy, thereby minimizing cumulative toxicity by long periods off each treatment. CONCLUSION: Rotation of available therapies for moderate to severe psoriasis may minimize long-term toxicity and allow effective treatments to be maintained for many years.

Combined Modality Therapy↗

Photoaging and the skin. The effects of tretinoin.

The appearance of photoaged skin is cosmetically unacceptable to many in our society. Ostensibly, avoidance of ultraviolet light and sunlight from early childhood is most desirable but not likely to happen in our culture. Tretinoin is the only pharmacologic compound shown to partially reverse some signs of photoaging. Improvement with tretinoin therapy has been quantified clinically and histologically. A major degree of improvement occurs in 6 to 12 months, and maintenance treatment one to three times per week may continue this response. Tretinoin therapy should optimally be used with daily moisturizer and sunscreen applications. Psychosocial benefits of tretinoin therapy, use of tretinoin for intrinsically aged or non-Caucasian skin, and higher-strength tretinoin therapy for severely photoaged skin need to be further explored. It is possible that some subsets of patients with photoaged skin may respond better than others.

Animals↗

Proliferating cells in psoriatic dermis are comprised primarily of T cells, endothelial cells, and factor XIIIa+ perivascular dendritic cells.

Determination of the cell types proliferating in the dermis of patients with psoriasis should identify those cells experiencing activation or responding to growth factors in the psoriatic dermal milieu. Toward that end, sections of formalin-fixed biopsies obtained from 3H-deoxyuridine (3H-dU)-injected skin of eight psoriatic patients were immunostained, followed by autoradiography. Proliferating dermal cells exhibit silver grains from tritium emissions. The identity of the proliferating cells could then be determined by simultaneous visualization with antibodies specific for various cell types. UCHL1+ (CD45RO+) T cells (recall antigen-reactive helper T-cell subset) constituted 36.6 +/- 3.1% (mean +/- SEM, n = 6) of the proliferating dermal cells in involved skin, whereas Leu 18+ (CD45RA+) T cells (recall antigen naive T-cell subsets) comprised only 8.7 +/- 1.5% (n = 6). The Factor XIIIa+ dermal perivascular dendritic cell subset (24.9 +/- 1.5% of proliferating dermal cells, n = 6) and Factor VIII+ endothelial cells (23.0 +/- 2.3%, n = 6) represented the two other major proliferating populations in lesional psoriatic dermis. Differentiated tissue macrophages, identified by phase microscopy as melanophages or by immunostaining with antibodies to Leu M1 (CD15) or myeloid histiocyte antigen, comprised less than 5% of the proliferating population in either skin type. In addition to calculating the relative proportions of these cells to each other as percent, we also determined the density of cells, in cells/mm2 of tissue. The density of proliferating cells within these populations was increased in involved versus uninvolved skin: UCHL1+, 9.0 +/- 1.7 cells/mm2 versus 1.8 +/- 0.6 cells/mm2, p less than 0.01; Factor XIIIa+, 6.0 +/- 0.7 cells/mm2 versus 1.5 +/- 0.5 cells/mm2, p less than 0.01; Factor VIII+, 5.5 +/- 1.4 cells/mm2 versus 0.0 cells/mm2, p less than 0.05. The presence of preferential active proliferation of a T-cell subset in lesional dermis suggests that activating signals specific for this subset are contained within the psoriatic dermis in vivo. The activation of recall antigen-reactive T cells may be a driving force behind the dendritic cell and endothelial cell proliferation. Alternatively, the selective proliferation and expansion of these two constitutive cell types (Factor XIIIa+ and Factor VIII+) may result in signals that promote activation of UCHL1+ (CD45RO+) T cells.

Cell Division↗

Specificity of human keratinocyte X HeLa cell hybrid murine monoclonal antibodies.

The immunofluorescent staining patterns of three differentiation-specific monoclonals (HLK3, HLK7, HLK20) that display different immunofluorescent (IF) reactivity in normal and psoriatic epidermis, were examined in basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), as well as other human normal epithelial and nonepithelial tissues. Similar staining patterns within epidermis were seen with HLK3 (intercellular) and HLK7 (perinuclear) in psoriasis, SCC, and BCC. HLK20 selectively stained BCC and SCC within epidermis and dermis, and was negative in psoriasis. The monoclonals did not react with nonepithelial tissues, but repetitively displayed positive, granular reactivity with simple epithelia and transitional epithelium. Stratified squamous epithelia showed IF staining similar to normal epidermis for all three monoclonals. These new monoclonal antibodies offer new investigative tools to study abnormalities in keratinocyte differentiation in benign and malignant hyperplastic skin diseases.

Antibodies, Monoclonal↗

Topical tretinoin for treatment of photodamaged skin. A multicenter study.

The clinical and histologic effects of a new emollient cream formulation of topical tretinoin at concentrations of 0.05% and 0.01% were examined in 251 subjects with mild to moderate photodamaged facial skin in a randomized, double-blind, vehicle-controlled, multicenter study. Seventy-nine percent of the subjects who received 0.05% tretinoin for 24 weeks showed overall improvement in photodamaged skin compared with improvement in 48% of the vehicle-treated control subjects. Significant reductions were found in fine wrinkling, mottled hyperpigmentation, roughness, and laxity after 0.05% tretinoin therapy when compared with controls. In addition, histologic changes of increased epidermal thickness, decreased melanin content, and stratum corneum compaction provide independent evidence supporting clinical improvement. Side effects of erythema, peeling, and stinging were usually mild and well tolerated.

Administration, Cutaneous↗

Cytotoxic and immunologic effects of methotrexate in psoriasis.

Based on recent experience that Cyclosporin A, an immunosuppressive drug, produces marked improvement in psoriasis, possible immunomodulatory activities of methotrexate (MTX) have been reviewed to look for alternate mechanisms of MTX action in psoriasis. It is generally considered that the therapeutic results of MTX in psoriasis are related to a direct effect on epidermal cell hyperplasia through inhibition of DNA synthesis. Several studies in the literature now suggest possible effects of MTX on the immune system of psoriatics as well as in animal models that may have some pathogenic similarities to psoriasis. In psoriatics receiving MTX, neutrophil chemotaxis is suppressed, resulting in a possible alteration in the potential pathologic activity of neutrophils commonly found in lesional skin. MTX does improve both psoriatic and rheumatoid arthritis. Animal studies of the latter using adjuvant arthritis and graft vs host disease (GVHD) have indicated several possible mechanisms for MTX that affect these processes. In GVHD, MTX selectively destroys cycling CD8+ cells, and in adjuvant arthritis the activation of macrophages is prevented by inhibition of T-cell function. While MTX generally has not been clinically utilized as an immunomodulatory drug for immunologically related diseases, it may, nonetheless, have selective actions that could be specific for some diseases. MTX and Cyclosporin A could work mechanistically in similar ways but at different steps in the activation of T cells and macrophages. It may be that the major direct effect of MTX on epidermal cell proliferation is complemented or even mediated by subtle immunoregulatory effects on the melange of cells in the affected skin and the systemic immune response.

Animals↗

Vasoactive pharmacologic responses of human skin xenografts in ciclosporin-treated rats.

Human skin xenografts in ciclosporin-treated rats have been reported to preserve many of the characteristics of normal human skin. This model was used to study the cutaneous responses of human skin xenografts and host rat skin to intradermal injections of vasoactive agents. The xenograft responses to corticosteroids (blanching), nicotinic acid (erythema), histamine HCl (urticaria), and privine (blanching) all paralleled those of the host rat skin. However, when quantitatively compared to the responses reported for human skin in vivo, the xenografts were less sensitive to these compounds. The large variability seen in the xenograft responses may be due to variable graft revascularization and to structural irregularities in the dermis from the recent grafting procedure. It is concluded that the lower sensitivity and variable responsiveness of the xenografts limit the potential usefulness of this pharmacologic model for evaluating vasoactive agents.

Animals↗

Topical methotrexate therapy for psoriasis.

In vitro percutaneous penetration of methotrexate is enhanced with 1-dodecylazacycloheptan-2-one (laurocapram [Azone]). Laurocapram-containing methotrexate formulations provide effective local inhibition of epidermal DNA synthesis in the in vivo hairless mouse and minipig models, providing the biochemical rationale for topical use in the treatment of psoriasis. Topical methotrexate (0.1%, 0.5%, and 1%) in a laurocapram-containing formulation was tested in a two-center double-blind pilot clinical study of 42 patients with plaque psoriasis. Drugs were applied twice a day for six weeks, and lesions were scored weekly for erythema, scale, and elevation. An overall improvement of 50% or more in the combined scores for erythema, scale, and elevation was obtained with 0.1% methotrexate (64% of patients), 0.5% methotrexate (59%), and 1% methotrexate (56%) vs the vehicle alone (25%). These preliminary findings suggest that methotrexate preparations that provide adequate percutaneous absorption may have a beneficial effect in the treatment of psoriasis.

Administration, Topical↗

Identification of differentiation-specific antigens in psoriatic versus normal skin using monoclonal antibodies.

Human cell hybrids derived from fusions between carcinoma (HeLa) and normal epidermal keratinocytes can be used as immunogens to generate monoclonal antibodies against keratinocyte differentiation-specific antigens. We examined the immunofluorescent staining patterns of these monoclonals in normal human and psoriatic (lesional and uninvolved) skin tissue sections. The immunofluorescent staining patterns indicate that the monoclonal antibodies are recognizing a number of different keratinocyte antigens. Three monoclonals (HLK7, HLK3, and HLK20) displayed different immunofluorescent reactivity in these tissues. These new monoclonal antibodies will be useful tools to study the differentiation abnormalities in psoriasis and may serve as a marker of the psoriatic diathesis.

Antibodies, Monoclonal↗

Modulation of polycation-induced redistribution of melanoma cell surface anionic macromolecules by retinoic acid.

The ability of cationized ferritin (CF) to redistribute negatively charged cell surface molecules has been shown to increase after malignant transformation. Pretreatment of murine melanoma S91-C2 and B16-F1 cells with retinoic acid (RA), which suppresses their transformed phenotype, decreased the ability of CF to cluster surface anionic sites. In contrast, a similar pretreatment of RA-resistant mutant clone S91-C154 and subline B16-F10 caused only a minor reduction in CF-induced patching of anionic sites. These results indicate that the effect of RA on the redistribution of negatively charged cell surface molecules is related to the growth-inhibitory action of this vitamin A metabolite.

Animals↗

Photosensitizers in dermatology.

Systemic injection of hematoporphyrin derivative (HpD) in contribution with visible light (red or blue-green) delivered by laser was used to treat a patient with psoriasis. The psoriatic lesions responded vigorously to laser treatments, forming eschars by 1 week post irradiation. In contrast, only minimal erythema was observed in the noninvolved, clinically normal appearing skin. Two approaches for localized HpD administration were investigated in the guinea-pig and minipig models as a means of achieving local photodynamic effects. Intracutaneous injection of HpD produced localized cutaneous photosensitization with either UVA or red light. Azone increased percutaneous penetration of HpD in human skin in vitro. Topical application of HpD and irradiation with UVA produced localized cutaneous photosensitivity and inhibition of epidermal DNA synthesis.

Animals↗

The treatment of severe psoriasis. A national survey.

In 1974, we conducted a randomized survey of dermatologists to determine trends in the use of chemotherapeutic agents for psoriasis. The present survey updates and extends the earlier one to include phototherapy, photochemotherapy, and other modalities being used in the treatment of psoriasis too extensive or severe for topical agents alone. Questionnaires were sent to approximately 20% of dermatologists nationwide and also to all training/research programs. Results of the survey include: (1) approximately 523,000 patients with psoriasis were treated by dermatologists in 1984, and 30% of these were severe enough to require more than topical care; (2) the majority of dermatologists use ultraviolet B (71%) and methotrexate (58%), while 36% use psoralen and ultraviolet A; (3) creatinine clearance rates and liver biopsy specimens are being obtained for approximately half of methotrexate-treated patients; and (4) of those physicians using methotrexate, most (74%) use weekly divided orally administered methotrexate doses.

Adult↗