Novel treatment of chronic severe hand dermatitis with bexarotene gel.

BACKGROUND: Hand dermatitis is an eczematous inflammation of the hands that is related to occupation or to routine activities. It often becomes chronic, and in some patients may become severe and disabling. Topical corticosteroids are effective treatment, particularly for milder forms, but they often lose effectiveness with time and can produce skin atrophy. OBJECTIVES: To evaluate bexarotene gel topical therapy for safety, tolerability and efficacy in patients with chronic hand dermatitis. METHODS: A phase I-II open-label randomized clinical study of bexarotene gel, alone and in combination with a low- and a mid-potency steroid, was conducted in 55 patients with chronic severe hand dermatitis at two academic clinics. RESULTS: Patients using bexarotene gel monotherapy reached a 79% response rate for > or = 50% clinical improvement and a 39% response rate for > or = 90% clearance of hands. Adverse events possibly related to treatment in all patients were stinging or burning (15%), flare of dermatitis (16%) and irritation (29%). Thirteen patients (24%) withdrew early, including two for related adverse events and five for inadequate response. CONCLUSIONS: Bexarotene gel appears to be safe, tolerated by most patients, with useful therapeutic activity in chronic severe hand dermatitis.

Bexarotene is effective and safe for treatment of refractory advanced-stage cutaneous T-cell lymphoma: multinational phase II-III trial results.

PURPOSE: Cutaneous T-cell lymphomas (CTCL) are malignancies of T cells appearing as skin lesions and are responsive to retinoid therapy. Safety and efficacy of a novel RXR-selective retinoid (rexinoid) bexarotene (Targretin, LGD1069; Ligand Pharmaceuticals Inc, San Diego, CA) was evaluated as a single-agent oral therapy administered once daily in an open-label study in patients with refractory advanced-stage CTCL. PATIENTS AND METHODS: Ninety-four patients with biopsy-confirmed CTCL in advanced stages (IIB-IVB) were enrolled at 26 centers. Fifty-six patients received an initial dose of 300 mg/m2/d oral bexarotene and 38 started at more than 300 mg/m2/d. RESULTS: Clinical complete and partial responses were reported by Primary End point Classification for the study in 45% (25 of 56) of patients enrolled at 300 mg/m2/d dosing. At more than 300 mg/m2/d, 55% (21 of 38) of patients responded, including 13% (five of 38) clinical complete. For the 300 mg/m2/d initial dose group, the rate of relapse after response was 36% and the projected median duration of response was 299 days. Improvements were also seen in overall body-surface area involvement, median index lesion surface area, adenopathy, cutaneous tumors, pruritus, and CTCL-specific quality of life. The most frequent drug-related adverse events included hypertriglyceridemia (associated rarely with pancreatitis), hypercholesterolemia, hypothyroidism, and headache. CONCLUSION: Bexarotene is the first in a novel class of pharmacologic agents, the RXR-selective retinoids, or rexinoids. Bexarotene is orally administered, safe, and generally well tolerated with reversible side effects, and is effective for the treatment of advanced, refractory CTCL.

Tacrolimus ointment for the treatment of atopic dermatitis in adult patients: part I, efficacy.

A total of 632 adults with atopic dermatitis applied tacrolimus ointment (0.03% or 0.1%) or vehicle twice daily for up to 12 weeks in two randomized, double-blind studies. This report focuses on the efficacy of tacrolimus ointment in these studies. The mean percent body surface area (%BSA) affected at baseline was 45%, and 56% of patients had severe atopic dermatitis. Evaluations included a physician's global evaluation of clinical response, %BSA affected, individual signs of atopic dermatitis, the Eczema Area and Severity Index (EASI) score, and the patient's assessment of pruritus. A 90% or greater improvement from baseline in disease status was observed for 6.6%, 27.5%, and 36.8% of patients in the vehicle, 0.03% tacrolimus ointment, and 0.1% tacrolimus ointment groups, respectively (P<.001), and 50% or better improvement was observed for 19.8%, 61.6%, and 72.7% of patients, respectively. Tacrolimus ointment-treated patients showed significantly greater improvement than vehicle-treated patients for all efficacy parameters evaluated, including the %BSA affected, the total score and individual scores for signs of atopic dermatitis, the patient's assessment of pruritus, and EASI score. The 0.1% concentration was more effective than the 0.03% concentration, particularly in patients with severe disease and/or extensive BSA involvement at baseline and in African Americans. Tacrolimus ointment is an effective therapy for the treatment of adult patients with atopic dermatitis on all skin regions including the head and neck.

The impact of tacrolimus ointment on health-related quality of life of adult and pediatric patients with atopic dermatitis.

BACKGROUND: Atopic dermatitis can have detrimental effects on health-related quality of life (QOL). OBJECTIVE: Our purpose was to examine the QOL impact of tacrolimus ointment in patients with atopic dermatitis. METHODS: The Dermatology Life Quality Index (DLQI), Children's DLQI (CDLQI), and Toddler QOL Survey were used to assess QOL in adults (16 years or older), children (5-15 years), and toddlers (2-4 years) enrolled in 12-week, randomized, double-blind studies comparing two concentrations of tacrolimus ointment (0.03% and 0.1%) versus vehicle ointment for treatment of atopic dermatitis. QOL was assessed at baseline, week 3, and week 12/early discontinuation. RESULTS: Of the 985 patients enrolled, 91.5% had evaluable QOL data. Among adults, both tacrolimus ointment groups experienced improved QOL relative to the vehicle control group for all QOL scales (P<.001). Among children and toddlers, both tacrolimus ointment groups demonstrated significant QOL improvements relative to the vehicle control group (P<.05) for all but the Personal Relationships scale in the 0.03% tacrolimus ointment group among children. CONCLUSION: Tacrolimus ointment is associated with significant QOL benefits in adults, children, and toddlers with atopic dermatitis.

The effect of antibacterial soap with 1.5% triclocarban on Staphylococcus aureus in patients with atopic dermatitis.

This double-blind study determined whether daily bathing with an antibacterial soap would reduce the number of Staphylococcus aureus on the skin and result in clinical improvement of atopic dermatitis. For 9 weeks, 50 patients with moderately severe atopic dermatitis bathed daily with either an antimicrobial soap containing 1.5% triclocarban or the placebo soap. They also used a nonmedicated moisturizer and 0.025% triamcinolone acetonide cream as needed, but the availability of the corticosteroid cream was discontinued after 6 weeks. The antimicrobial soap regimen caused significantly greater improvement in the severity and extent of skin lesions than the placebo soap regimen, which correlated with reductions both in S aureus in patients with positive cultures at baseline and in total aerobic organisms. Outcome measures included reductions in S aureus, total aerobic organisms, and dermatologic assessments. Overall, daily bathing with an antibacterial soap was well tolerated, provided clinical improvement, and reduced levels of skin microorganisms.

Tazarotene 0.1% gel plus corticosteroid cream in the treatment of plaque psoriasis.

BACKGROUND: Topical corticosteroids are often used in the treatment of psoriasis, but long-term use may be associated with serious adverse events such as tachyphylaxis or atrophy of the skin. Tazarotene, a new topical retinoid, has demonstrated significant clinical benefits but can cause mild to moderate local irritation. OBJECTIVE: We evaluate whether a combination treatment of topical tazarotene and a topical corticosteroid would increase efficacy while reducing the incidence of local adverse events associated with a topical retinoid. METHODS: Three hundred patients enrolled in an investigator-masked study were randomly assigned to 1 of 4 treatment groups: tazarotene 0.1% gel in combination with placebo cream, or with a low-, mid-, or high-potency corticosteroid cream, for 12 weeks of treatment and a posttreatment follow-up at week 16. RESULTS: Tazarotene 0.1% gel in combination with a mid- or high-potency corticosteroid, when compared with tazarotene plus placebo cream, achieved significantly greater reductions in scaling, erythema, and overall lesional severity, and a decreased incidence of adverse events. CONCLUSION: All tazarotene combinations (including tazarotene plus placebo) were highly effective in rapidly reducing the severity of psoriasis. Combining tazarotene with a topical corticosteroid increased efficacy while reducing the incidence of local adverse events.

Once-weekly fluconazole (150, 300, or 450 mg) in the treatment of distal subungual onychomycosis of the toenail.

BACKGROUND: Onychomycosis is a prevalent infection of the nail caused primarily by dermatophytes. Fluconazole is active in vitro against the most common pathogens of onychomycosis, penetrates into the nail bed, and is clinically effective in the treatment of a wide variety of superficial fungal infections. OBJECTIVE: The purpose of this study was to compare the efficacy and safety of three different doses of fluconazole (150, 300, and 450 mg) given orally once weekly to that of placebo in the treatment of distal subungual onychomycosis of the toenail caused by dermatophytes. METHODS: In this multicenter, double-blind study, 362 patients with mycologically confirmed onychomycosis were randomized to treatment with fluconazole, 150, 300, or 450 mg once weekly, or placebo once weekly for a maximum of 12 months. To enter the study, patients were required to have at least 25% involvement of the target nail with at least 2 mm of healthy nail from the nail fold to the proximal onychomycotic border. Patients who were clinically cured or improved at the end of treatment were further evaluated over a 6 month follow-up period. At both the end of therapy and the end of follow-up, clinical success of the target nail was defined as reduction of the affected area to less than 25% or cure. RESULTS: At the end of therapy, 86% to 89% of patients in the fluconazole treatment groups were judged clinical successes as defined above compared with 8% of placebo-treated patients. Clinical cure (completely healthy nail) was achieved in 28% to 36% of fluconazole-treated patients compared with 3% of placebo-treated patients. Fluconazole demonstrated mycologic eradication rates of 47% to 62% at the end of therapy compared with 14% for placebo. The rates at the end of follow-up were very similar, indicating that eradication of the dermatophyte was maintained over the 6-month period. All efficacy measures for the fluconazole groups were significantly superior to placebo (p=0.0001); there were no significant differences between the fluconazole groups on these efficacy measures. The clinical relapse rate among cured patients over 6 months of follow-up was low at 4%. Fluconazole was well tolerated at all doses over the 12-month treatment period, with the incidence and severity of adverse events being similar between the fluconazole and placebo treatment groups. Mean time to clinical success in the fluconazole treatment groups was 6 to 7 months. This time frame may be used as a guideline for fluconazole treatment duration. CONCLUSION: The results of this study support the use of fluconazole in the treatment of distal subungual onychomycosis of the toenail caused by dermatophytes. Doses between 150 to 450 mg weekly for 6 months were clinically and mycologically effective as well as safe and well tolerated.

Once-weekly fluconazole (150, 300, or 450 mg) in the treatment of distal subungual onychomycosis of the fingernail.

BACKGROUND: Onychomycosis is a prevalent infection of the nail caused primarily by dermatophytes. Fluconazole is active in vitro against the most common pathogens, penetrates into the nail bed, and is clinically effective in the treatment of a wide variety of fungal infections. OBJECTIVE: The purpose of this study was to assess the safety and efficacy of oral fluconazole 150, 300, and 450 mg administered once weekly compared with placebo in the treatment of distal subungual onychomycosis of the fingernail caused by dermatophytes. METHODS: This was a multicenter, randomized, double-blind, placebo-controlled study enrolling 349 patients with onychomycosis of the fingernails. Clinical and mycologic efficacy as well as measures of safety were assessed monthly for a maximum of 9 months of treatment, with additional safety visits occurring at weeks 2 and 6. For inclusion, patients were required to have clinically and mycologically documented onychomycosis of the fingernail caused by dermatophytes with at least 25% involvement of the target fingernail. After end of therapy, patients with improved or cured fingernails entered a blinded 6-month follow-up without drug treatment during which efficacy was assessed every 2 months. Efficacy was assessed by clinical (visual) and mycologic (microscopic and culture) measures. Clinical measures included assessments of the percentage of target nail involvement, measurement of the distance from the nail fold to the proximal onychomycotic border, and signs and symptoms of onychomycosis. RESULTS: Fluconazole was significantly superior to placebo in eradicating clinical and mycologic symptoms of onychomycosis, both at the end of active treatment and at 6 months after treatment (p=0.0001 for all efficacy measures). At the end of therapy, 91% to 100% of patients in the fluconazole groups were judged clinical successes, defined as reduction of the affected area of the target nail to less than 25% or cure, compared with 8% for placebo. Clinical cure rates at end of therapy were 76%, 85%, and 90% for fluconazole 150, 300, and 450 mg, respectively, compared with 3% for placebo. These clinical success and cure rates were largely maintained or improved during follow-up. Clinical relapse in cured patients during the follow-up period was very low (1.5% to 3.3%). Fluconazole demonstrated mycologic eradication rates of 89% to 100% at the end of treatment and 90% to 99% at the end of follow-up; for placebo the rates were 8% and 12%, respectively. CONCLUSION: Fluconazole administered once weekly is safe and effective in eradicating distal subungual onychomycosis of the fingernail caused by dermatophytes.

Pharmacokinetics of three doses of once-weekly fluconazole (150, 300, and 450 mg) in distal subungual onychomycosis of the toenail.

BACKGROUND: Preliminary clinical data suggest that fluconazole is effective in the treatment of patients with onychomycosis. To design optimum dosage regimens, a better understanding of fluconazole's distribution into and elimination from nails is needed. OBJECTIVE: The purpose of this study was to determine plasma and toenail concentrations of fluconazole. METHODS: In this multicenter, randomized, double-blind investigation, fluconazole (150 mg, 300 mg, or 450 mg) or matching placebo was administered once a week for a maximum of 12 months to patients with onychomycosis of the toenail. A total of 151 subjects participated in the pharmacokinetic assessment. Blood samples and distal toenail clippings from both affected and healthy nails were obtained for fluconazole concentration determinations at baseline, at the 2-week visit, at each monthly visit until the end of treatment, and then at 2, 4, and 6 months (nail samples only at the latter two) after fluconazole was discontinued. RESULTS: Fluconazole was detected in healthy and affected nails at the 2-week assessment in nearly all subjects. The median time to reach steady-state fluconazole concentrations in healthy nails was 4 to 5 months in the three fluconazole dose groups. In affected nails, steady-state fluconazole concentrations were achieved more slowly, with a median time of 6 to 7 months. At the 8-month assessment, affected toenail fluconazole concentrations were higher than corresponding plasma fluconazole concentrations, with ratios of 1.31 to 1.50 in the three active treatment groups. Toenail concentrations of fluconazole declined slowly after treatment was discontinued, with elimination half-lives of 2.5, 2.4, and 3.7 months for the 150, 300, and 450 mg doses, respectively. Measurable fluconazole concentrations were still present in toenails at 6 months after treatment in most subjects. CONCLUSION: Fluconazole penetrates healthy and diseased nails rapidly, yielding detectable concentrations after two weekly doses. Once it penetrates nail, fluconazole persists for up to 6 months or longer after therapy is stopped. These favorable pharmacokinetic characteristics support a once-weekly fluconazole dosage regimen for the treatment of patients with onychomycosis.

Cutaneous pseudolymphomas.

Cutaneous pseudolymphoma refers to a heterogeneous group of benign reactive T- or B-cell lymphoproliferative processes of diverse causes that simulate cutaneous lymphomas clinically and/or histologically. The inflammatory infiltrate is bandlike, nodular, or diffuse and is composed predominantly of lymphocytes with or without other inflammatory cells. Depending on the predominant cell type in the infiltrate, cutaneous pseudolymphomas are divided into T- and B-cell pseudolymphomas. Cutaneous T-cell pseudolymphomas include idiopathic cutaneous T-cell pseudolymphoma, lymphomatoid drug reactions, lymphomatoid contact dermatitis, persistent nodular arthropod-bite reactions, nodular scabies, actinic reticuloid, and lymphomatoid papulosis. Cutaneous B-cell pseudolymphomas include idiopathic lymphocytoma cutis, borrelial lymphocytoma cutis, tattoo-induced lymphocytoma cutis, post-zoster scar lymphocytoma cutis, and some persistent nodular arthropod-bite reactions. This review attempts to discuss current aspects of the classification, pathogenesis, clinical spectrum, histopathologic and immunohistochemical diagnosis, and laboratory investigations for clonality in the various types of cutaneous pseudolymphomas.

Pharmacokinetics of three once-weekly dosages of fluconazole (150, 300, or 450 mg) in distal subungual onychomycosis of the fingernail.

BACKGROUND: Fluconazole has proven to be safe and effective for a variety of superficial and systemic fungal infections. Preliminary analysis of extensive Phase III studies suggests that it is very effective for the treatment of onychomycosis. Its pharmacokinetic properties, including low molecular weight and high water-solubility, suggest a unique ability to penetrate the nail. This feature is likely to account in part for fluconazole's effectiveness in the treatment of onychomycosis. OBJECTIVE: Determinations of plasma and fingernail concentrations of fluconazole were performed as part of a larger study comparing the safety and efficacy of once-weekly fluconazole (150, 300, and 450 mg) to placebo in the treatment of distal subungual onychomycosis of the fingernails caused by dermatophytes. The relationship between fluconazole concentrations and efficacy was also examined. METHODS: Pharmacokinetic studies were performed by means of plasma and fingernail samples from 133 patients, a subset of 349 patients participating in a double-blind, placebo-controlled clinical trial of fluconazole administered in once-weekly doses of 150, 300, or 450 mg until cure of onychomycosis or for a maximum of 9 months. Blood and fingernail samples for pharmacokinetic analysis were taken at baseline, at week 2, and at monthly intervals during the treatment phase of the study. Patients considered clinically cured or improved also participated in a 6-month follow-up study. During this phase, patients were monitored and samples taken every 2 months. RESULTS: Significant amounts of fluconazole were detected in the earliest fingernail samples taken (after 2 weeks of treatment). After two weekly doses, 30% to 33% of steady-state concentrations had been achieved in healthy nails and 22% to 29% in affected nails. Steady state was achieved in 3 to 5 months. Fluconazole concentration in nails as well as plasma followed dose-proportional pharmacokinetics. Nail:plasma ratios in affected nails were 0.4 to 0.6 at 2 weeks and 1.7 to 1.8 at 6 months. Fluconazole concentrations fell slowly after drug discontinuation and were still detectable 4 months after end of treatment. A statistically significant correlation was found between steady-state concentration and clinical and global outcomes. CONCLUSION: Fluconazole rapidly penetrates the fingernail, where it is retained at detectable levels for at least 4 months after drug discontinuation. A significant correlation exists between fluconazole concentration in the fingernails and clinical and global outcomes.

Administration of DAB389IL-2 to patients with recalcitrant psoriasis: a double-blind, phase II multicenter trial.

BACKGROUND: Current therapies for recalcitrant psoriasis focus on immunoregulation and targeting of activated T-lymphocytes rather than keratinocytes. Previous studies with low doses of the lymphocyte-selective fusion protein DAB389IL-2 have shown benefit to patients with psoriasis. OBJECTIVE: We examined the safety and efficacy of DAB389IL-2 in 41 volunteers receiving more frequent and higher doses than in a previous trial. METHODS: Patients were randomized to receive either placebo or 5, 10, or 15 microg/kg daily of DAB389IL-2 intravenously for 3 consecutive days each week for 4 consecutive weeks with a subsequent 4-week observation period. RESULTS: Of the placebo group, 17% (2 of 12) exhibited at least 50% improvement from baseline Psoriasis Area and Severity Index scores at the end of the study, whereas 24% of all treated patients (7 of 29) showed the same improvement. Overall, 3 of 12 (25%) patients given placebo as opposed to 12 of 29 (41%) patients treated with DAB389IL-2 improved to this same extent at some point during the study. The rate of improvement for treated patients was significantly greater than for placebo patients (p = 0.04; repeated measures ANOVA). Among treated patients, decreases in Psoriasis Area and Severity Index scores were paralleled by changes in the Physician's Global Assessment and the Dermatology Life Quality Index. Treatment in ten patients was discontinued because of adverse events. Flu-like symptoms were the most common with severity increasing at the two higher doses. Only one serious adverse event was reported. This occurred in a patient receiving 5 microg/kg daily who experienced vasospasm and a coagulopathy resulting in arterial thrombosis. CONCLUSION: Our findings are consistent with the potential antipsoriatic activity of DAB389IL-2 demonstrated in an earlier study. However, DAB389IL-2 was less well tolerated at this dosing regimen, particularly at the highest dose, and it was too toxic at these doses and schedules to be considered in the routine treatment of psoriasis.

Mometasone furoate 0.1%-salicylic acid 5% ointment versus mometasone furoate 0.1% ointment in the treatment of moderate-to-severe psoriasis: a multicenter study.

Topical corticosteroids and keratolytics are both used widely in the management of patients with psoriasis. A combination of the two types of agents may provide enhanced relief. The purpose of this study was to compare the efficacy and safety of the combination ointment mometasone furoate 0.1% plus salicylic acid 5% with that of mometasone furoate 0.1% ointment in the treatment of moderate-to-severe psoriasis vulgaris. A total of 408 patients were enrolled in this controlled, randomized, double-masked, parallel-group, multicenter comparison. Patients applied either mometasone furoate-salicylic acid ointment or mometasone furoate ointment alone to target lesions twice daily for 21 days. Severity of erythema, induration, and scaling were scored at baseline and at days 4, 8, 15, and 22. An evaluation of overall change in disease status of all treated lesions was performed at each follow-up visit. Adverse events were also monitored and scored, including signs of skin atrophy. Beginning on day 8, the combination of mometasone furoate-salicylic acid was significantly more effective than mometasone furoate alone, as indicated by the mean percentage of improvement in total disease scores, mean total disease sign scores, and the individual score for scaling. Similarly, the combination was more effective beginning on day 15, as indicated by the global evaluation of overall clinical response and individual scores for erythema and induration. Both treatments were well tolerated. Mometasone furoate-salicylic acid ointment provides more effective treatment of moderate-to-severe psoriasis than does mometasone furoate ointment alone and is safe and well tolerated.

A double-blind, multicenter clinical trial comparing efficacy of once-daily metronidazole 1 percent cream to vehicle in patients with rosacea.

The efficacy and safety of a new formulation of metronidazole 1 percent cream applied once daily was compared to vehicle cream in a double-blind, randomized, parallel group, ten-week clinical study. The results showed that metronidazole 1 percent cream was significantly better than vehicle in reducing the lesions of rosacea, improving erythema, and physician's global rosacea scores. The incidence of adverse events related to the skin was low.

Cetirizine versus hydroxyzine and placebo in chronic idiopathic urticaria.

OBJECTIVE: To compare the safety and efficacy of cetirizine with that of hydroxyzine and placebo in the treatment of chronic idiopathic urticaria. DESIGN: A 4-week multicenter, randomized, double-blind, double-dummy, placebo-controlled safety and efficacy study. SETTING: Patients were treated in a variety of allergy practice settings. PATIENTS: The study population consisted of 188 patients who were at least 12 years of age, with symptomatic chronic idiopathic urticaria that had occurred episodically for at least 6 weeks. INTERVENTIONS: Patients were given either cetirizine 10 mg once daily, hydroxyzine 25 mg tid, or placebo for 4 weeks. MAIN OUTCOME MEASURES: Patients and investigators used a 4-point scale to evaluate symptoms of urticaria and adverse effects of treatment. Ratings were compared among those taking cetirizine, hydroxyzine, or placebo. RESULTS: After 1 day of treatment, patients randomized to receive cetirizine 10 mg/d exhibited a reduction in the number of episodes of urticaria (and a reduction in pruritus) compared with patients who received hydroxyzine 25 mg tid and patients who received placebo (p = 0.002). The number of urticarial episodes in patients treated with hydroxyzine did not reach significance until day 2 (p = 0.001). Compared with patients who received placebo, patients who received cetirizine and those who received hydroxyzine showed reductions during weeks 1, 2, and 3 and at end-point analysis in the number and size of lesions and in the severity of pruritus (p < 0.04). Patient and physician evaluations at the end of week 4 revealed an improvement in urticarial symptoms for the hydroxyzine and cetirizine groups compared with the placebo group (p < 0.001). Four patients in the hydroxyzine group, 1 patient in the cetirizine group, and 1 patient in the placebo group discontinued the study because of sedation. No patient withdrew because of lack of efficacy. CONCLUSIONS: Cetirizine 10 mg once daily was equivalent to hydroxyzine 25 mg tid in controlling the symptoms of patients with chronic urticaria, as assessed by patient and investigator evaluations.