Effects of acitretin on the liver.

BACKGROUND: Therapy with aromatic retinoids for psoriasis is associated with abnormal liver function test findings and toxic hepatitis (in 1.5% of patients). OBJECTIVE: Our purpose was to determine the safety of acitretin with respect to liver function, on the basis of biopsy. METHODS: We treated 128 adults (with chronic, stable psoriasis) with oral acitretin (25-75 mg/day) for four 6-month intervals in a prospective, open-label, 2-year multicenter study. Liver biopsies were performed before and after study completion (2 years). RESULTS: Eighty-three available pairs of pretreatment and posttreatment liver biopsies demonstrated no change in 49 patients (59%), improvement in 20 (24%), and worsening in 14 (17%). Of these 14 patients with decrements in biopsy status, most changes were mild. There was no correlation between liver function test abnormalities or cumulative acitretin dose and changes in liver biopsy status. CONCLUSION: Acitretin therapy elicited no biopsy-proven hepatotoxicity in this prospective 2-year study. These findings suggest that periodic liver biopsy may not be necessary with acitretin treatment.

Tretinoin emollient cream for photodamaged skin: results of 48-week, multicenter, double-blind studies.

BACKGROUND: The ability of topical tretinoin to improve certain signs of skin photodamage has been shown previously. OBJECTIVE: Our purpose was to assess the effectiveness of tretinoin emollient cream in maintaining or further improving photodamaged skin during extended use. METHODS: Photodamaged subjects who completed 24 weeks of once-daily use of tretinoin emollient cream 0.05% (n = 149) or 0.01% (n = 149) continued to use the same strength formulation in a 24-week double-blind extension. RESULTS: Maintenance of improvement or continued reduction in signs of photodamage was noted in both investigators' and subjects' evaluations of the 0.05% and 0.01% preparations; these results were confirmed by skin replica analyses. Cutaneous side effects were less common during the extension study than during the first 24 weeks of therapy. CONCLUSION: Both strengths of tretinoin emollient cream (0.05% and 0.01%) appeared safe and effective in the treatment of photodamaged skin during a 48-week treatment period.

Sustained improvement in photodamaged skin with reduced tretinoin emollient cream treatment regimen: effect of once-weekly and three-times-weekly applications.

BACKGROUND: Previous studies have documented reversal of long-term photodamage with once-daily applications of topical tretinoin. OBJECTIVE: Our purpose was to assess the effectiveness of tretinoin emollient cream in maintaining improvement in photodamage with a reduced frequency of applications. METHODS: A total of 126 subjects who completed 48 weeks of once-daily treatment with tretinoin emollient cream 0.05% were enrolled for an additional 24 weeks of tretinoin once weekly, three times weekly, or no therapy. RESULTS: The clinical improvement observed during 48 weeks of once-daily treatment was sustained with three-times weekly applications and to a lesser extent with once-weekly dosing, whereas effects tended to regress in subjects off therapy. The overall incidence of adverse events in the skin and subcutaneous tissues appeared to vary with dose frequency. CONCLUSION: After 48 weeks of once-daily treatment, the continued use of tretinoin emollient cream 0.05% at a dose of three times per week maintains and, in some cases, may further enhance improvement in photodamage. Discontinuation of therapy results in some reversal of beneficial effects.

Esophageal acanthosis nigricans in association with adenocarcinoma from an unknown primary site.

A case of acanthosis nigricans with esophageal involvement is presented. Six months after the patient's initial examination, metastatic adenocarcinoma from an unknown primary site was discovered. This represents the ninth reported case of esophageal acanthosis nigricans; six of the eight previously described cases were in association with malignancy localized to the gastrointestinal tract. Esophageal acanthosis nigricans may be a more specific marker for associated malignancy than cutaneous or oral mucosal manifestations. If present, esophageal acanthosis nigricans may serve as an indication for an extensive search for occult malignancy.

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.

N1N8-bis(gamma-glutamyl)spermidine cross-linking in epidermal-cell envelopes. Comparison of cross-link levels in normal and psoriatic cell envelopes.

N1N8-Bis(gamma-glutamyl)spermidine was found in exhaustive proteolytic digests of isolated cell envelopes from human epidermis at levels comparable with those of epsilon-(gamma-glutamyl)lysine. Significantly higher than normal amounts of these compounds, particularly the bis(gamma-glutamyl)polyamine, were observed in envelopes from afflicted areas (scales) of psoriatic patients. These findings support the notions that N1N8-bis(gamma-glutamyl)spermidine, like epsilon-(gamma-glutamyl)lysine, functions in cell envelopes as an enzyme-generated protein cross-link and stabilizing force and that individuals with the chronic, recurrent skin disease, psoriasis, exhibit in involved epidermis abnormal cell-envelope-protein cross-linking.

Subacute cutaneous lupus erythematosus during PUVA therapy for psoriasis: case report and review of the literature.

Lesions typical of subacute cutaneous lupus erythematosus developed in an elderly woman after 6 months of PUVA (8-methoxypsoralen and longwave ultraviolet light) therapy for psoriasis. Pancytopenia, antibodies to double-stranded DNA, and hypocomplementemia developed concurrently with the appearance of the cutaneous lesions. With discontinuation of photochemotherapy, the cutaneous lesions disappeared and the pancytopenia improved.

Epidermal and hair follicle transglutaminases. Partial characterization of soluble enzymes in newborn mouse skin.

Treatment of skins of newborn mice with the neutral protease Dispase in order to separate dermis and epidermis causes pronounced changes in the levels of transglutaminase activity in the epidermis. Two soluble transglutaminases, one anionic enzyme and one cationic enzyme, of Mr approximately 90,000 and approximately 50,000, respectively, are extracted from epidermis; and the activities of both enzymes increase as a function of the time of Dispase treatment of skin. When the anionic Mr approximately 90,000 enzyme is incubated with Dispase after its chromatographic isolation from epidermal extracts, it is converted to a lower molecular weight enzyme. Hair follicles isolated from dermis prepared by a 12-h Dispase treatment of the skin of newborn mice contain two soluble cationic transglutaminases, one of which is indistinguishable from that of epidermis and the other which is not seen in epidermis. Both of these hair follicle enzymes are of Mr approximately 50,000 and appear to exist in monomeric form. They have been partially purified. Based upon these findings, we suggest that transglutaminase processing and control occur during normal differentiation of keratinocytes in epidermis and of hair follicle epidermal cells in dermis and that production of the proper forms of the enzyme may be essential to the formation of mature cornified envelopes and hair shafts, respectively.

Modulation of cellular transglutaminase: protease-induced activation.

Multiple molecular forms of transglutaminase are found in cells and each form is widely distributed. We find a 95 K dalton enzyme associated with membrane fractions. A 50 K dalton enzyme occurs primarily in epidermis and hair follicles. Cells after treatment with proteases show greater transglutaminase activity. The activated enzyme in rat chondrosarcoma cells is one of 95 K daltons, whereas mouse epidermal cells and rabbit endometrium cells after protease activation display enzymes of both 95 K daltons and 50 K daltons. The 95 K dalton enzyme, but not that of 80 K daltons, can be activated by proteases or sulfhydryl compounds after cell lysis. In cells that undergo terminal differentiation, e.g., reticulocytes, megakaryocytes, monocytes, chondrocytes, and epidermal cells, the forms of transglutaminase are modulated. Our findings suggest that these modulations in differentiating cells are the results of transglutaminase post-translational modifications that cause pronounced changes in catalytic activity.

Psoralens and ocular effects in humans.

The safety of psoralen photochemotherapy (PUVA) in relation to the eye has been an area of research at the Washington Hospital Center for the last 6 years. Our studies indicate that, with proper shielding of the eye, safety for acute lenticular damage can be established. However, the potential for cataract formation from low-dose, long-term ambient UVA exposure is not known. The guidelines for proper shielding of the eye with PUVA therapy have been established and are enumerated in the text. Our studies on 68 patients for an average length of 4 years and 7 months while they received PUVA have established that the rate in the development of cataracts in treated patients had not increased as compared with the Framingham Eye Study.

A new skin manifestation of progressive systemic sclerosis.

This paper describes a pigmentary abnormality found in three patients with progressive systemic sclerosis. This consists of pigment retention over superficial blood vessels in an area of depigmentation. Sequential clinical observations demonstrated the dynamic nature of this abnormality, and on the basis of thermographic examination in one patient, we suggest that local thermal mechanisms may affect its development. This abnormality has been seen only in patients with progressive systemic sclerosis.

Vesicular pemphigoid vs dermatitis herpetiformis.

We describe a patient with clinical features of dermatitis herpetiformis (DH) and histopathologic features suggestive of both DH and bullous pemphigoid (BP). Immunofluorescent (IF) studies of skin biopsy revealed IgG and C3 deposits along the basement membrane zone (BMZ) in a linear pattern and circulating BMZ antibodies in the serum consistent with BP. The patient's condition evolved over 5 years into a typical case of DH characterized by histologic findings of papillary edema and neutrophilic infiltrates and evidence by IF findings of granular IgA deposits in the dermal papillae and the presence of antigliadin antibodies in the serum.

Human lymphocyte antigens characterizing psoriatic arthritis and its subtypes.

We performed human lymphocyte alloantigen determinations in patients with psoriatic arthritis (PsPA) who were clinically classified into arthritic subtypes and disease severity. The total PsPA group demonstrated elevations of HLA-BW38, CW6, DR4 when compared with controls (p less than 0.001). Severe arthritics have increased DR4 frequency when compared with less severe arthritics (p less than 0.02). Those with mild disease have increased A3, B7 frequency which was absent in patients with moderate or severe arthritis. Rheumatoid-like PsPA patients have increased DR4, B40 frequencies; those with spondylitis, B27, CW1. PsPA is associated with many genes in the major histocompatibility complex. Distinct groups of patients with PsPA as determined by type and severity are identifiable by the presence of specific human lymphocyte antigens.

General clinical toxicology of oral retinoids.

Four retinoids - retinol (vitamin A), tretinoin (retinoic acid), etretinate (the ethyl ester of trimethoxymethylphenyl retinoic acid), and isotretinoin (13-cis-retinoic acid, Accutane) - have been administered orally in humans for therapeutic purposes. A review of the available information on the clinical toxic effects of these substances indicated that, while they express similar spectra of toxicity, they also differ in the extent to which they affect various body systems. This suggests that differential efficacy of the retinoids may be related, in part, to the cutaneous sites of maximum activity.

Kinetics of [14C-5] 8-methoxypsoralen distribution in rabbits.

Distribution, kinetics and localization of 8-methoxypsoralen (8-MOP) was determined in rabbits over 24 h following i.v. administration of [14C-5] labeled and carrier 8-MOP at respective concentration of 50 muCi and 5 mg/kg. Peak levels were reached by kidneys at 1 h (18,500 ng/g) at 2 h by liver (2,470 ng/g) and at 8 h by bile (64,000 ng/g). Muscles, lymphatic tissues and brain showed low drug uptake (800 ng/g). Endocrine organs also had low drug concentration. In gastrointestinal tract the maximum level of 8-MOP was 1,500 mg/g at 1 h in jejunum. Plasma 8-MOP concentration was 3,700 ng/ml at 5 min post injection with 100 ng/ml still detectable at 24 h. Urine label concentration peaked at 1 h (4 x 10(5) cpm/ml) and was 2 x 10(2) cpm/ml at 24 h. The intact skin concentration was at the maximum during the first 30 min (1,958 ng/g) declining progressively thereafter to 155 ng/g at 24 h. The UVA irradiated skin (320-380 nm at the rate of 14.2 mW/cm2 x s-1 for 1 h) had a higher 8-MOP concentration (2,834 ng/g at 1 h and 280 ng/g at 24 h).