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Biomedical subjects

M Lebwohl

Publications and source records attributed to M Lebwohl.

At least 73 records · Page 4Linked to original sources
PubMed1998

Once-daily tazarotene gel versus twice-daily fluocinonide cream in the treatment of plaque psoriasis.

BACKGROUND: A new class of topical receptor-selective acetylenic retinoids, the first of which is tazarotene, has been developed. OBJECTIVE: Our purpose was to compare the safety, efficacy, and duration of therapeutic effect of 12 weeks of once-daily tazarotene 0.1% and 0.05% gel with that of twice-daily fluocinonide 0.05% cream in the treatment of patients with plaque psoriasis. METHODS: Three hundred forty-eight patients with plaque psoriasis were enrolled and 275 patients completed a multicenter, investigator-masked, randomized, parallel-group clinical trial. RESULTS: Both tazarotene gels were as effective as fluocinonide in reducing plaque elevation after 1 week of treatment, and tazarotene 0.1% gel was similar to fluocinonide in reducing scaling of trunk/limb lesions at all study weeks except week 4. Tazarotene 0. 1% gel was similar to fluocinonide in reducing scaling of knee/elbow lesions at weeks 8 and 12. Fluocinonide had a significantly greater effect on erythema than tazarotene at weeks 2 through 8. However, treatments were not significantly different at week 12, and tazarotene demonstrated significantly better maintenance of therapeutic effect after cessation of therapy. CONCLUSION: Tazarotene 0.1% and 0.05% gels were safe and effective in the treatment of mild-to-moderate plaque psoriasis.

Administration, Cutaneous↗
PubMed1998

Differential regulation of P53 and Bcl-2 expression by ultraviolet A and B.

The induction of apoptosis by ultraviolet (UV) radiation and other DNA damaging agents plays a critical role in monitoring the accumulation of genetic damage and the suppression of tumor development. We hypothesize that UVA and UVB induce apoptosis by modulating balances between p53 and/or bcl-2 genes. Using MCF-7 cells that express both wild-type P53 and Bcl-2 proteins, we demonstrated that UVA and UVB induced apoptosis through regulating expression of apoptosis promoting or inhibiting genes. UVA induced immediate apoptosis and downregulated bcl-2 expression. Bcl-2 expression was reduced by approximately 40% at 4 h post-150 kJ UVA irradiation per m2 with a maximum downregulation (over 70%) at 24 h. The dose-response studies revealed that significant reduction of bcl-2 expression was observed at UVA doses ranging from 50 to 200 kJ per m2; however, p53 levels were not affected by UVA. In contrast, UVB exhibited a entirely different action than UVA in that UVB substantially induced p53 expression, but had no effect on bcl-2 expression. The induction of P53 by UVB was dose and time dependent with the maximum expression at 24 h post-2 and post-4 kJ UVB irradiation per m2. Down-regulation of bcl-2 and fragmentation of DNA induced by UVA occurred earlier (approximately at 4 h) than upregulation of p53 and DNA fragmentation by UVB (12-24 h). These results suggest that UVA and UVB cause cell damage through different mechanisms and that the balances between the expression of p53 and bcl-2 may play an important role in regulating the apoptosis induced by UV irradiation.

Apoptosis↗
PubMed1998

Inhibition of ultraviolet B (UVB)-induced c-fos and c-jun expression in vivo by a tyrosine kinase inhibitor genistein.

We reported the inhibitory effects of genistein, an inhibitor of tyrosine protein kinase (TPK), on ultraviolet B (UVB)-induced expression of c-fos and c-jun in SENCAR mouse skin. UVB irradiation substantially increased transcript levels of c-fos and c-jun mRNA in mouse skin. Topical application of genistein 60 min before UVB radiation reduced c-fos and c-jun expression in the mouse skin in dose-dependent manner. Inhibition was more pronounced in skin exposed to the low dose (5 kJ/m2) than to the high dose (15 kJ/m2) of UVB radiation. In addition, genistein exhibited more inhibition of c-fos than that of c-jun. Post-application of genistein after UVB exposure down-regulated the expressions of c-fos and c-jun, but to a lesser extent compared with pre-application. A431 human epidermoid carcinoma cells, which excessively express epidermal growth factor receptors (EGF-R), were used to investigate the possible mechanism of genistein's action. The results showed that genistein down-regulated the UVB-mediated phosphorylation of TPK-dependent EGF-R in a dose-dependent manner. We concluded that inhibition of UVB-induced c-fos and c-jun expression in mouse skin by genistein may, at least in part, result from the inhibition of TPK activities and down-regulation of EGF-R phosphorylation. Suppression of UVB-induced proto-oncogene expression in mouse skin suggests that genistein may serve as a potential preventative agent against photodamage and photocarcinogenesis.

Animals↗
PubMed1998

Tamoxifen reduces endogenous and UV light-induced oxidative damage to DNA, lipid and protein in vitro and in vivo.

We have investigated the effect of tamoxifen (TAM) on endogenous or ultraviolet radiation (UVR)-induced oxidative damage to macromolecules in vitro and in vivo. In a system containing calf thymus DNA exposed to a germicidal UV lamp, both TAM and 4-hydroxytamoxifen (4-OH-TAM) inhibited UVR-induced the formation of 8-hydroxy-2'-deoxyguanosine (8-OHdG) in DNA in a dose-dependent manner. At low concentrations, 4-OH-TAM quenched 8-OHdG more potently than TAM. However, the reduction of 8-OHdG by TAM and 4-OH-TAM became similar at a concentration of 10 microM. In contrast, ascorbic acid had the similar effect to TAM, whereas glutathione exhibited little effect on UVR-induced 8-OHdG. The order of quenching efficacy was: 4-OH-TAM > TAM approximately = ascorbic acid > glutathione. We have further determined the effect of TAM on endogenous 8-OHdG formation, lipid peroxidation, and protein oxidation in the skin of SENCAR mice. Topical application of 5 micromol TAM significantly reduced the level of 8-OHdG in mouse epidermis by approximately 27% (P < 0.05). Endogenous lipid peroxidation and protein oxidation, measured as malondialdehyde (MDA) and carbonyl groups, were also substantially reduced by topical TAM. Further study was conducted to evaluate the effect of TAM on UVR-induced 8-OHdG and MDA in skin of hairless mice. In mice subacutely exposed to low dose (3.4 kJ/m2 x six doses) and high dose (16.8 kJ/m2 x three doses) of UVB irradiation, TAM significantly blocked the formation of 8-OHdG in mouse epidermis by 57-81% and MDA by 37-65%, respectively. Our studies suggest that reduction of oxidative damages to biological macromolecules in vitro and in vivo may at least in part explain the anti-carcinogenic and chemopreventive actions of tamoxifen.

8-Hydroxy-2'-Deoxyguanosine↗
PubMed1998

Isoflavone genistein inhibits the initiation and promotion of two-stage skin carcinogenesis in mice.

Isoflavone genistein is a specific inhibitor of protein tyrosine kinase (PTK) and has been shown to have a variety of anticancer activities in cultured cells and animal models. We report here that genistein significantly inhibits 7,12-dimethylbenz[a]anthracene (DMBA)-initiated and 12-O-tetradecanoyl phorbol-13-acetate (TPA)-promoted skin tumorigenesis in a two-stage carcinogenesis model. In an initiation study, 10 micromol genistein was applied daily to female SENCAR mouse skin for 1 week, followed by initiation with 10 nmol DMBA. Mice were then treated with twice weekly 4 microg TPA. Genistein was shown to reduce tumor incidence and multiplicity in DMBA-initiated skin tumors by approximately 20 (P < 0.05) and 50% (P < 0.01), respectively. Two promotion studies were conducted using CD-1 and SENCAR mice. In experiment 1, CD-1 mice were initiated with 100 nmol DMBA and followed by a twice weekly regimen of 1 and 5 micromol genistein/4 microg TPA. In experiment 2, SENCAR mice were initiated with 10 nmol DMBA and followed by a regimen of 5, 10 and 20 micromol genistein/2 microg TPA. Both studies consistently showed that genistein substantially inhibited TPA-promoted skin tumorigenesis by reducing the tumor multiplicity by approximately 60 and 75%, respectively (P < 0.01). However, the tumor incidence appeared to be less affected. Mechanistic studies showed that genistein inhibited DMBA-induced bulky DNA adduct formation and substantially suppressed TPA-stimulated H2O2 and inflammatory responses in mouse skin by >60% (P < 0.01). In contrast, genistein only exhibited a moderate inhibition of TPA-induced ornithine decarboxylase activity (P > 0.05). Our results suggest that genistein exerts its anti-initiational and anti-promotional effects on skin carcinogenesis probably through blockage of DNA adduct formation and inhibition of oxidative and inflammatory events in vivo.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1998

Dermatologic manifestations of systemic disease.

As the body's point of contact with the weight-bearing surface, the foot resists abrasive forces and is constantly bombarded with dermatologic insults. It is the site of a variety of local and systemic afflictions, some which even indicate a state of relative emergency. Paying careful attention to the consideration and exclusion of serious or systemic conditions, this article presents an algorithmic approach that is useful in a clinical setting.

Foot Dermatoses↗
PubMed1998

Clinical efficacy and safety of tazarotene: optimizing clinical results.

Tazarotene is the first topical retinoid demonstrated to be both effective and tolerable in the treatment of psoriasis. The clinical efficacy and safety of topical tazarotene have been investigated in vehicle-controlled and active-controlled studies. Ongoing studies are evaluating its use in combination with other antipsoriasis medications. Tazarotene has been demonstrated to be significantly more effective than vehicle, and comparable in efficacy to fluocinonide 0.05%, but with a more sustained therapeutic effect after treatment is stopped. Its adverse effects consist primarily of mild to moderate local irritation with no reports of treatment-related systemic adverse effects. Combining tazarotene with a mid- to high-potency corticosteroid gives greater efficacy with fewer adverse effects than either agent used alone. The use of tazarotene in combination with phototherapy or calcipotriene is currently being investigated. Overall, topical tazarotene is a highly useful addition to the array of options available for the topical treatment of mild to moderate plaque psoriasis.

Administration, Topical↗
PubMed1997

Effectiveness of norgestimate and ethinyl estradiol in treating moderate acne vulgaris.

BACKGROUND: An excess of androgen is believed to contribute to development of acne in some patients. Because oral contraceptives (OCs) may reduce the active androgen level, hormonal therapy with OCs has been used successfully to treat patients with acne, although this treatment has previously not been studied in placebo-controlled trials. OBJECTIVE: Our purpose was to evaluate the efficacy of a triphasic, combination OC (ORTHO TRI-CYCLEN [Ortho-McNeil Pharmaceutical, Raritan, N.J.], norgestimate/ethinyl estradiol) compared with placebo in the treatment of moderate acne vulgaris. METHODS: Two hundred fifty-seven healthy female subjects, 15 to 49 years of age with moderate acne vulgaris, were enrolled in a multicenter, randomized, double-blind, placebo-controlled clinical trial. Each month for 6 months, subjects received either 3 consecutive weeks of the OC (i.e., tablets containing a fixed dose of ethinyl estradiol [0.035 mg] and increasing doses of norgestimate [0.180 mg, 0.215 mg, 0.250 mg]) followed by 7 days of inactive drug or placebo (color-matched tablets). Efficacy was assessed by facial acne lesion counts, an investigator's global assessment, a subject's self-assessment, and an analysis of within-cycle variation (cycle 6) in lesion counts. RESULTS: Of the 160 subjects in whom efficacy could be evaluated, the OC group showed a statistically significantly greater improvement than the placebo group for all primary efficacy measures. The mean decrease in inflammatory lesion count from baseline to cycle 6 was 11.8 (62.0%) versus 7.6 (38.6%) (p = 0.0001), and the mean decrease in total lesion count was 29.1 (53.1%) versus 14.1 (26.8%) (p = 0.0001) in the OC and placebo groups, respectively. In the investigator's global assessment, 93.7% of the active treatment group versus 65.4% of the placebo group were rated as improved at the end of the study (p < 0.001). Six of the seven secondary efficacy measures (total comedones, open comedones, closed comedones, papules, pustules, and the subject's self-assessment of study treatment) were also significantly more favorable in the OC group compared with the placebo group. CONCLUSION: An OC containing 0.035 mg of ethinyl estradiol combined with the triphasic regimen of norgestimate is a safe and effective treatment of moderate acne vulgaris in women with no known contraindication to OC therapy.

Acne Vulgaris↗
PubMed1997

Interactions between calcipotriene and ultraviolet light.

BACKGROUND: Calcipotriene is often used with UVB or PUVA, but interactions between UV radiation and calcipotriene have not been examined extensively. OBJECTIVE: Our purpose was to examine interactions between calcipotriene and UV light. METHODS: Minimal erythema doses (MEDs) were determined with UVB and immediate pigment darkening was measured for UVA. The effect of calcipotriene ointment applied before phototesting was examined. Thick and thin applications of calcipotrience were compared. Calcipotriene ointment was applied to a small area on the skin before phototherapy. Patients received either UVB, PUVA, UVA, or no phototherapy. After phototherapy, the ointment was collected and assayed by reverse-phase, high-performance liquid chromatography. RESULTS: MEDs for UVB and immediate pigment darkening for UVA were unaffected by calcipotriene. Thick application of calcipotriene, however, increased the MED, UVA caused substantial reductions in the concentration of detectable calcipotriene. CONCLUSION: When used in conjunction with PUVA, calcipotriene should be applied after exposure to UVA.

Calcitriol↗
PubMed1997

Identification of possible reactive oxygen species involved in ultraviolet radiation-induced oxidative DNA damage.

We have previously demonstrated that each region of the ultraviolet (UV) spectrum (UVA, UVB, and UVC) induces the formation of 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodGuo) in purified calf thymus DNA and HeLa cells in a fluence-dependent manner. In the present study, we further characterize the possible reactive oxygen species (ROS) that are involved in the induction of 8-oxodGuo by UV radiation. Sodium azide, a singlet oxygen (1O2) scavenger though its quenching effect on HO. was also reported, inhibited 8-oxodGuo production in calf thymus DNA exposed to UVA, UVB, or UVC in a concentration-dependent fashion with maximal quenching effect of over 90% at a concentration of 10 mM. Catalase, at a concentration of 50 U/ml, reduced the yields of UVA- and UVB-induced 8-oxodGuo formation by approximately 50%, but had little effect on UVC-induced 8-oxodGuo production. In contrast, 50 U/ml of superoxide dismutase (SOD) did not affect induction of 8-oxodGuo by any portion of the UV spectrum. Hydroxyl radical (HO.) scavengers mannitol and dimethylsulfoxide (DMSO) moderately reduced the levels of 8-oxodGuo induced by UVA and UVB, but not those by UVC. Instead, mannitol and DMSO enhanced the formation of 8-oxodGuo induced by UVC. These results suggest that certain types of ROS are involved in UV-induced 8-oxodGuo formation with 1O2 playing the predominant role throughout the UV spectrum. Except for UVC, other ROS such as hydrogen peroxide (H2O2) and HO. may also be involved in UVA- and UVB-induced oxidative DNA damage. Superoxide anion appears not to participate in UV-induced oxidation of guanosine in calf thymus DNA, as SOD did not display any quenching effects.

Catalase↗
PubMed1997

Topical calcipotriene in combination with UVB phototherapy for psoriasis.

A total of 20 patients with symmetric plaque-type psoriasis were recruited for a controlled, investigator-blinded, right-left study. None of the patients had used any therapy other than emollients for 2 months prior to starting in the trial. All patients had a negative antinuclear antibody. By history, all patients had previously improved upon exposure to sunlight or ultraviolet light. Two symmetrical sites of equal severity were selected as target areas. Each patient was treated on one side with mineral oil twice daily and on the opposite side with calcipotriene 0.005% ointment twice daily. The investigator was blinded as to which site received which topical treatment. Both sides were treated with equal doses of ultraviolet B (UVB) three times weekly in graduated suberythemogenic doses. Ultraviolet B radiation was emitted by a group of 6-ft fluorescent bulbs (Light Sources FS72 T12 UVB HO) in a standard phototherapy unit. The above regimen was continued for a total of 12 weeks. The severity of psoriasis in the target sites was rated by the examiner at baseline and at weekly intervals for the 12 weeks of study. Target sites were rated by severity of erythema, scaling, plaque elevation, and pruritus, with each of these parameters being assigned a score on a four-point scale: 0, clear; 1, mild; 2, moderate; 3, severe. The four scores were added together to arrive at a total severity score for each of the target sites. Statistical analysis was performed using the paired t test, P values less than 0.05 were considered statistically significant. Eleven of the 20 patients (55%) showed a greater decrease in the severity of their psoriasis with UVB plus calcipotriene compared with UVB plus mineral oil. The difference in severity scores between the two groups was statistically significant as early as week 1 (P < 0.05). The difference between the UVB and calcipotriene group versus the UVB and mineral oil group peaked between weeks 3 and 6. The differences then decreased but remained statistically significant through to week 12 (Fig. 1). There were no instances of local cutaneous irritation, but mild photosensitivity occurred symmetrically on both sides in three patients.

Calcitriol↗