Stratum corneum pharmacokinetics of the anti-fungal drug, terbinafine, in a novel topical formulation, for single-dose application in dermatophytoses.

OBJECTIVE: The stratum corneum (SC) pharmacokinetics of terbinafine following single-dose administration of a novel cutaneous solution (film-forming solution, FFS) containing terbinafine hydrochloride and a film-forming agent, was investigated in three studies. Terbinafine 1% cream (Lamisil) was included as a benchmark in two of these studies. RESEARCH DESIGN AND METHODS: Drugs were applied to areas of the back, and skin strips were taken from defined areas at baseline and from 1 to 312 h after application. Samples were analysed using validated liquid chromatography/mass spectrometry. RESULTS: The residence time of the film on the skin was up to 72 h after application (up to 12 h for the 1% cream). After application of terbinafine FFS, 30% of the total amount of drug delivered into the SC occurred during the first 2 h, 31% from 2-12 h, and 39% thereafter. The C(max) was observed as early as 1.5 h (t(max)). SC levels were still detected after 13 days (24 ng/cm(2)) (t(1/2)) was 162 h). Terbinafine 1% cream showed a similar t(max) (2 h) with a lower C(max) than terbinafine 1% FFS, and mean SC levels after 7 days of treatment were 46 ng/cm(2) (day 13). The t(1/2) was 68 h. Washing at 30 min removed 86% of the film still present on the surface; the decrease of terbinafine concentration in the SC was 84%. A later washing at 12 h removed 73% of the film in comparison to non-washed skin and induced a decrease in the terbinafine content in the SC of 27%. CONCLUSIONS: The SC pharmacokinetic profile of terbinafine 1% FFS indicates that this novel formulation is efficient in delivering high amounts of terbinafine to the skin for a prolonged time and supports its use in the treatment of dermatophytoses with a single application.

Efficacy and safety of a new single-dose terbinafine 1% formulation in patients with tinea pedis (athlete's foot): a randomized, double-blind, placebo-controlled study.

BACKGROUND: Tinea pedis is a common dermatophyte infection with frequent recurrences. Terbinafine (presently used as a 1-week topical treatment of tinea pedis) is now available in a novel topical solution (film-forming solution--FFS), developed to allow single application. OBJECTIVES: To demonstrate the efficacy and safety of terbinafine 1% FFS in a randomized, double-blind, placebo-controlled, phase III trial, and to determine relapse or re-infection rate of tinea pedis at 12 weeks. PATIENTS/METHODS: Fifty-four centres (27 in France; 27 in Germany) enrolled 273 evaluable patients (2 : 1 randomization). Patients applied terbinafine 1% FFS or placebo only once between, under and over the toes, soles and sides of both feet. Efficacy assessments included direct microscopy, mycological culture, and clinical signs and symptoms at baseline, and at weeks 1, 6 and 12 after the single drug application. RESULTS: Effective treatment (negative mycology plus absent/minimal symptoms) at week 6 in the terbinafine 1% FFS group was 63%; vehicle was 17% (P

Prevention of edema and flight microangiopathy with Venoruton (HR), (0-[beta-hydroxyethyl]-rutosides) in patients with varicose veins.

The aim of this open study was the evaluation of the effects of HR (Venoruton) at a dose of 1 g/day on the prevention and control of flight microangiopathy and edema in subjects with varicose veins and moderate chronic venous insufficiency flying for more than 11 hours. Patients with varicose veins, edema, but without initial skin alterations or complications, were included. Measurements of skin laser Doppler (LDF) resting flux (RF) venoarteriolar response (VAR), ankle swelling (RAS), and edema were made within 12 hours before and within 3 hours after the flights. The resulting edema after the flights was evaluated with a composite edema score (analogue scale line). A group of 20 subjects was treated with HR (1 g/day, starting 2 days before the flight and 1 g for every 12 hours on day of travel). Another group of 18 subjects formed the control group. The length of the flights was between 11 and 13 hours; all seats were in coach class. Fifty patients were enrolled and 38 patients were evaluable at the end of the trial. The 2 groups (treatment and control) were comparable for age and sex distribution. The decrease in RF was significant in both groups with a higher flux at the end of the flight in the HR group (p < 0.05). The venoarteriolar response was decreased at the end of the flights; the decrease was lower in the HR group (p < 0.05). The increase in RAS and the edema score were significantly lower in the HR group. In conclusion HR is useful for reducing the level of microangiopathy and the increased capillary filtration and in controlling edema in patients with venous disease in long flights. The higher level of flux and VAR and the reduction in edema indicate a positive effect of HR on the microcirculation. This study confirms that HR prophylaxis is effective to control flight microangiopathy associated with edema.

A randomized trial of amorolfine 5% solution nail lacquer combined with oral terbinafine compared with terbinafine alone in the treatment of dermatophytic toenail onychomycoses affecting the matrix region.

In view of recent advances in the development of antifungal agents, this study examined the possible synergy of two new antifungal agents, terbinafine and amorolfine. The study compared two different courses of terbinafine treatment combined with amorolfine 5% solution nail lacquer. Terbinafine was given orally for 6 (AT6 group) or 12 weeks (AT12 group) and amorolfine nail lacquer applied weekly for 15 months. A control group received terbinafine alone for 12 weeks. This was a randomized, prospective, open study of severe dermatophyte toenail onychomycosis with matrix region involvement. Nail samples were taken before the start of the study, at inclusion and at the visits at 6 weeks, 3, 9, 15 and 18 months. To assess the value of such combined therapy we chose an early parameter as the principal outcome variable, which was the result of mycological examination, including direct microscopy and culture, at 3 months (allowing a margin of 15 days). The secondary parameters of success were the mycological results at the later visits, clinical evaluation and a combined mycological-clinical response. Safety and tolerance were also assessed. Adverse events were recorded and liver function tests were performed monthly during the terbinafine treatment. Of the 147 patients included in the trial, 121 attended the 3-month visit, within a time limit of 15 days of 3 months after the beginning of treatment: 40 in the AT6 group, 40 in the AT12 group and 41 in the control group. In all, 32 of 121 patients (26. 4%) had negative mycological results on direct microscopy and culture: 14 of 40 (35.0%) in the AT6 group, 11 of 40 (27.5%) in the AT12 group and seven of 41 (17.1%) in the control group. The cure rate for the global (mycological and clinical cure) response measured at 18 months in 145 patients was 44.0% (22 patients) in the AT6 group, 72.3% (34 patients) in the AT12 group and 37.5% (18 patients) in the terbinafine group. These results suggest that the combination of amorolfine and terbinafine may be of value in the treatment of severe onychomycosis. At the same time a pilot pharmacoeconomic analysis was performed demonstrating a better cost per cure ratio for the patients receiving combination treatment.

Topical application of isotretinoin did not modify human Langerhans cell allostimulatory function.

The beneficial effect of isotretinoin on the repair of photodamaged skin is well documented. Little is known, however, on the action of this compound on immunological functions of epidermis. In a double-blind study, we analyzed the effect of topical applications of isotretinoin on human Langerhans cell (LC) function by using the mixed epidermal cell lymphocyte reaction (MELR). Isotretinoin cream (0.1%) was applied daily for 4 months on the back of one hand of 5 healthy volunteers, 50-60 years of age. The back of the other hand received vehicle alone and was used as control. Skin biopsy specimens were taken at the end of treatment. Epidermal cell (EC) suspensions were obtained by the use of trypsin and allogeneic T cells were purified from the peripheral blood of allogeneic donors. MELR was performed in microtiter plates and T cell proliferation was assessed by 3H-thymidine incorporation during the last 18 h of culture. Results did not show any differences between allogeneic T cell responses to EC from isotretinoin-treated or nontreated skin. These results therefore suggest that isotretinoin, applied topically onto photodamaged skin, did not alter human LC antigen-presenting function.

Retinoic acid as modulator of UVB-induced melanocyte differentiation. Involvement of the melanogenic enzymes expression.

Retinoic acid (RA) is a hormone-like agent involved in the control of cell differentiation. The most characteristic feature of melanocyte differentiation, melanogenesis, is stimulated by UV radiations. Excessive chronic sun exposure results in irregular skin hypermelanosis that can be partially corrected by topical RA. The basic mechanisms underlying this effect of RA are unknown. To determine whether RA can directly modulate excessive melanin synthesis, we analyzed the in vitro effect of cis- and trans-RA on UVB-induced melanogenesis in S91 mouse melanoma cells and in normal human melanocytes (NHM). In both cells types, the two RA isoforms significantly decreased the UVB-stimulated melanogenesis in term of tyrosinase activity and melanin neosynthesis. To correlate changes in melanogenesis with the expression of melanogenic enzymes, we determined the neosynthesis rate of tyrosinase, tyrosinase-related protein-1 (TRP-1/gp 75) and tyrosinase-related protein-2 (TRP-2/DOPAchrome tautomerase). Here we show that UVB-induced melanogenesis in NHM is related to an increased synthesis of tyrosinase and TRP-1 and to a dramatic decrease of TRP-2 expression. RA inhibition of UVB-induced melanogenesis acts at the post-transcriptional level leading to a decreased tyrosinase and TRP-1 synthesis. We also show that in NHM, inhibition of TRP-2 following UVB-treatment is significantly reversed by RA. This demonstrates a negative correlation between melanogenesis and TRP-2 expression.

Evaluation of cutaneous photodamage using a photographic scale.

Clinical assessments of photodamage are based upon a subjective evaluation of characteristic features such as wrinkling and pigmentary change, and are influenced by inter-observer differences in grading criteria. In an effort to standardize the grading of photodamage severity, we have developed a six-point photographic scale in which each of the six grades of overall photodamage severity is depicted by three photographs. The use of three photographs to portray each grade illustrates the diversity and range of manifestations within each grade. This photographic scale was tested by two groups of dermatologists, who used it on two occasions to grade the overall photodamage severity of a single group of female Caucasian subjects. Results indicate high inter-observer agreement, with chance-corrected agreement ranging from 0.44 to 0.63 and from 0.54 to 0.76 on the first and second occasions, respectively. Intra-observer repeatability was high, with chance-corrected agreement ranging from 0.56 to 0.78. Inter- and intra-observer differences were within one category in nearly all cases. Similar grades were assigned by dermatologists with and without experience in treating photodamaged patients. We conclude that application of this scale results in consistent and reproducible clinical evaluations of overall photodamage severity in Caucasian subjects. The scale may be useful in categorizing subjects for epidemiological studies, or in selecting patients for clinical trials.

Effect of testicular hyaluronidase on hyaluronate synthesis by human skin fibroblasts in culture.

The effect of hyaluronidase treatment on the incorporation of [3H]glucosamine into hyaluronate in human skin fibroblast cultures was investigated. Fourth passage cells in confluent cultures were treated with hyaluronidase from bovine tests, Streptomyces and leech in Dulbecco's minimum essential medium in the presence of 3% fetal calf serum. The medium was removed from the control (non-treated) and the treated cultures and the washed cell layers were incubated with [3H]glucosamine and [35S]sulfate. [3H]Hyaluronate was separated by DEAE Trisacyl chromatography and identified by specific enzymic assays. Hyaluronidase treatment induced an increase in the amount of labelled hyaluronate secreted into the medium and into the pericellular compartment. This amount reached a plateau with increasing enzyme concentration and with the time of treatment. Oligosaccharides derived from hyaluronate did not produce this effect. The maximal increase was about 3-fold, and was not inhibited by exogenous hyaluronate (25-100 micrograms/ml) or by oligosaccharides from hyaluronate. Cycloheximide (0.03 mM) inhibited hyaluronate synthesis by 18% or less in the control cells and by 50% in the hyaluronidase-pretreated fibroblasts. No significant difference was found in the hyaluronate synthase activity between control and treated cells, at 60 min following treatment, indicating the reversibility of the effect. The persistence of the stimulation required the presence of hyaluronidase. The treatment of cells with specific hyaluronidases (from Streptomyces and leech) or with testicular hyaluronidase did not modify the labelling of the sulfated glycosaminoglycans. The incorporation kinetics of the [3H]glucosamine into labeled hyaluronate and the increased amount of non-labelled hyaluronate determined by radiometric assay indicated a specific stimulation of hyaluronate synthesis in the hyaluronidase-pretreated fibroblast cultures.