Dermal absorption of permethrin following topical administration.

OBJECTIVE: Permethrin is an insecticide used in the treatment of lice and scabies infections. Although its efficacy and safety have been well documented, pharmacokinetic data are sparse. The objective of this study was to determine the systemic exposure of permethrin and the duration of residence in the human body following topical administration. METHODS: The study consisted of three parts. In six young healthy men (part 1), 50 ml of an ethanolic solution containing 215 mg permethrin (cis/trans: 25/75) was administered to the hair of the head. In another six young healthy men (part 2) and in six male or female scabies patients (part 3), 60 g of cream containing 3 g permethrin was administered to the skin of the whole body. Urine was collected up to 168 h post-dose. Urinary excretion of the main metabolite of permethrin, 3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropane carboxylic acid, and its conjugates was measured using a gas chromatography/electron capture detection method. RESULTS: Pharmacokinetics were similar in all study parts. The time of maximal urinary excretion rate was 12.3, 20.0 and 14.6 h, terminal elimination half-life was 32.7, 28.8 and 37.8 h and urinary recovery of the metabolite reached 0.35, 0.47 and 0.52 M percent of the permethrin dose, respectively, in parts 1, 2 and 3 (means). The treatment was well tolerated. CONCLUSIONS: The extent of systemic exposure following external therapeutic administration of permethrin is very low compared with doses used for preclinical toxicity studies, and elimination is virtually complete after 1 week. These data provide the pharmacokinetic basis for the clinical safety of topical permethrin.

[Multiple autoimmune syndrome. Reynolds-syndrome (acral scleroderma, primary biliary cirrhosis, Sjögren syndrome) associated with the lupus erythematosus/lichen planus overlap syndrome]. / Multiples Autoimmunsyndrom. Assoziation eines Reynolds-Syndroms (akrale Sklerodermie, primär biliäre Zirrhose, Sjögren-Syndrom) mit einem Lupus erythematodes/Lichen-ruber-planus-Overlap-Syndrom.

A female patient presented with acral scleroderma, Sjögren syndrome, antibodies specific for primary biliary cirrhosis and clinical as well as histological features of lichen planus and subacute lupus erythematosus. In addition an euthyroid Hashimoto thyroiditis was found. Her findings correspond to type II of the multiple autoimmune syndrome (MAS) and can be described as an association of Reynolds syndrome and the lupus erythematosus/lichen planus-overlap syndrome.

Cyclosporine in severe psoriasis. Results of a meta-analysis in 579 patients.

OBJECTIVE: A meta-analysis of 3 major German studies conducted between 1989 and 1994 with cyclosporine in severe psoriasis was performed to allow an integrated evaluation of the efficacy and tolerability of cyclosporine in this indication. DESIGN AND SETTING: All 3 studies were prospective, randomized, parallel group studies. The studies were conducted in 61 dermatologic centers in Germany. PATIENTS AND INTERVENTIONS: The studies involved 597 patients with severe plaque type psoriasis. Treatment consisted of cyclosporine (at a dosage of 1.25, 2.5 or 5 mg/kg/day), etretinate (at a mean daily dose of 0.53 mg/kg/day) or placebo in a total of 756 treatment cycles with a maximum duration of 12 weeks. MAIN OUTCOME MEASURES: The main outcome measures were the psoriasis area and severity index (PASI) and serum creatinine level. RESULTS: The meta-analysis revealed that cyclosporine given in a dosage of 2.5 and 5 mg/kg/day was significantly superior to etretinate. In addition cyclosporine 1.25 mg/kg/day proved to be significantly more effective than placebo. An increase in serum creatinine level that required intervention occurred in 3.4% of cyclosporine treatment cycles. CONCLUSION: Cyclosporine is highly effective and well tolerated in the short term treatment of severe psoriasis.

Enhancement of the antiparakeratotic potency of calcitriol and tacalcitol in liposomal preparations in the mouse tail test.

In order to test the advantage of vitamin D(3) preparations in liposomal form, calcitriol, the natural activated form of vitamin D(3), and tacalcitol, a vitamin D(3) analogue, were employed in various concentrations and using different vehicles in the mouse tail test, an animal model for testing the antiparakeratotic efficacy of topical medications. The optimal concentration in petrolatum turned out to be similar to that in commercial preparations. The liposomal preparations were superior to those in petrolatum and to those in nonliposomal phospholipids. The antiparakeratotic potency (drug activity) of liposomal tacalcitol in a concentration of 2 microg/g was twice that of the commercial preparation with a higher concentration of 4 microg/g. These results suggest that the use of liposomal vitamin D(3) preparations can achieve a given antipsoriatic effect with a reduced concentration of the active substance thereby reducing the risk of skin irritation and of hypercalcemia.

The antipsoriatic dimethyl-fumarate suppresses interferon-gamma -induced ICAM-1 and HLA-DR expression on hyperproliferative keratinocytes. Quantification by a culture plate-directed APAAP-ELISA technique.

The derivatives of fumaric acid show antipsoriatic effects but details of the mechanism of action are largely unknown. The study focused on the effect of fumaric acid, dimethyl-fumarate, Zn-, Ca- and Mg-monoethyl-fumarate on the interferon-gamma (IFN-gamma)-induced expression of ICAM-1 and HLA-DR molecules on keratinocytes. Human hyperproliferative keratinocytes of the HaCaT cell line were exposed to IFN-gamma (10 U/ml) alone or in combination with fumaric acid and its derivatives for 48 hrs. The effect of fumarates was investigated semiquantitatively using the alkaline phosphatase-anti-alkaline phosphatase (APAAP) method. Subsequently, the effect of dimethyl-fumarate, the main component of "fumaric acid therapy", was evaluated quantitatively by means of an APAAP-ELISA technique. The semiquantitative evaluation revealed that in the micromolar dose range investigated only dimethyl-fumarate demonstrated substantial growth inhibition and down-regulation of the cell surface markers. In the quantitative evaluation, dimethyl-fumarate significantly (p

Anti-inflammatory efficacy of low-dose cyclosporin A in psoriatic arthritis. A prospective multicentre study.

Fifty-five patients with psoriatic arthritis were treated with a low dose of cyclosporin A (CyA) (mean dose 2.7 mg/kg per day) for a period of 6 months to investigate the efficacy of CyA on disease parameters. Significant improvement in the joint complaints and inflammation parameters was observed including a decrease in the number of painful (-46%) and swollen (-45%) joints, tenderness (Ritchie Index: -50%) and degree of swelling (-46%), patient's assessment of pain (-35%), the duration of morning joint stiffness (-37%), as well as a decrease in C-reactive protein (-52%). A 50% reduction of joint complaints required a total of 24 weeks, whereas a 50% reduction of skin involvement was achieved after 5-6 weeks of treatment. Four patients left the study due to adverse events: creatinine level increase in two patients, hypertension in one patient and gastroenteritis in the fourth patient. Joint scintigraphy in 18 patients indicated an improvement or stable condition in 61% of cases after a mean follow-up of approximately 8 months. The results of this prospective study show that low-dose CyA effectively improves not only skin lesions, but also joint complaints in psoriatic arthritis.

Soluble Pityrosporum-derived chemoattractant for polymorphonuclear leukocytes of psoriatic patients.

The chemoattraction of polymorphonuclear leukocytes (PMNs) from psoriatic patients, atopic patients and healthy control persons by Pityrosporum orbicularelovale was investigated using the Boyden chamber method. The chemotactical attraction of PMNs from psoriatic patients by Pityrosporum (stimulation index SI = 58 +/- 50) was significantly increased (p < 0.05) compared to PMNs from atopic patients (SI = 20 +/- 17) and control persons (SI = 26 +/- 24). This effect seems to be specific for Pityrosporum, since the chemotactical response to Staphylococcus epidermidis was not increased in psoriasis. The chemotactical factor produced by Pityrosporum is hydrophilic and is destroyed by acid hydrolysis, indicating its protein nature. The yeast Pityrosporum may thus play a role in the koebnerization of psoriasis.

Effect of fumaric acid, its dimethylester, and topical antipsoriatic drugs on epidermal differentiation in the mouse tail model.

Fumaric acid, fumaric acid dimethylester, and the dithranol derivative C4-lactone were studied in the mouse tail test to evaluate their effects on epidermal cell differentiation compared with other topical antipsoriatic drugs, such as betamethasone, calcipotriol, and dithranol. Mouse tails were treated for 2 weeks and longitudinal histological sections prepared of the tail skin. The length of the orthokeratotic regions (stratum granulosum) was measured on 10 sequential scales per tail and expressed as percentage of the full length of the scale. In addition, epidermal thickness was measured and the efficacy of the various compounds evaluated. In comparison to 2% salicylic acid ointment, all tested compounds except fumaric acid significantly (p < or = 0.05) increased the proportion of the orthokeratotic region. C4-lactone and calcipotriol were less effective than dithranol, fumaric acid dimethylester only moderately influenced cell differentiation, and betamethasone showed the least potent effect. Dithranol was the most potent substance inducing orthokeratosis without increasing epidermal thickness.

Human keratinocyte culture from the peritonsillar mucosa.

Tonsillectomy tissue can be used as a routine source for cultures of oropharyngeal keratinocytes. In so doing, a peritonsillar strip of unaltered mucosa was dissected in the upper submucosa. Subsequent trypsinization yielded 7.0 +/- 3.4 x 10(6) keratinocytes per bilateral tonsillectomy. Keratinocyte attachment and growth in primary culture were promoted by sublethally irradiated 3T3 murine fibroblasts. Three subcultures could be performed without a feeder layer and were characterized by a population doubling time of 4.5 days during log growth phase. Electrophoretic and immunoblot analysis of the third subculture revealed a strong expression of keratin pairs 5/14 and 6/16 as well as keratins 7 and 19, whereas keratins 8/18 were expressed less intensely. The lowest intensity, was found for keratin 13, which is known to be indicative of the differentiated mucosa. The culture technique thus provides an easily available in vitro model for morphological and functional studies on the epithelial compartment of human oropharyngeal mucosa.

Immunologically confirmed disseminated, asymptomatic Encephalitozoon cuniculi infection of the gastrointestinal tract in a patient with AIDS.

Microsporidia are obligate intracellular protozoan parasites that infect a broad range of vertebrates and invertebrates. They are increasingly recognized as human pathogens, especially in patients infected with human immunodeficiency virus (HIV). Organisms of the genus Encephalitozoon have been implicated as a major cause of disseminated microsporidian infections in persons with AIDS. Until recently, E. hellem was the only Encephalitozoon species confirmed by antigenic or nucleic acid methods to have infected humans. We describe the clinical course and morphological features of a case of disseminated microsporidian infection with Encephalitozoon cuniculi in an HIV-infected patient with chronic sinusitis, rhinitis, and keratoconjunctivitis. Parasites were found in conjunctival swab, nasal discharge, sputum, urine, stool, and duodenal biopsy specimens, but no pulmonary, renal, or gastrointestinal symptoms were documented. The patient was treated with albendazole (400 mg po b.i.d.), resulting in complete remission of his ocular and nasal symptoms, and microsporidian spores disappeared from all sites. To our knowledge, this case is only the second of E. cuniculi infection in humans that has been confirmed by either antibody- or nucleic acid-based methods, and it is the first in which an Encephalitozoon species has been found in the intestinal tract of a human. Microsporidiosis is an important emerging opportunistic infection in HIV-infected patients and, as documented in this report, has an expanding clinicopathologic spectrum.

Intestinal microsporidiosis with Septata intestinalis in a patient with AIDS--response to albendazole.

Microsporidiosis is a common finding in HIV-infected patients who have diarrhoea. The species most commonly causing gastrointestinal disease is Enterocytozoon bieneusi. Recently Septata intestinalis has been described as a cause of diarrhoea and disseminated infection in patients with AIDS. A 44-year-old homosexual man with severe immunodeficiency (CD4 cell count 40/microliters) had a history of watery diarrhoea for 2 weeks. Microsporidian spores measuring 1.2 to 1.5 x 2.5 to 3.0 microns were found in stool samples. Electron microscopy of duodenal biopsies confirmed the diagnosis of intestinal microsporidiosis and showed parasitophorous vacuoles with the typical ultrastructure of S. intestinalis. The patient was treated with albendazole (400 mg twice daily) and became asymptomatic within 4 days. No spores could be detected in stool samples after a treatment period of 14 days. About 25 infections with S. intestinalis have been reported to date, and the case presented here is the first in a German patient.

Tissue diagnosis of intestinal microsporidiosis using a fluorescent stain with Uvitex 2B.

AIMS: To detect intestinal microsporidiosis in paraffin wax embedded biopsy specimens using a fluorescence technique incorporating optical brighteners. METHODS: Eight HIV infected patients with confirmed intestinal microsporidiosis (six with Enterocytozoon bieneusi, one with Encephalitozoon intestinalis and one with Encephalitozoon cuniculi infection) and 10 without infection were studied. Tissue sections of paraffin wax embedded duodenal biopsy specimens were stained with 1% Uvitex 2B, coded and analysed independently by two investigators. RESULTS: In all eight cases with confirmed intestinal microsporidian infection, spores could be detected easily in tissue sections using the fluorescence technique. Spores or other elements consistent with microsporidiosis were not found in the 10 patients without infection. CONCLUSION: Staining of tissue sections from paraffin wax embedded intestinal biopsy specimens with stains incorporating Uvitex 2B is a rapid and easy technique for the diagnosis of intestinal microsporidiosis.

Efficacy and tolerability of multiple-dose SDZ IMM 125 in patients with severe psoriasis.

Although cyclosporin is effective in immunosuppression following organ transplantation and in the treatment of psoriasis, its use is limited by its side-effects, notably impaired renal function and hypertension. As SDZ IMM 125, a new derivative of the cyclosporin family, showed considerable immunosuppressive activity in experimental studies, with less effect on renal function, it was considered a potential successor to cyclosporin for both indications. In this multicentre, double-blind, placebo-controlled study, the efficacy and tolerability of 40, 100, 200 and 400 mg SDZ IMM 125 daily were studied in 59 patients with psoriasis. Patients were followed for a period of 5 weeks (4 weeks treatment, and 1 week post-treatment observation). A dose-dependent effect of SDZ IMM 125 was observed. A significant correlation was found between the dose of SDZ IMM 125 and changes in the sum of severity scores of three indicator plaques. There was a significant decrease in the body surface area affected by psoriasis in the 400-mg group (P < or = 0.01), whereas a decrease of the global psoriasis severity was observed in the 200-mg (P < or = 0.01) and the 400-mg groups (P < or = 0.001). No serious adverse events occurred during the 4 weeks of treatment. Three patients discontinued treatment because of adverse events (one sore throat, two influenza). Clinical adverse events were similar to those reported with cyclosporin, the most frequent being gastrointestinal disturbances. Estimation of renal function indices showed that increases from baseline values were dose-dependent, and appeared to be similar to those seen with cyclosporin.(ABSTRACT TRUNCATED AT 250 WORDS)

Up-regulation of keratin 17 expression in human HaCaT keratinocytes by interferon-gamma.

The immortalized human keratinocyte cell line HaCaT was used to assess the effect of interferon-gamma (IFN-gamma) on expression of keratin K17. Both IFN-gamma and K17 have been implicated in the pathophysiology of psoriasis. Western and quantitative enzyme-linked immunosorbent assay analyses demonstrated increasing induction of K17 protein by 48 h exposure to IFN-gamma at concentrations of 10, 50, and 250 U/ml. At 50 U/ml IFN-gamma, immunohistochemical analysis revealed numerous K17-positive foci, whereas in situ hybridization demonstrated K17 message in the majority of cells. In addition, at low (5 U/ml) concentrations of IFN-gamma, cell proliferation and protein synthesis decreased, as determined by 3H-thymidine labeling and 14C-amino acid uptake. These data suggest that aberrant K17 expression observed in psoriatic lesions may be a consequence of IFN-gamma overexpression, and that the HaCaT cell line may be a useful in vitro model system to elucidate the underlying mechanisms.

Low-dose short-term cyclosporine versus etretinate in psoriasis: improvement of skin, nail, and joint involvement.

BACKGROUND: High-dose cyclosporine therapy significantly alleviates psoriasis within 2 to 4 weeks but is associated with a high rate of side effects. Reports are conflicting on the frequency and promptness of relapse after discontinuation of cyclosporine therapy. OBJECTIVE: Our purpose was to compare the efficacy and safety of low-dose cyclosporine with that of etretinate and the stability of remission after replacing cyclosporine therapy with topical anthralin during tapering of cyclosporine. METHODS: In a multicenter study 210 patients with moderate to severe chronic plaque-type psoriasis were randomly assigned to treatment with cyclosporine or etretinate. The initial dosages were 2.5 mg/kg/day for cyclosporine and 0.5 mg/kg/day for etretinate, which could be individually adjusted to 5.0 and 0.75 mg/kg/day, respectively. After a treatment phase of 10 weeks (phase 1) patients receiving cyclosporine were again randomly assigned to a group in which cyclosporine was replaced by topical dithranol (anthralin), or to another group in which the drug was tapered during the next 12 weeks (phase 2). All patients treated with etretinate discontinued therapy after 10 weeks and used topical dithranol. RESULTS: Mean Psoriasis Area and Severity Index decreased by 71% in the cyclosporine group and by 47% in the etretinate group during phase 1. After 10 weeks of treatment 47% of the patients treated with cyclosporine and 10% of those treated with etretinate showed a reduction of more than 80% in skin involvement. Sixty-four percent of the cyclosporine group and 48% of the etretinate group did not require an increase in the initial dosage, resulting in a mean daily dose of 3.0 and 0.53 mg/kg, respectively. There was significant alleviation of nail involvement and joint complaints in both groups. In phase 2 the increase in mean Psoriasis Area and Severity Index and the incidence of relapse were significantly higher in patients in whom cyclosporine was discontinued and replaced by dithranol than in patients in whom cyclosporine was tapered or who were pretreated with etretinate. During treatment four patients from the cyclosporine group and three patients of the etretinate group discontinued the study because of side effects. CONCLUSION: Low-dose short-term cyclosporine therapy for psoriasis is, in comparison with etretinate, highly effective and well tolerated. Individually adjusted cyclosporine therapy allows the majority of patients to continue the low dosage of 2.5 mg/kg/day and still achieve a good clinical response. Remission can be better preserved by tapering the drug than by discontinuing treatment abruptly.

Intestinal microsporidiosis in patients with acquired immunodeficiency syndrome--report of three more German cases.

Intestinal microsporidiosis with Enterocytozoon bieneusi was diagnosed in three of 18 HIV-infected patients with chronic diarrhoea. In two cases all known stages of the life cycle of E. bieneusi (merogonial plasmodia, sporogonial plasmodia, sporoblasts, spores) were found in duodenal biopsies by electron microscopical examination, whereas in the third case only merogonial and sporogonial stages were seen. Spores were also visible by light microscopy in semithin sections. Two patients were treated with albendazole (2 x 400 mg/day for 4 weeks) but showed no response. These findings underline the concept of the worldwide distribution of this parasite and verify that it is also frequent in Germany.

[Peritumoral administered IL-2-induced tumor regression in melanoma. Pilot study]. / Peritumoral appliziertes IL-2 induziert Tumorregression beim Melanom. Eine Pilotstudie.

Since the immune system plays an important role in the rejection of tumours, current tumour therapy includes immunostimulation. This can be done by interleukin 2 (IL-2), which activates T and killer cells and induces lysis of the tumour. Because the intravenous application of IL-2 may have serious side effects, we treated two patients with peritumoral injections in a pilot study. Both patients suffered from multiple cutaneous metastases of melanoma. A total of 31 and 39 x 10(6) IU recombinant IL-2 (Proleukin) respectively was injected in increasing concentrations in one metastasis of each patient. Histologically, almost complete necrosis of the tumour was induced. In comparison with the control specimen, the T-cell-rich infiltrate increased intra- and, in particular, peritumorally. While the ratio of helper to suppressor T cells remained unchanged, the proportions of NK cells, monocytes/macrophages and IL-2-receptor-bearing cells increased. This reaction was restricted to treated metastases. No clinical side effects or laboratory changes were registered apart from local erythema and swelling.