Virginia C. Fiedler

The effects of finasteride on scalp skin and serum androgen levels in men with androgenetic alopecia

BACKGROUND Data suggest that androgenetic alopecia is a process dependent on dihydrotestosterone (DHT) and type 2 5alpha-reductase. Finasteride is a type 2 5alpha-reductase inhibitor that has been shown to slow further hair loss and improve hair growth in men with androgenetic alopecia. OBJECTIVE We attempted to determine the effect of finasteride on scalp skin and serum androgens. METHODS Men with androgenetic alopecia (N = 249) underwent scalp biopsies before and after receiving 0.01, 0.05, 0.2, 1, or 5 mg daily of finasteride or placebo for 42 days. RESULTS Scalp skin DHT levels declined significantly by 13.0% with placebo and by 14.9%, 61.6%, 56. 5%, 64.1%, and 69.4% with 0.01, 0.05, 0.2, 1, and 5 mg doses of finasteride, respectively. Serum DHT levels declined significantly (P <.001) by 49.5%, 68.6%, 71.4%, and 72.2% in the 0.05, 0.2, 1, and 5 mg finasteride treatment groups, respectively. CONCLUSION In this study, doses of finasteride as low as 0.2 mg per day maximally decreased both scalp skin and serum DHT levels. These data support the rationale used to conduct clinical trials in men with male pattern hair loss at doses of finasteride between 0.2 and 5 mg.

Clinical dose ranging studies with finasteride, a type 2 5α-reductase inhibitor, in men with male pattern hair loss

BACKGROUND Androgenetic alopecia is a common condition of adult men. Finasteride, a type 2 5alpha-reductase inhibitor, decreases the formation of dihydrotestosterone from testosterone. OBJECTIVE Two separate clinical studies were conducted to establish the optimal dose of finasteride in men with this condition. METHODS Men from 18 to 36 years of age with moderate vertex male pattern hair loss received finasteride 5, 1, 0.2, or 0.01 mg/day or placebo based on random assignment. Efficacy was determined by scalp hair counts, patient self-assessment, investigator assessment, and assessment of clinical photographs. Safety was assessed by clinical and laboratory measurements and by analysis of adverse experiences. RESULTS Efficacy was demonstrated for all end points for finasteride at doses of 0.2 mg/day or higher, with 1 and 5 mg demonstrating similar efficacy that was superior to lower doses. Efficacy of the 0.01 mg dose was similar to placebo. No significant safety issues were identified in the trials. CONCLUSION Finasteride 1 mg/day is the optimal dose for the treatment of men with male pattern hair loss and was subsequently identified for further clinical development.

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.

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.

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 α and δ 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 rechal‐lenged 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 α 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 α was detected. The level of PKC δ 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 α was down‐regulated. This down‐regulation may play a role in DPCP‐ACD induced hair growth; 2) after the elicitation, PKC α was over‐expressed and this over‐expression was roughly correlated with the enhancement of mouse hair growth, suggesting that over‐expression of PKC δ may also play a part in the proliferation of hair follicle cells; and 3) over‐expression of PKC δ after second elicitation may have an inhibitory effect on hair growth that keeps hair growth in balance.

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 α, β, γ, and δ 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.

Alteration of Skin Protein Kinase C α 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 α 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 α 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 α protein level was decreased. At 10 days after depilation, when the induced hair cycle was in mature anagen, the PKC α protein level was increased. At 17 days after plucking the hair, when the induced hair cycle was in early catagen, PKC α protein returned to the control level. PKC α 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 α mRNA reverted to the control level. These results suggest that: 1) in early and mid anagen of the induced hair growth cycle, PKC α 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 α was overexpressed, and this overexpression may play a part in maintaining the hair growth. Since the expression of PKC α was roughy correlated with mouse skin pigmentation, we hypothesize that PKC α may regulate hair growth partially through modulation of skin melanogenesis.

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)

Diseases of the Hair and Scalp

Diseases of the Hair and Scalp is an excellent, comprehensive, well-referenced, updated text that covers the biology and clinical assessment of normal and abnormal hair growth. The first two chapters provide a good overview of the embryology, physiology, structure, and function of the hair follicle. Clinically relevant physical properties of the hair shaft are clearly presented as well. Normal and abnormal body hair growth in children through the age of puberty is well discussed and nicely illustrated in chapters 3,6, and 7. Androgenetic alopecia, hirsutism, and various other endocrinologic, metabolic, and chemical causes of alopecia are well explained and categorized. Other topics include traumatic alopecia, alopecia areata, cicatricial alopecia, hair color, infections and infestations, psychological factors, hair cosmetics, nevi, tumors, and cysts. Discussions of systemic, skin, and scalp diseases affecting hair growth are very useful. The last chapter provides relevant techniques for evaluation of the patient complaining of hair loss. This book is not only comprehensive but also well-indexed and well-organized so that the reader with a specific question can rapidly

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.