The role of hair follicles in the percutaneous absorption of caffeine.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: * In recent years, it has been suggested that hair follicles represent important shunt routes into the skin for drugs and chemicals [1-3]. * In vitro studies have shown the importance of skin appendages for skin penetration by hydrophilic compounds [4]. Investigation of follicular penetration in vivo has been difficult due to the absence of appropriate analytical methods or suitable animal model systems. * Recently, a new method was described that quantifies follicular penetration in vivo by using selective closure of hair follicles [5]. * Caffeine is frequently used in skin penetration experiments as a model for highly water-soluble compounds. Occlusion [6] and skin thickness [7] seem to have little influence on the penetration of caffeine. However, percutaneous absorption rates for caffeine exhibit regional skin differences in humans in vivo[1]. WHAT THIS STUDY ADDS: * The results of the present study demonstrate that a fast drug delivery of caffeine occurs through shunt routes. Therefore, hair follicles are considerable weak spots in our protective sheath against penetration into the body by hydrophilic substances. * We showed that there is a quantitative distinction between follicular penetration and interfollicular diffusion of caffeine in vivo. * These findings are of importance for the development and optimization of topically applied drugs and cosmetics. In addition, such properties must be considered in the development of skin protection measures. AIMS: The skin and its appendages are our protective shield against the environment and are necessary for the maintenance of homeostasis. Hypotheses concerning the penetration of substances into the skin have assumed diffusion through the lipid domains of the stratum corneum. It is believed that while hair follicles represent a weakness in the shield, they play a subordinate role in the percutaneous penetration processes. Previous investigation of follicular penetration has mostly addressed methodical and technical problems. Our study utilized a selective closure technique of hair follicle orifices in vivo, for the comparison of interfollicular and follicular absorption rates of caffeine in humans. METHODS: Every single hair follicle within a delimited area of skin was blocked with a microdrop of a special varnish-wax-mixture in vivo. Caffeine in solution was topically applied and transcutaneous absorption into the blood was measured by a new surface ionization mass spectrometry (SI/MS) technique, which enabled a clear distinction to be made between interfollicular and follicular penetration of a topically applied substance. RESULTS: Caffeine (3.75 ng ml(-1)) was detected in blood samples, 5 min after topical application, when the follicles remained open. When the follicles were blocked, caffeine was detectable after 20 min (2.45 ng ml(-1)). Highest values (11.75 ng caffeine ml(-1)) were found 1 h after application when the follicles were open. CONCLUSIONS: Our findings demonstrate that hair follicles are considerable weak spots in our protective sheath against certain hydrophilic drugs and may allow a fast delivery of topically applied substances.

Treatment of bullous pemphigoid with dapsone, methylprednisolone, and topical clobetasol propionate: a retrospective study of 62 cases.

Dapsone has been used successfully as adjuvant therapy for bullous pemphigoid (BP). The effectiveness of dapsone for this indication, however, remains controversial. We evaluated the effectiveness and adverse events of dapsone (1.0-1.5 mg/kg per day) in combination with oral methylprednisolone (tapering doses of 0.5 mg/kg per day) and topical clobetasol propionate (initially applied once daily on lesions only) in the treatment of BP. Sixty-two patients treated with this regimen were analyzed retrospectively. Patients were free of new blisters after a mean (+/- SD) of 22 +/- 13 days (median, 20 days). After 3 and 6 months of treatment, methylprednisolone could be reduced to less than 10 mg/d in 71% and 91% of patients, respectively; after 12 months of treatment, 53% of patients were in complete remission without receiving further therapy. Dapsone-related side effects were usually mild except in 3 patients (5%), 2 patients with anemia (hemoglobin level, <7 g/dL) and 1 with agranulocytosis. Our data suggest that dapsone used in combination with systemic and topical corticosteroids may be a relatively safe and effective treatment option for BP.

[Significant decrease in quality of life in patients with pemphigus vulgaris. Results from the German Bullous Skin Disease (BSD) Study Group]. / Deutliche Einschrankung der Lebensqualitat bei Patienten mit Pemphigus vulgaris: Ergebnisse der deutschen Bullous Skin Disease (BSD)-Studiengruppe.

BACKGROUND: Pemphigus vulgaris is a potentially life-threatening autoimmune disorder of the skin and mucous membranes characterized by antibodies against epidermal adhesion molecules. Clinically characteristic are painful chronic blisters or erosions of mucous membranes and skin. There are no published studies on the impact o this disease on quality of life. PATIENTS AND METHODS: This registration was performed within the scope of the German BSD (Bullous Skin Disease) study group, from November 1997 until January 2002. A total of 36 patients with the first diagnosis of pemphigus vulgaris were registered at the university hospitals of Dresden, Erlangen, Kiel, Mannheim, München and Würzburg. Thirty of the 36 (83 %) patients participated in the quality of life questionnaire utilizing the German version of 'Dermatology Life Quality Index' (DLQI) provided by A. Y. Finlay. The DLQI varies from 0 to 30 with an increased DLQI score indicating a decrease in quality of quality. RESULTS: The overall DLQI total score of 10 +/- 6.7 in the investigated pemphigus patients was significantly increased in comparison to other skin diseases. CONCLUSIONS: These results suggest that the DLQI can be a very useful additional outcome criteria for clinical studies with pemphigus vulgaris and in the treatment of these patients.

In vivo determination of skin surface topography using an optical 3D device.

BACKGROUND/PURPOSE: Topography of the skin surface is a mirror of the functional skin status. Therefore, its evaluation is of great interest for dermatological research. In the present study, a new optical measuring system was applied to evaluate human skin surface topography in vivo and non-invasively, in order to determine elastotic and mimic wrinkles dependent on age, body site and therapy. METHODS: The measurements were performed on the back (n=5), the flexor forearm (n=14) of volunteers in different age groups and on the face of women (n=4) participating in an anti-wrinkle study. The evaluation of the three-dimensional-profiles was performed determining skin surface parameters (mean roughness (R(a)), mean depth of roughness (R(z)), maximum roughness (R(m)) and waviness (W(t))) and applying Fourier analysis. RESULTS: Significant increases in all surface parameters were obtained on the forearms with increasing age. Differences between the surface topographies of forearm and back were only expressed by the waviness and the Fourier analysis. The treatment with botulinum Toxin A led to a diminution of mimic wrinkles as reflected by the furrow profiles. CONCLUSIONS: The results show a significant dependence of the skin surface topography on the age of the volunteer and the body site measured. Particularly the waviness, the Fourier analysis and the furrow profiles reflect such dependencies. The system used also fulfils the requirements for the testing of therapies, as was demonstrated by the reduction of mimic wrinkles after treatment with botulinum Toxin A.

[Randomized, placebo-controlled, double blind clinical trial for the evaluation of the efficacy and safety of oral methantheliniumbromide (Vagantin) in the treatment of focal hyperhidrosis]. / Randomisierte, plazebokontrollierte klinische Doppelblindstudie zur Wirksamkeit und Verträglichkeit der oralen Therapie mit Methantheliniumbromid (Vagantin) bei fokaler hyperhidrose.

BACKGROUND: Methanthelinium bromide is a quaternary ammonium derivate with anticholinergic activity. Since 1951 it has been used to treat patients with hyperhidrosis. However, all efficacy data has so far been limited to case reports and case series. We here report on the results of the first randomised clinical controlled trial on the efficacy and safety of methanthelinium bromide. PATIENTS AND METHODS: A total of 41 patients with a mean age (+/- standard deviation) of 28 +/- 9.8 years (Range 18.7-54.8) were included, 31 (76%) of them were females. Main inclusion criteria were are focal hyperhidrosis of a one year or longer duration and a gravimetrically assessed sweat production of > or =50 mg/min. Patients were treated with 2 x 50 mg methanthelinium bromide or placebo orally daily for 4 weeks. The therapeutic effect was determined by repeated gravimetric measurement of sweat production and by recording the patients' degree of satisfaction. RESULTS: The efficacy was most pronounced for patients with an axillary hyperhidrosis of > or =50 mg/min (p = 0.02, chi2-test, two-sided). For the total group the main axillary sweat production decreased in the verum-treated arm from a mean value of 89.2 +/- 73.4 mg/min prior to therapy to 53.3 +/- 48.7 mg/min during therapy (p = 0.02, Wilcoxon test, two-sided). In contrast, no difference was detected in the placebo arm with 60.7 +/- 42.8 mg/min prior to and 59.1 +/- 40.6 mg/min during therapy (p = 0.92, Wilcoxon test, two-sided). For the palmar sweat production no difference between the verum- and the placebo-treated group was found. No serious adverse events were reported. As expected, dryness of the mouth, a known adverse reaction of anticholinergics, was reported significantly more frequently in the verum-treated arm. CONCLUSIONS: Methanthelinium bromide has been considered for many years as a therapeutic option for the treatment of focal hyperhidrosis. However, its efficacy and safety have not previously been investigated in controlled randomised studies. We demonstrated both a decline in axillary sweat production and good tolerance. Therefore, the treatment of axillary hyperhidrosis with methanthelinium bromide in a regimen of 50 mg twice daily can be recommended, especially in those cases which are refractory to topical treatment with for example aluminium chloride hexahydrate solution. In contrast, we found no evidence for a clinically relevant diminution of palmar sweating.

[Efficacy, side effects and patient satisfaction with wrist conduction block anaesthesia prior to the treatment of palmar hyperhidrosis with botulinum toxin type A]. / Wirksamkeit, Nebenwirkungen und Patienten- zufriedenheit bei Leitungsanästhesie durch Handblock vor Behandlung der palmaren Hyperhidrose mit Botulinumtoxin A.

BACKGROUND: The treatment of palmar hyperhidrosis with botulinum toxin type A (BTX A) injections is one of the most effective therapeutic options. However, without adequate anaesthesia this treatment is not feasible in most patients. The anaesthesia of the radial, median and ulnar nerves (wrist block) is despite the absence of good data considered effective but risky. PATIENTS AND METHODS: Between 1.10.1999 and 30.9.2001 retrospectively the efficacy, side effects and the patient satisfaction regarding the overall performance of the wrist block prior to the treatment of the palmar hyperhidrosis with BTX A was investigated. The study took place at the department of dermatology in Mannheim. RESULTS: Of the 38 patients treated, 33 were finally included into the trial. The patients chose the average score of 7,9 +/- 2,1 (sd) on a scale from "0" to "10" (not at all effective--maximally effective) for the efficacy of the wrist block in reducing pain. The patients were very content with the wrist block and granted it the average score of 7,7 +/- 2,1 (sd) on a scale from "0" to "10" (not at all content--maximum content). Unwanted effects could be seen in 31/33 patients (93,9%): these were dizziness, headache or haematoma at the spot of injection as well as pain caused by the injections of the local anaesthesia or paresthesias such as tickling of the hand or arm. All side effects caused by the wrist block were reversible and lasted--except in one patient--only for a short time. 29/33 patients (87,9%) recommended the wrist block prior to treating palmar hyperhidrosis with BTX A and 28/33 patients (84,9%) could not imagine to agree to such a treatment without local anaesthesia. CONCLUSION: The wrist block effectively reduces pain due to the treatment of palmar hyperhidrosis with BTX A. Major side effects are rare; patient acceptance and satisfaction are high.

Risk factors for lethal outcome in patients with bullous pemphigoid: low serum albumin level, high dosage of glucocorticosteroids, and old age.

BACKGROUND: Although bullous pemphigoid (BP) is the most frequent autoimmune bullous disease and is associated with a considerable case-fatality rate, little is known about factors that influence its prognosis. OBJECTIVE: To identify prognostic factors for lethal outcome in the first year after the initial hospitalization in patients with BP. DESIGN: A multicenter retrospective cohort study. SETTING: Seven dermatologic university hospitals in Germany. PARTICIPANTS: A total of 369 patients diagnosed as having BP between January 1, 1987, and December 31, 1997. STATISTICS: Univariate (Kaplan-Meier) and multivariate (Cox regression) analysis. RESULTS: Of the 369 patients with BP, 209 (57%) died, 106 (29%) within the first year after hospitalization. Fifty-four percent were women. The mean +/- SD age at entry was 77.3 +/- 11.1 years. The patients with BP were followed up to 10.5 years, with a median time of 1.8 years to death or interview (25th and 75th quartiles, 0.5 and 4.0 years). The major risk factors for lethal outcome in the first year after hospitalization were an increased age, with a multivariate risk estimate of 3.2 (95% confidence interval [CI], 1.9-5.2) for age greater than 80.4 years (median); a daily glucocorticosteroid dosage of more than 37 mg (75th quartile) at discharge, with a multivariate risk estimate of 2.5 (95% CI, 1.5-4.3); serum albumin levels of 3.6 g/dL or less (25th quartile), with a multivariate risk estimate of 2.6 (95% CI, 1.5-4.4); and an erythrocyte sedimentation rate greater than 30 mm/h (75th quartile), with a multivariate risk estimate of 1.7 (95% CI, 1.1-2.8). CONCLUSIONS: There is a considerable case-fatality rate in patients with BP. Older patients who require a higher dosage of oral glucocorticosteroids at hospital discharge and who have low serum albumin levels are at greater risk of death within the first year after hospitalization. These prognostic factors should be considered in the care of patients with BP as well as in the design of future clinical trials.