Pharmacokinetics of acitretin.

Acitretin, the metabolite of etretinate, is eliminated far more rapidly from the human body than is etretinate. It has therefore been suggested that only a short period of contraception would be required following the completion of long-term therapy. However, recent studies have demonstrated the presence of etretinate in the plasma of acitretin-treated patients. In this paper, we review the results of studies at our centre in view of the recently discovered metabolic pathways for acitretin. Re-esterification of acitretin to etretinate, however, results in a loss of the metabolic advantages of acitretin. Because of this new knowledge, the recommended contraception period after acitretin therapy has been lengthened to 2 years.

Skin, adipose tissue and plasma levels of acitretin with rare occurrence of esterified acitretin during long-term treatment.

In a previous study acitretin and its 13-cis-metabolite were monitored in the plasma and epidermis of healthy volunteers. They were given 50 mg of trans-acitretin daily. No drug accumulation was observed in the skin, nor in the plasma. The purpose of the present study was to extend the data from non-psoriatic to psoriatic (n = 11) subjects, treated for at least 1 month with 25 mg acitretin. Plasma, skin biopsies and subcutaneous fat samples were analysed using HPLC. Trough levels of acitretin in skin were below the quantification limit, increasing to 28 +/- 16 ng/g within 5 h after dosing. Fat tissue levels exceeded those of skin, with values of 98 +/- 71 ng/g within 5 h after drug intake. In 2 patients, additional samples were taken 3 days post-therapy. Here, concentrations were below the quantification limit in adipose tissue, confirming that acitretin is not stored in subcutaneous fat. Esterification of acitretin into etretinate was observed in 2 subjects. This observation illustrates the recently described new metabolic pathway for acitretin. On both occasions, the unexpected ethylester metabolite was extensively stored in fat tissue.

An immunohistochemical and histochemical study of cytokeratin, involucrin and transglutaminase in seborrhoeic keratosis.

The mode of differentiation of seborrhoeic keratoses was investigated by immunohistochemical staining using cytokeratin (CK) polypeptide-specific monoclonal antibodies and an antibody specific for the particulate form of epidermal transglutaminase (ETgase), and by applying an anti-human involucrin serum. The role played by (E)Tgase was further evaluated using an activity assay based on the covalent attachment of monodansylcadaverine. Samples of uninvolved epidermis served as reference tissue. CK reactivities suggested that seborrhoeic keratoses is a hyperproliferative disease with an epidermal CK composition. CK5 and CK14 were prominent markers of basal and basaloid keratinocytes, whereas a decrease in staining occurred in advanced maturation stages and areas of terminal keratinization. In contrast, CK1 and CK10 were prominent markers of suprabasaloid differentiation stages and produced complementary stainings to those of CK5 and 14. Generally, CK10 staining was more impressive than CK1 staining and seemed to start before CK1 staining. In contrast to CK10 staining, cornified areas lost CK1 reactivity. These staining patterns were similar to those observed in uninvolved reference tissues. The epidermal CK subset was further supplemented with the 'hyperproliferative' CK6 and 16 which occur sequentially. Positive staining for CK6 was noted from basal and proximal basaloid cells onwards, whereas distal basaloid cells additionally showed CK16 staining. The presence of other non-epidermal CK polypeptides could not be shown. The competence for other differentiation markers belonging to the group of (E)Tgase and cornifying cell membranes also evolved with a typical epidermal pattern. (E)Tgase activity was restricted to advanced and terminal stages of keratinization and was dual in nature, i.e. a diffuse cytoplasmic staining occurred together with a prominent staining of cornifying cell membranes.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacokinetics and drug interactions of etretinate and acitretin.

Acitretin, the metabolite of etretinate, is eliminated far more rapidly from the human body than is etretinate. It had therefore been suggested that only a short period of contraception would be required after the cessation of long-term therapy with acitretin. However, recent studies have demonstrated the presence of etretinate in the plasma of patients who were treated with acitretin. In this article we provide results from a study in our center and discuss earlier data in light of the recently discovered metabolic pathways for acitretin. Reesterification of acitretin to etretinate, however, results in a loss of the metabolic advantages of acitretin. Because of this situation the recommended contraception period after acitretin therapy has been lengthened to 2 years.

The distribution of cis- and trans-acitretin in human epidermis.

The concentrations of trans-acitretin and its principal metabolite, cis-acitretin, were measured by h.p.l.c. after single and multiple dosing (50 mg orally for 13 days) in plasma, blister fluid and epidermal samples from four healthy male volunteers. Within-day epidermal concentrations of trans-acitretin exceeded those of the cis-form which were at the limit of assay sensitivity. No accumulation of trans-acitretin was observed in plasma or blister fluid but AUC values for the drug in blister roof cells tended to be higher after multiple dosing.

Acitretin as cancer chemoprophylaxis in a renal transplant recipient.

The use of acitretin in a renal transplant recipient who had been treated for several premalignant and malignant skin lesions is the subject of this case report. During the treatment period no new dysplastic lesions developed.

Use of topical lithium succinate in the treatment of seborrhoeic dermatitis.

Twenty-one patients with seborrhoeic dermatitis were included in an open trial of lithium succinate ointment (LSO) for a total duration of 8 weeks. The same clinician made assessments of the severity of redness, scaling, greasiness and overall clinical impression of the condition every 2 weeks. Because the results appeared to be satisfactory, we decided to perform a double-blind, placebo-controlled trial of LSO. Thirty patients with seborrhoeic dermatitis were included. The results also demonstrated the beneficial effect of LSO. A significantly higher number of patients treated with LSO showed remission or marked improvement compared with placebo. The main adverse events demonstrated consisted of minor transient skin irritation and/or stinging sensation. Studying the in vivo inhibitory effect of LSO on the growth of Pityrosporum revealed that Pityrosporum did not significantly have its growth inhibited by lithium. Topical lithium succinate appears to be a safe and an effective treatment for seborrhoeic dermatitis. The product presumably acts as an anti-inflammatory agent.

High-performance liquid chromatographic determination of etretinate and all-trans- and 13-cis-acitretin in human plasma.

A high-performance liquid chromatographic procedure is described for the simultaneous determination of etretinate (Tigason), all-trans-acitretin (Neotigason) and 13-cis-acitretin in human plasma. The compounds are extracted from the plasma with n-hexane under acidic conditions. Quantification is performed on a normal-phase column (CP-Spher Si, 5 microns), followed by UV detection at 350 nm. The limit of quantification is 3 ng/ml. The day-to-day precision was 6.7, 13.6 and 9.1% for etretinate (means = 53 ng/ml), all-trans-acitretin (means = 95 ng/ml) and 13-cis-acitretin (means = 149 ng/ml), respectively (n = 13 for each compound). The within-day precision of nine determinations was 3.2, 11.7 and 6.5%, respectively, with mean concentrations of 128.53 and 261 ng/ml, respectively. The method was also applied to the study of the long-term pharmacokinetic behaviour of etretinate in psoriatic patients previously treated with etretinate but now on therapy with all-trans-acitretin.

Keratinization of middle ear cholesteatomas. I. A histochemical study of epidermal transglutaminase.

A histochemical study was performed to determine the involvement of epidermal transglutaminase (ETgase) in the keratinization of middle ear cholesteatomatous lesions, and to compare it with its role in the middle ear mucosa and epidermis. In a first assay, we localized the (E)Tgase activity in situ. A second immunohistochemical assay revealed the distribution of the particulate form of ETgase, which is involved in cross-linked envelope formation. A remarkable difference between strongly keratinized epidermal tissues and the cholesteatoma matrix is the frequent observation in the latter of the remnants of (E)Tgase activity in cytosol, even in advanced stages of differentiation. As a consequence, the cell-membrane-associated ETgase activity, and thus the extent of cross-linking within the envelope, is at a lower level than expected. This aspect is reminiscent of the keratinization phenomenon manifested by thin epidermal tissues. In addition, our findings are the first to show that ETgase is a substantial marker of middle ear mucosa.

An investigation of cytokeratin expression in skin epithelial cysts and some uncommon types of cystic tumours using chain-specific antibodies.

The differentiation state of skin epithelial cysts and some uncommon types of epithelial skin tumours was investigated by immunohistochemical staining, mainly using cytokeratin (CK) polypeptide-specific monoclonal antibodies. Samples of interfollicular epidermis, hair follicles and eccrine sweat glands were included as reference tissues. The CK reactivity in epidermoid cysts and milia is not restricted to CKs involved in epidermal-type differentiation, i.e. CK1, 5, 10 and 14, but in addition CK16, a hyperproliferative keratinocyte marker is suprabasally expressed. CK1 and 10 are other prominent suprabasal markers, while CK14 seems to be preferentially expressed in the basal cell layer. Of the non-epidermal CKs, only CK4 was focally or more extensively detected in about 50% of the cases. In terms of CK reactivity, keratinization of trichilemmal cysts corresponds to the keratinization of the anagen-phase hair follicle in the isthmus. The CK reactivity is again restricted to CK1, 5, 10, 14 and 16. However, the CK1 as well as CK10 reactivity is subject to serious limitations, since both CKs were only convincingly observed in foci of terminal differentiation. Eccrine hydrocystoma obligatorily expresses a complex CK set, including CK7, 8, 14, 18 and 19. This CK set perfectly corresponds to the CK composition observed in acini of eccrine sweat glands. In addition, a discontinuous CK4 and 16 reactivity was seen in about 50% of the sites, while CK1 and 10 displayed a strictly focal appearance. On the other hand, syringoma produces in its distinct structures, a CK pattern reminiscent of the one observed in eccrine sweat gland ducts and includes CK1, 5, 10, 14, 16 and 19.(ABSTRACT TRUNCATED AT 250 WORDS)

A comparative immunohistochemical study of cytokeratin and vimentin expression in middle ear mucosa and cholesteatoma, and in epidermis.

Cytokeratin expression was studied in human middle ear cholesteatoma lesions, using a variety of immunohistological techniques and a wide range of polyclonal antisera and monoclonal antibodies against cytokeratin (CK) subgroups or individual CK polypeptides. The expression of the other cytoskeletal proteins, vimentin and desmin, was also investigated. Middle ear mucosa and epidermal tissues were used as reference tissues. Our investigations also included epithelial structures present in the cholesteatoma perimatrix and in dermal tissues. The results indicate that, compared with epidermal tissues, the expression profile of CKs in cholesteatoma matrix is representative of a hyperproliferative disease. Evaluating the presence of a marker of terminal keratinization - the 56.5 kD acidic CK n degrees 10 - we found supportive evidence of a pronounced retardation of its expression, which did not parallel histological differentiation. In epidermal tissues, the first prickle cell layers are CK10 positive whereas in many cholesteatomas this finding was observed near the stratum granulosum only. Probing the early stages of keratinization - the 58 kD basic CK n degrees 5 and the 50 kD acidic CK n degrees 14 - we regularly observed an extended staining area in the cholesteatoma matrix. In epidermal reference tissues, only the basal and nearest suprabasal layers were convincingly labeled. As a rule, non-epidermal CKs did not belong to the cholesteatoma CK set. However, exceptions to that rule were noticed as a focal or more extended expression of one or more non-epidermal CKs in about half of the cases. Together with the extended CK5 topography, this is further evidence that CK expression is seriously affected by the diseased state. CK expression in the perimatrix is limited to mucous glands, either normal, atrophic or hyperplastic. CKs n degrees 4, 5, 7, 14, 18 and 19, also displayed by middle ear mucosa, were consistently observed. Where ductal arrangements were present, CK10 was also detected, in analogy with the CK10 registration in ductal portions of mucous glands in the external ear canal skin. The absence of CK8 in mucous glands of the perimatrix, however, strongly differentiates these structures from the mucous gland acini and ducti in the external ear canal, where CK8 is systematically expressed. Vimentin staining was restricted to dendritic cells of the matrix (Langerhans cells) and to perimatrix fibroblasts, blood cells and vascular endothelium. Coexpression of CK and vimentin was not observed.

Multiple clear cell acanthomas. A clinical, histological, and ultrastructural report.

A case of multiple clear cell acanthomas in a 64-year-old woman is reported. The clinical and histological findings of this rare entity are consistent with the hypothesis that clear cell acanthomas are benign epidermal tumors. An ultrastructural study was performed with special emphasis on the melanocytic-keratinocytic interaction.

A retrospective study of the inpatient treatment of psoriasis with dithranol.

This study reports the results of the Ingram dithranol regimen for the treatment of psoriasis in 275 inpatients. The median duration of hospitalization until clearance was 25 days and the medians of the interval until a next treatment or hospitalization was needed were 11 and 8.5 months, respectively.