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.

Alteration of skin protein kinase C alpha protein and mRNA levels during induced mouse hair growth.

Protein kinase C (PKC) has been implicated in regulation of hair growth. In this study, the role of PKC alpha in induced mouse hair growth was studied. Hair growth in C57BL6 mice, a well known model for hair growth research, was induced by plucking the telogen hair. PKC alpha protein levels during the induced hair growth cycle were analyzed by Western immunoblot and mRNA levels were measured by RT-PCR. At 1 day and 4 days postdepilation, when the induced hair cycle was in early and midanagen, the PKC alpha protein level was decreased. At 10 days after depilation, when the induced hair cycle was in mature anagen, the PKC alpha protein level was increased. At 17 days after plucking the hair, when the induced hair cycle was in early catagen, PKC alpha protein returned to the control level. PKC alpha mRNA was relatively unchanged at 1 day and 4 days after plucking the hair but significantly elevated at 10 days postdepilation. At 17 days after hair growth induction, PKC alpha mRNA reverted to the control level. These results suggest that: 1) in early and mid anagen of the induced hair growth cycle, PKC alpha was downregulated posttranscriptionally. This downregulation may play a role in the induction of hair growth; 2) in mature anagen of induced hair growth cycle, PKC alpha was overexpressed, and this overexpression may play a part in maintaining the hair growth. Since the expression of PKC alpha was roughly correlated with mouse skin pigmentation, we hypothesize that PKC alpha may regulate hair growth partially through modulation of skin melanogenesis.

Induction of hair growth by skin irritants and its relation to skin protein kinase C isoforms.

Induction of hair growth by skin irritants and its relation to skin protein kinase C (PKC) isoforms were evaluated. Dorsal skin of BALB/c mice was shaved and anthralin (0.1% in corn oil) was applied on one side of the shaved backs in 20 mice daily for 5 days. The corresponding opposite side treated with corn oil served as a control. In another 20 mice, sodium dodecyl sulphate (SDS, 10% in water) was applied on one side of the shaved backs for 5 days by the same procedure as above and the corresponding opposite side treated with water served as control. Visible acceleration of hair growth on anthralin-treated skin was observed as early as 14 days after the application of anthralin and significant hair growth was observed at about 17-20 days. Enhancement of hair growth on SDS-treated skin was observed at about 3 weeks from the beginning of the treatment. None of the mice showed remarkable hair growth on the control side in either group. Mouse skin PKC isoforms levels detected by Western blot showed a similar pattern in both treatment groups. PKC alpha was downregulated initially, and was then elevated from 3 days after anthralin treatment and 14 days after SDS application. PKC beta was unchanged initially, decreased at 8 and 14 days after anthralin and SDS treatment, respectively, and reverted to the control level at 25 days after anthralin treatment, when it was still lower than the control in SDS-treated skin. PKC delta was also unchanged at first, but was elevated from 3 days after anthralin treatment and 14 days after SDS application. These results suggest that involvement of PKC may be a general phenomenon in irritant-induced hair growth in mice. Considering the stimulatory effect of PKC alpha and inhibitory effect of PKC delta on cell growth, we postulate that PKC alpha may be responsible for enhancement of hair growth while PKC delta may inhibit hair growth to keep the hair growth in balance.

The potential role of skin protein kinase C isoforms alpha and delta in mouse hair growth induced by diphencyprone-allergic contact dermatitis.

The levels of protein kinase C (PKC) isoforms alpha and delta in mouse hair growth induced by diphencyprone (DPCP)-allergic contact dermatitis (ACD) were studied. BALB/c mice were sensitized by 2% DPCP in acetone on one side of their shaved backs and rechallenged with 0.1% DPCP on the same side weekly for 2 weeks. The opposite side treated with acetone served as a control. Before each elicitation, mice were shaved again in order to observe the hair growth that followed. Enhancement of hair growth on DPCP treated skin was observed in 94% of mice after first elicitation and significant hair growth was shown in all mice after second elicitation. No remarkable hair growth was seen on the control side. Western immunoblot analysis revealed that the level of skin PKC alpha on the DPCP treated side was decreased at 2 and 4 days after sensitization and returned to the control level after first elicitation. At 5 days after the second elicitation, a higher level of PKC alpha was detected. The level of PKC delta remained at the control level and increased at 5 days after second elicitation. These results suggest that: 1) In the first week after sensitization, PKC alpha was down-regulated. This down-regulation may play a role in DPCP-ACD induced hair growth; 2) after the elicitation, PKC alpha was over-expressed and this over-expression was roughly correlated with the enhancement of mouse hair growth, suggesting that over-expression of PKC alpha may also play a part in the proliferation of hair follicle cells; and 3) overexpression of PKC delta after second elicitation may have an inhibitory effect on hair growth that keeps hair growth in balance.

Pruritic urticarial papules and plaques of pregnancy: clinical and immunopathologic observations in 57 patients.

BACKGROUND: Pruritic urticarial papules and plaques of pregnancy (PUPPP) has been described either as a homogeneous or a polymorphic clinical process. Its cause is unknown. OBJECTIVE: We attempted to characterize the clinical and immunopathologic findings in PUPPP on the basis of long-term clinical and immunopathologic observations. METHODS: The clinical and immunopathologic features of 57 patients with PUPPP were evaluated. RESULTS: The clinical features in 57 patients with PUPPP were categorized into three types: mainly urticarial papules and plaques (type I), nonurticarial erythema, papules, or vesicles (type II), and combinations of the two forms (type III). Direct immunofluorescence studies in 48 of the 57 patients showed nonspecific immunoreactants in dermal blood vessels and/or moderate granular deposits at the dermoepidermal junction in 15 patients. CONCLUSION: Type I PUPPP differed from types II and III in clinical appearance and distribution (absence of face, palm, and sole lesions), but trimester onset, parity, and direct immunofluorescence findings were not significantly different among the three groups.

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.

Protein kinase C isoform levels in normal and sodium dodecyl sulphate-irritated mouse skin.

Protein kinase C (PKC) comprises a family of related phospholipid-dependent serine/threonine protein kinases. PKC is important in signal transduction, regulating cell proliferation and differentiation. Recently, it has also been suggested that PKC may play a part in the pathogenesis of contact dermatitis. However, the expression of PKC isoforms in the skin of mice with irritant contact dermatitis (ICD) has not been examined. In this study, ICD was induced in mouse skin by applying 5%, 10% and 20% sodium dodecyl sulphate (SDS) in Finn chambers on the backs of mice and fixing with surgical dressings for 24 h. Depending upon the SDS concentration, mild to strong skin irritant reactions were observed 24 h after removal of the irritant patches. The intensity of the reactions increased with the increasing concentration of SDS. PKC isoforms alpha, beta, gamma and delta were all detected in normal mouse skin by Western immunoblotting. The specificity of the PKC isoforms detected was identified further by competitive Western immunoblotting. Compared with normal mouse skin treated with double-distilled water, the levels of PKC isoforms alpha, beta, gamma and delta in the SDS-irritated mouse skin was decreased by 24.8-75.8%. These results suggest that, in SDS-ICD, mouse skin PKC isoforms alpha, beta, gamma and delta are down-regulated. The significance of this decrease is under further investigation.

Down-regulation of protein kinase C isoforms in irritant contact dermatitis.

Protein kinase C (PKC) isoforms are important in cell signal transduction associated with regulation of cell proliferation and differentiation. In this study, alterations of PKC isoform levels in irritant patch test reactions were detected by Western immunoblots. 4 chemically and structurally different irritants, 4% and 8% hydrochloric acid (HCl); 1% and 2% sodium hydroxide (NaOH); 20% and 40% nonanoic acid (NON) in 1-propanol; and 5% and 10% sodium dodecyl sulfate (SDS) were applied on the backs of mice in Finn Chambers and fixed with surgical dressings. The patches were kept on the skin for 24 h and removed. 24 h after removal, mild erythema with thickening of skin without vesicles was observed in all irritated skin, except that 4% HCl and 1% NaOH treated skin showed unremarkable skin reaction. No visible skin reaction was detected in vehicle-treated skin. PKC isoform alpha, beta, gamma, and delta levels in irritated skin revealed a 10% to 65% decrease compared to vehicle treated skin. These results indicate that in HCl, NaOH, NON and SDS-induced irritation, activation of the PKC related cell signal transduction cascade may be involved, and that PKC mediated events may be a common phenomenon in irritant contact dermatitis.

Tacrolimus (FK506) ointment for atopic dermatitis: a phase I study in adults and children.

BACKGROUND: Tacrolimus is a potent immunosuppressant used in organ transplant recipients; an ointment formulation is being developed as a therapeutic agent for atopic dermatitis. OBJECTIVE: Our purpose was to define the pharmacokinetics and evaluate tacrolimus 0.3% ointment as therapy for moderate to severe atopic dermatitis. METHODS: Thirty-nine patients, 5 to 75 years of age, received 14 applications over 8 days. Serial blood samples were collected on days 1 and 8, with predose samples collected on days 2 through 7. Overall response and signs/symptoms were rated daily on days 1 through 11. Incidence of adverse events and laboratory profile were determined. RESULTS: Mean area under the curve (0.9 to 42.5 ng x hr/ml) was highly variable and appeared to be related to size of application area. No systemic accumulation of tacrolimus was observed. Comparison to historical intravenous data indicates that absolute bioavailability of topical tacrolimus was less than 0.5%. Ninety-five percent of patients showed at least good improvement. All adverse events were transient. Burning was the most common application site adverse event and vasodilatation ("flushing/warmth") was the most common nonapplication site adverse event. No drug-related changes in laboratory profile were observed. CONCLUSION: The results of this study suggest that tacrolimus 0.3% ointment may be a safe and effective therapy for atopic dermatitis.

Treatment of alopecia areata.

Some individuals question whether any treatment is effective in severe alopecia areata. Certainly many patients, especially those with mild disease, experience spontaneous hair regrowth; however, results of double-blind studies clearly indicate that some treatments do promote hair regrowth even in those with extensive disease. Some patients never show either spontaneous or treatment-related hair regrowth; others experience hair regrowth only while maintained on treatment, repeatedly losing hair within a few weeks of discontinuing treatment and regrowing it within several weeks after restarting treatment. Some patients who have been responsive to treatment may experience exacerbation of their disease such that even high-dose systemic steroids do not prevent the development of alopecia universalis. Some treatments appear to work on some patients some or all of the time, but no treatment appears to work on all patients all of the time. We would suggest a few practical points that we find useful: To maximize the potential for cosmetic hair growth in alopecia areata that is extensive or flaring, treat the entire scalp instead of "chasing" patches. Do not change any topical treatment sooner than 3 months after starting it; early regrowth may first be present at 3 months. Cosmetic regrowth may take a year or more to achieve. Maintenance treatment increases the likelihood of maintenance of cosmetic hair growth, but patches of hair loss may still come and go. Atopic patients who experience seasonal hair loss may benefit (ie, have less severe hair loss flares or respond more readily to topical therapy) by using an antihistamine or mast cell stabilizer prophylactically. Whether one looks at the therapeutic cup as half full or half empty, most patients urge us to continue to try to find safe, effective long-term treatments for this disease.

Alopecia areata. A review of therapy, efficacy, safety, and mechanism.

Although it is clear from the foregoing that some of the drugs and chemicals used to treat severe alopecia areata are efficacious to some degree, it is impossible to draw any meaningful comparisons among the data outlined in Tables 1 and 2. Virtually all of the studies were designed differently. Differences in chronicity and extent of disease as well as history of previous treatment resistance may significantly affect efficacy data even as two investigators compare the same drug. Drug-induced hair regrowth in alopecia areata may be very slow; a cosmetic response may take 1 to 2 years to achieve. Efficacy determinations made at shorter intervals may, therefore, not reflect true therapeutic potential. Efficacy end points vary significantly and need to be standardized. From a practical standpoint, scalp hair coverage that is deemed by the patient to be cosmetically acceptable seems to be a reasonable efficacy end point to report. Maintenance of cosmetic effect with continued treatment and/or following discontinuation of treatment also is useful to document. Table 3 outlines my approach to therapy of alopecia areata. Topical treatments often must be used for as long as 3 months before evidence of regrowth can be seen. In my experience with severe disease, if topical treatments cannot control a flare or induce regrowth, then the patient will often require either lengthy or frequent courses of systemic steroids. In my experience, prednisone doses as low as 20 mg/d may be associated with aseptic neurosis of the hip or severe gastrointestinal bleeding. Severe alopecia areata is a disease for which all therapies are, at best, palliative and, at worst, potentially harmful to patients who are usually otherwise very healthy. The psychosocial significance of this disease is enormous. The insights shared by a long-time sufferer of the disease mirror those expressed by the many patients with whom I have worked during the past 12 years. Three key elements to effectively treat the patient are (1) to help the patient understand the disease; (2) to encourage the patient to share his or her feelings with the physician, family, friends, and other sufferers of the disease; and (3) to help the patient to maintain a sense of hope for future scientific knowledge and treatment of the disease. With a thorough knowledge of the potential benefits and risks of each treatment or combination treatment, the physician with the patient's understanding and cooperation may then embark on what may be in severe cases a lengthy and sometimes unproductive therapeutic process.

HLA-D locus associations in alopecia areata. DRw52a may confer disease resistance.

Because predisposition to autoimmunity has been associated with HLA-D alleles and alopecia areata is hypothesized to be a T-cell mediated autoimmune hair loss, we determined DR and DQ alleles in 88 white and 10 American black patients with alopecia areata as well as controls with the use of restriction fragment length polymorphism typing with cDNA probes. White patients with alopecia areata have an increase in the phenotype frequencies of DR4 and DQw8 and an increase in genotype frequencies of DR4 and DR5 (now DRw11[5]). These associations are in agreement with those reported in two other studies but are not significant when corrected by the number of HLA antigens tested. Sixty-one percent of all patients with AA have DR4 and/or DRw11(5) specificities vs 40% of controls, with more DR4,DRw11(5) and DQw7(w3), DQw8(w3) heterozygotes among patients. DQw6(w1) phenotype frequencies and DRw52a phenotype and genotype frequencies are significantly decreased in patients with alopecia areata relative to controls. This highly significant negative association with the HLA DRB3 allele DRw52a in whites persisted even when DR4- or DRw11(5)-positive individuals were excluded from the patient and control groups. These data suggest that HLA-DR4 and DRw11(5) with their associated DQw7(w3) and DQw8(w3) specificities may confer susceptibility to alopecia areata, while DRw52a may confer resistance.

Treatment-resistant alopecia areata. Response to combination therapy with minoxidil plus anthralin.

Combination therapy with 5% minoxidil plus 0.5% anthralin was used to treat 51 patients with severe treatment-resistant alopecia areata. History of a cosmetically inadequate response to one or both drugs used as a single agent was present in 50 of the 51 patients. Therapy was relatively well tolerated except by 1 patient who developed a severe irritant reaction and was dropped from the study. Mild to moderate irritant dermatitis was seen in all remaining patients. Cosmetic response was seen in 5 (11%) of 45 patients who completed the 6-month study. Cosmetic response was maintained in 4 (80%) of 5 patients who continued treatment for as long as 84 weeks. All responders had evidence of hair regrowth by week 12. The rapidity and extent of hair regrowth were greater with combination therapy than with either drug used as a single agent. Serum and 24-hour urinary minoxidil determinations showed enhanced systemic minoxidil absorption, which was probably secondary to the irritant dermatitis in some patients; however, no clinical evidence of a systemic minoxidil effect was found. These data suggest that combination therapy using drugs with probable different mechanisms of action may provide a synergistic effect in alopecia areata.

Altered theophylline metabolism in patients with psoriasis.

We observed two patients on theophylline therapy with concomitant severe psoriasis and a two- to threefold greater theophylline clearance than that reported in healthy, nonsmoking adults. There were no factors known to induce theophylline clearance. In both cases, the induction of theophylline metabolism was relatively selective for the 1-methyluric acid pathway. The altered metabolism in these patients appeared to correlate with the clinical severity of the disease. The data suggest the possibility that an observed lack of efficacy for theophylline in psoriasis may be related to pharmacokinetic effects. The concept that altered drug metabolism may occur in the presence of skin disease has important implications for pharmacotherapeutics in dermatology.

Interaction of phospholipids, retinoids and PMA with calcium, phospholipid-dependent protein kinase-catalyzed reaction in skin.

Previous investigations suggested that a mechanism independent of cAMP may be associated with the action of some retinoids. An alternative pathway involving calcium, phospholipid-dependent protein kinase (C-kinase), was therefore studied. In order to demonstrate this, C-kinase was partially purified from skin of hairless, Balb/c normal and Balb/c nude mouse. Interaction and effects of various response modifiers such as phospholipids, retinoids and phorbol ester tumor promoters showed both major and minor differences among these enzymes. In general, retinal, retinoic acid, 13-cis-retinoic acid and etretinate stimulated skin enzyme activity in the absence of the natural stimulants, phosphatidyl serine and diacylglycerol (DAG). However in their presence the C-kinases were inhibited by retinoids. Our data further indicated that the active retinoids may compete with DAG for binding sites on the enzyme. However, the high concentrations of retinoids needed to elicit these effects suggested a pharmacological role for retinoid action as a result of hydrophobic interaction with lipid domains on the enzyme. These investigations also revealed some of the complexity associated with retinoid effects on C-kinase. Tumor promoter, phorbol-12-myristate 13-acetate (PMA) interacted with its receptor (C-kinase) from hairless and normal mouse skin and stimulated enzyme activity. However, PMA-dependent stimulation of nude mouse C-kinase was about half of that noted with the other two C-kinases. Furthermore, unlike its effect on hairless and Balb/c normal C-kinases, PMA was unable to potentiate the retinoid-stimulated activity of nude mouse skin enzyme. This behavior suggested that nude mouse C-kinase may be a variant form of the normal enzyme. The presence of this variant C-kinase may, therefore, be responsible for the lack of phorbol ester-induced tumor promotion observed earlier in nude mouse skin by other investigators. Endogenous substrate phosphorylation catalyzed by C-kinase from hairless and Balb/c normal mice resulted in 32P incorporation into four target polypeptides of molecular weights 75-78, 47-50, 25-29 and 14-18 kilodaltons. However, with the nude mouse enzyme, only the 75- to 78-kilodalton protein served as the target supporting the suggestion that this may be a variant C-kinase. Neither retinoic acid (10(-3) M) nor PMA (10(-6) M) seemed to affect the phosphorylation of any of the four polypeptides.(ABSTRACT TRUNCATED AT 400 WORDS)

Immunohistochemical characterization of the cellular infiltrate in severe alopecia areata before and after minoxidil treatment.

The mechanism of minoxidil-induced hair regrowth in alopecia areata (AA) is unknown. In vitro studies suggest that pharmacologic tissue levels of minoxidil may have both epithelial and T cell effects. Response in 36 of 47 patients with severe AA to topical minoxidil 5% b.i.d. was characterized by a return toward normal of hair follicle diameter, depth and structure, and an apparent shift in T cell populations from the skin into the peripheral blood. Nonresponders showed none of these changes. Biopsies from 34 patients subsequently treated with oral minoxidil 5 mg q. 12 h showed no further changes in perifollicular total T, helper-inducer T or suppressor-cytotoxic T cell counts; they did, however, demonstrate significant decreases in perifollicular Langerhans cell and activated T cell counts, and nearly significant decreases in perifollicular monocyte counts. It is possible that minoxidil may be altering a presumed follicular chemoattractive stimulus to a variety of cell types. Decreases in activated T cell counts suggest the possibility of direct immunomodulatory effects of minoxidil on T cells which might contribute to a hair regrowth response in AA.