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Biomedical subjects

J M Hanifin

Publications and source records attributed to J M Hanifin.

At least 19 recordsLinked to original sources
PubMed1998

Long-term effectiveness and safety of recombinant human interferon gamma therapy for atopic dermatitis despite unchanged serum IgE levels.

OBJECTIVE: To assess the long-term effects of recombinant human interferon gamma treatment of atopic dermatitis (AD). DESIGN: Case series. Patients were treated for up to 24 months. SETTING: University dermatology outpatient clinics in Ann Arbor, Mich, and Portland, Ore. PATIENTS: Twenty-four of 32 eligible patients who participated in a previously reported, 12-week, double-blind, placebo-controlled study of recombinant human interferon gamma treatment for AD were enrolled. INTERVENTION: Patients self-administered recombinant human interferon gamma, 50 microg/m2, by daily subcutaneous injection. MAIN OUTCOME MEASURES: Overall response; body surface area of involvement; clinical severity scores for pruritus, erythema, edema, excoriations, dryness, scaling, and lichenification; other atopic symptoms; and laboratory parameters, including serum IgE levels, were monitored at quarterly visits. Results at 1 and 2 years were compared with baseline values. RESULTS: All efficacy parameters improved (P<.05). For example, pruritus was reduced by 50% after both 1 (n=24, P<.001) and 2 (n=16, P=.005) years. Allergic conjunctivitis and allergic rhinitis also improved (P<.01). Eosinophil counts decreased significantly (P<.001). IgE levels increased. Clinical improvement more closely correlated with changes in eosinophil counts (r=0.3-0.5) than with changes in IgE levels (r=0.0-0.2). Only 1 patient discontinued therapy because of adverse effects (flulike symptoms). CONCLUSIONS: The initial efficacy and adverse effects reported for recombinant human interferon gamma treatment of patients with AD were maintained after 2 years of long-term use. Recombinant human interferon gamma seems to be a well-tolerated and effective agent in the long-term therapy of patients with AD. Therapies that correct cellular immune defects, but not humoral immune defects, may be effective in the treatment of patients with AD.

Adolescent↗
PubMed1998

A randomized, vehicle-controlled trial of tacrolimus ointment for treatment of atopic dermatitis in children. Pediatric Tacrolimus Study Group.

BACKGROUND: A topical formulation of tacrolimus, an immunosuppressant currently marketed for the prevention of rejection after solid organ transplant, is a potential therapeutic agent for atopic dermatitis. OBJECTIVE: We sought to determine the safety and efficacy of tacrolimus ointment in pediatric patients with moderate-to-severe atopic dermatitis. METHODS: In this double-blind, vehicle-controlled multicenter trial, children ages 7 to 16 years were treated with twice daily application of tacrolimus ointment at 1 of 3 concentrations (0.03% [n = 43], 0.1% [n = 49], or 0.3% [n = 44]) or vehicle (n = 44) for up to 22 days, with a 2-week follow-up period. RESULTS: The Physician's Global Evaluation of clinical response showed that 69% (95% confidence interval: 53-82) of patients in the 0.03% tacrolimus ointment group, 67% (95% confidence interval: 52-81) in the 0.1% tacrolimus ointment group, and 70% (95% confidence interval: 54-83) in the 0.3% tacrolimus ointment group, compared with 38% (95% confidence interval: 24-54) in the vehicle group, had a marked to excellent (> or =75%) improvement or clearing of their atopic dermatitis (P =.005, .007, and .004, respectively for the 3 tacrolimus groups compared with the vehicle group). The mean percent improvement for a modified Eczema Area and Severity Index at end of treatment for each of the 3 tacrolimus groups (0.03%, 72%; 0.1%, 77%: and 0.3%, 81%) was significantly better than that of the vehicle group (26%; P <.001). The median percent reduction in pruritus was significantly greater for tacrolimus-treated patients (74% to 89%) than for vehicle-treated patients (51%, P = .027). No serious systemic adverse events were noted, and systemic absorption was minimal. CONCLUSION: Tacrolimus ointment appears to be safe and effective in children with atopic dermatitis.

Administration, Topical↗
PubMed1998

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.

Adolescent↗
PubMed1998

Once-weekly fluconazole (450 mg) for 4, 6, or 9 months of treatment for distal subungual onychomycosis of the toenail.

BACKGROUND: Fluconazole is a bis-triazole antifungal agent approved for the treatment of oropharyngeal, esophageal, and vaginal candidiasis, serious systemic candidal infections, and cryptococcal meningitis. OBJECTIVE: The purpose of this study was to evaluate three different durations of once-weekly fluconazole for the treatment of onychomycosis of the toenail caused by dermatophytes. METHODS: In a multicenter, randomized, double-blind, parallel, placebo-controlled trial, 384 patients with distal subungual onychomycosis of the toenail received fluconazole, 450 mg once weekly, or placebo for 4, 6, or 9 months. For inclusion, patients were required to have mycologically confirmed distal subungual onychomycosis of the toenail with a large toenail at least 25% clinically affected but having at least 2 mm of healthy nail between the nail fold and the proximal onychomycotic border. Efficacy was assessed by clinical and mycologic (microscopic and microbiologic) measures at screening, at every treatment visit starting at month 3, and at months 2, 4, and 6 after therapy. Observed or volunteered adverse events were recorded and classified at all visits. RESULTS: At the end of treatment, very significantly superior clinical and mycologic results were achieved in all fluconazole groups compared with placebo (p=0.0001). This superiority was largely maintained over 6 months of follow-up. The clinical and mycologic responses of the 9-month treatment duration were significantly superior to the 4- and 6-month durations. Similar percentages of patients in the fluconazole and placebo groups reported adverse experiences for all three durations of the study. CONCLUSION: Results of this study support the efficacy and safety of fluconazole in the treatment of distal subungual onychomycosis of the toenail.

Adolescent↗
PubMed1998

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.

Adult↗
PubMed1997

Critical evaluation of food and mite allergy in the management of atopic dermatitis.

The subject of allergic causation of atopic dermatitis (AD) has been a source of controversy for over sixty years. While there is general agreement of allergen-induced asthma and allergic rhinoconjunctivitis, AD lesions cannot be readily or consistently induced by foods and inhalants. The most consistent perturbators of atopic conditions are irritants, probably reflecting the consistent inflammatory cell hyper-reactivity due to elevated cyclic AMP-phosphodiesterase activity. The immunologic reactions are another manifestation of that general cellular dysregulation.

Animals↗
PubMed1996

The spectrum of cutaneous patch-test reactions in patients with atopic dermatitis.

We have outlined rationale and problems associated with three types of patch tests that may provide diagnostic help in patients with difficult-to-manage AD. Each of these methods is imperfect and in need of greater study using a critical approach, better techniques, more attention to irritant controls, and better definition of atopic populations. Proof of validity for aeroallergen patch testing will necessarily require large quantities of purified antigens. In spite of all these problems, patch testing can be useful and sometimes essential for the diagnosis and management of difficult AD.

Adult↗
PubMed1996

Prostaglandin E2 control of T cell cytokine production is functionally related to the reduced lymphocyte proliferation in atopic dermatitis.

Past studies of peripheral blood mononuclear cells (PBMC) from patients with atopic dermatitis (AD) have demonstrated reduced proliferation. We have studied phytohemagglutinin-induced lymphocyte proliferation in the context of interleukin-4 (IL-4), interferon-gamma (IFN-gamma), and prostaglandin E2 (PGE2) production in cultures of PBMC from patients without and with AD. The proliferation index was found to correlate proportionally to IFN-gamma production and inversely to T-cell IL-4 and monocyte PGE2 production. Assays in parallel cultures showed significantly increased PGE2 production by purified AD monocytes. The proliferation index in PBMC from persons with AD was significantly reduced compared with normal PBMC. This difference was normalized in the presence of extrinsic IFN-gamma but exaggerated when IL-4 was added. Increased AD monocyte production of inflammatory factors (e.g., PGE2) and cytokines appears to increase IL-4 production by Th2 while suppressing IFN-gamma production by Th1. Restoration of the normal proliferation of PBMC by the addition of IFN-gamma may represent one mechanism for the clinical efficacy of IFN-gamma treatment of AD.

Adult↗
PubMed1996

Type 4 phosphodiesterase inhibitors have clinical and in vitro anti-inflammatory effects in atopic dermatitis.

Increased cyclic AMP-phosphodiesterase activity in peripheral blood leukocytes is associated with the immune and inflammatory hyperreactivity that characterizes atopic dermatitis. Atopic phosphodiesterase has high sensitivity to a variety of enzyme inhibitors, suggesting an increased therapeutic advantage. The objective of this study was to use in vitro assays to identify a potent phosphodiesterase inhibitor and then to investigate its effectiveness in treating atopic dermatitis. Leukocyte enzyme activity was measured by radioenzyme assay, whereas prostaglandin E2 and interleukins 10 (IL-10) and 4 (IL-4) were measured in 24-h culture supernatants of mononuclear leukocytes by immunoassays. The effect of a topical phosphodiesterase inhibitor on atopic dermatitis lesional skin was assessed by double-blind, paired comparisons of active drug and placebo ointments applied to symmetrically involved sites over a 28-d period. Using in vitro, assays, we demonstrated the ability of selective high-potency phosphodiesterase inhibitors to reduce prostaglandin E2, IL-10, and IL-4 production in atopic mononuclear leukocyte cultures. We selected the Type 4 phosphodiesterase inhibitor, CP80,633, based on its inhibitory potency, for clinical testing by topical, bilateral paired comparisons in 20 patients with atopic dermatitis and demonstrated significant reductions of all inflammatory parameters. Phosphodiesterase inhibitors modulate several pathways contributing to the exaggerated immune and inflammatory responses, which characterize atopic dermatitis. This in vivo demonstration of anti-inflammatory efficacy may provide a useful alternative to the over-reliance on corticosteroid therapy in atopic disease.

Administration, Topical↗
PubMed1996

Abnormal IL-4 gene expression by atopic dermatitis T lymphocytes is reflected in altered nuclear protein interactions with IL-4 transcriptional regulatory element.

Among the atopic disease, atopic dermatitis is characterized by the highest levels of serum IgE and by increased peripheral blood T-cell interleukin-4 (IL-4) production. IL-4 promotes IgE synthesis by B cells and stimulates the growth of IL-4-producing T cells and may contribute to the pathogenesis of this disease. In this study, in situ hybridization established that atopic dermatitis patients have a higher frequency of IL-4-producing peripheral blood T cell when compared to normal subjects. These in vivo-derived T cells were used to examine the signaling requirements of IL-4 production and the nuclear factors that associate with a critical IL-4 transcriptional regulatory element between -88 and -60 relative to the IL-4 transcription initiation site, the activation responsive element. We demonstrate that, as in T-cell lines, proteins belonging to the NF-AT and AP-1 family of transcription factors are present in stimulated cell extracts and specifically associate with the activation responsive element. Dysregulated IL-4 production is reflected in the nuclear proteins that associated this element. Using gel shift assays, we found that 12 of 12 nuclear extracts from stimulated atopic T cells formed the activation-dependent protein-DNA complex, compared to only 2 of 12 normal T-cell extracts. Activation complex formation correlated with the relative level of IL-4 mRNA and protein produced in stimulated T cells, suggesting that abnormal IL-4 gene expression in atopic disease may be linked to alterations in nuclear protein interactions with these promoter elements.

Base Sequence↗
PubMed1996

Allergic and irritant patch test reactions and atopic disease.

This study presents a profile of patients with chronic recalcitrant eczematous disease referred by dermatologists for contact allergy evaluation. Allergic contact dermatitis (ACD) and irritant responses were carefully defined, as was the presence or absence of atopy obtained by history. Of 410 patients studied, 44% had no history of atopic disease and 46% were classed as definitely atopic. Among relevant ACD patch test reactors (n = 198), 51.5% had atopy, compared with 40.9% with no atopy but this difference was not significant. Likewise, among atopics (n = 189), 54% had definite, relevant ACD patch test responses while 33.9% had negative ACD (again not significant). Significance was seen in the higher mean number of positive allergic patch tests in the atopic group (2.7 versus 2.0, p = 0.0223). Irritant patch tests were highest among patients with both ACD and atopy (p = 0.0308) and the proportion of irritant responses correlated with increasing numbers of positive ACD tests. We conclude that atopics are at least as likely to have ACD as are non-atopics. Irritancy is increased in these patients with chronic dermatitis and the frequency of irritant reactions correlates with both greater numbers of ACD responses and with presence of atopy.

Adolescent↗
PubMed1996

Research and dermatologic excellence.

Nearly everyone, even within our small specialty, has a slightly different idea, or bias, as to what constitutes research. We hear of clinical research and academic research and pharmaceutical research and descriptive research and cutting-edge research, but the distinctions often blur and are unimportant. What is important is that research of all kinds increases knowledge and adds information that improves patients' well-being. Perhaps we can agree with a general definition: Research is inquiry. In its simplest form, it may be nothing more than a literature review pertinent to an observation or interest. More often we think of systematic research (a progression starting with questions and ideas) moving forward to a hypothesis, then planning approaches and methods for experiments, all directed toward characterizing normal features and disease mechanisms to prevent and treat illness.

Dermatology↗
PubMed1995

Overexpression of IL-10 in atopic dermatitis. Contrasting cytokine patterns with delayed-type hypersensitivity reactions.

The skin lesions of patients with atopic dermatitis provide a model to study immunoregulation in human allergy. To determine the local cytokine pattern of cells present (both endogenous and recruited) at the site of disease, we extracted RNA from skin biopsy specimens from patients with atopic dermatitis, allergic contract dermatitis, and positive tuberculin reactions and used PCR to assay for cytokine mRNA. cDNAs were normalized to the intensity of the CD3 delta PCR product as a marker of T cell mRNA. We found overexpression of IL-10 mRNA in atopic dermatitis lesions, in comparison with allergic contact dermatitis lesions and tuberculin reactions. In contrast, IL-4 mRNA was most strongly expressed in allergic contact dermatitis lesions and IFN-gamma mRNA was the predominant cytokine in tuberculin reactions. Using an anti-IL-10 mAb with immunoperoxidase, we localized IL-10 protein to large mononuclear cells in the dermal infiltrate of atopic lesions. After immunomagnetic sorting of mononuclear cell populations from PBMC of atopic dermatitis subjects, IL-10 mRNA as measured by PCR was found to be strongly expressed in CD14+ cells. Spontaneous release of IL-10 from PBMC-derived adherent cells was greater in atopic dermatitis donors than normal controls. We therefore renormalized skin biopsy cDNA according to the level of beta-actin PCR product, as a marker of total cellular mRNA, and found by PCR that IL-10 was nevertheless greatest in atopic dermatitis subjects. We conclude that the relative overexpression of IL-10 in atopic dermatitis greatest in atopic dermatitis subjects. We conclude that the relative overexpression of IL-10 in atopic dermatitis may contribute to the up-regulation of humoral responses and the down-regulation of Th1 responses.

Adult↗
PubMed1995

Monocyte phosphodiesterase abnormalities and dysregulation of lymphocyte function in atopic dermatitis.

The immunologic aberrations associated with atopic dermatitis include the paradox of reduced cell-mediated immune responses in the setting of increased cell-mediated immunity features that resemble allergic contact dermatitis. In this review, we present evidence that abnormalities in monocytes and Langerhans cells alter the function of T-helper-cell subpopulations to cause the immunologic defects associated with atopic dermatitis. Increased monocyte prostaglandin E2 production inhibits Th1 responses, accentuating interleukin (IL)-4 secretion by Th2 cells. Elevated prostaglandin E2 secretion correlates with abnormally increased cyclic adenosine monophosphate-phosphodiesterase activity in monocytes and this, along with other defective inflammatory cell responses, can be normalized in vitro by phosphodiesterase inhibitors. It appears that in addition to prostaglandin E2, IL-10 acts to regulate the balance between Th1 and Th2 functional responses accounting for many atopic features, including increased IL-4, IL-5, and IL-6 production by T cells; increased IgE synthesis; decreased interferon-gamma production; and impaired cell-mediated immune responses. All of these abnormalities can be related to increased phosphodiesterase activity in atopic monocytes, and inhibition of this key enzyme appears to reverse atopic dermatitis inflammatory abnormalities in vitro and in vivo.

Animals↗
PubMed1995

Primary penile lymphoma presenting as a penile ulcer.

Primary penile lymphoma is rare. The clinical manifestations can be quite subtle, which may lead to misdiagnosis. Treatments have included radical surgery, chemotherapy and radiation. We report on an 18-year-old man with primary penile lymphoma whose lesion caused prolonged diagnostic uncertainty. He was treated with chemotherapy alone, and he has had no tumor recurrence for 27 months.

Adolescent↗