Hair follicles contribute significantly to penetration through human skin only at times soon after application as a solvent deposited solid in man.

AIMS: The aim of this study was to define the underlying relative penetration of caffeine through hair follicles and through intact stratum corneum with time in vivo through pharmacokinetic modelling. METHODS: Caffeine plasma concentration-time profiles after topical application into skin with or without hair follicle blocking were modelled using the Wagner-Nelson method or a compartmental model with first order absorption and elimination. Pharmacokinetic parameters describing absorption rate and extent of absorption through hair follicles or the stratum corneum were determined separately and compared with each other. RESULTS: The obtained pharmacokinetic parameters from the two methods were similar. The absorption rate constant of caffeine for hair follicles was nearly 10 times higher than that for the stratum corneum and the percentage of absorption from hair follicles was more than half of that of the stratum corneum. In addition, the absorption from the stratum corneum showed an approximately 10 min delay while there was no delay for absorption from hair follicles. All caffeine absorbed by hair follicles occurs within 30 min of application and accounts for 10.5 to 33.8% of the total amount absorbed across the skin for all subjects, whereas absorption of caffeine through the stratum corneum can occur over several hours. CONCLUSION: Hair follicles contribute significantly to percutaneous absorption of caffeine after topical application in man in vivo only at times soon after application.

Systemic treatment for alopecia areata.

Of the world population, 1.7% is suffering from alopecia areata at some point in their lives. The exact etiology of this disease is still unknown, and the course of the disease is unpredictable. Effective treatments, especially for severe multifocal alopecia areata, alopecia areata totalis, and alopecia areata universalis, are lacking. The present article will discuss side effects and relapse rates of different systemic agents for treatment of severe and rapid progressive alopecia areata.

Strategy of topical vaccination with nanoparticles.

Liposomes in the nanosize range have been recognized as a versatile drug delivery system of both hydrophilic and lipophilic molecules. In order to develop a liposome-based topical vaccination strategy, five different types of liposomes were tested as a putative vaccine delivery system on pig ear skin. The investigated liposomes mainly varied in size, lipid composition, and surface charge. Using hydrophilic and hydrophobic fluorescent dyes as model drugs, penetration behavior was studied by means of confocal laser scanning microscopy of intact skin and histological sections, respectively. Follicular penetration of the liposomes was measured in comparison to a standard, nonliposomal formulation at different time points. Dependent on time but independent of their different characters, the liposomes showed a significantly higher penetration depth into the hair follicles compared to the standard formulation. The standard formulation reached a relative penetration depth of 30% of the full hair follicle length after seven days, whereas amphoteric and cationic liposomes had reached approximately 70%. Penetration depth of negatively charged liposomes did not exceed 50% of the total follicle length. The fluorescence dyes were mainly detected in the hair follicle; only a small amount of dye was found in the upper parts of the epidermis.

Permeation of topically applied caffeine through human skin--a comparison of in vivo and in vitro data.

AIMS: Due to ethical reasons, in vivo penetration studies are not applicable at all stages of development of new substances. Therefore, the development of appropriate in vitro methods is essential, as well as the comparison of the obtained in vivo and in vitro data, in order to identify their transferability. The aim of the present study was to investigate the follicular penetration of caffeine in vitro and to compare the data with the in vivo results determined previously under similar conditions. METHODS: The Follicular Closing Technique (FCT) represents a method to investigate the follicular penetration selectively. In the present study, FCT was combined with the Franz diffusion cell in order to differentiate between follicular and intercellular penetration of caffeine into the receptor medium in vitro. Subsequently, the results were compared with the data obtained in an earlier study investigating follicular and intercellular penetration of caffeine in vivo. RESULTS: The comparison of the data revealed that the in vitro experiments were valuable for the investigation of the follicular penetration pathway, which contributed in vivo as well as in vitro to approximately 50% of the total penetration, whereas the kinetics of caffeine penetration were shown to be significantly different. CONCLUSIONS: The combination of FCT with the Franz diffusion cell represents a valuable method to investigate follicular penetration in vitro. Nevertheless, in vivo experiments should not be abandoned as in vitro, structural changes of skin occur and blood flow and metabolism are absent, probably accounting for reduced penetration rates in vitro.

Uncombable hair syndrome.

Uncombable hair syndrome is a relatively rare anomaly of the hair shaft, with less than 100 cases reported to date, that results in a disorganized, unruly hair pattern that is impossible to comb flat. The characteristic longitudinal grooves along the hair shaft, along with the triangular or kidney-shaped cross section allows this condition to be diagnosed microscopically. The majority of cases are inherited in an autosomal-dominant manner with either complete or incomplete penetrance. There is no definitive treatment, and most cases improve with the onset of puberty.

Clinical applicability of in vivo fluorescence confocal microscopy for noninvasive diagnosis and therapeutic monitoring of nonmelanoma skin cancer.

Excisional biopsies and routine histology remains the gold standard for the histomorphologic evaluation of normal and diseased skin. However, there is increasing interest in the development of noninvasive optical technologies for evaluation, diagnosis, and monitoring of skin disease in vivo. Fluorescent confocal microscopy is an innovative optical technology that has previously been used for morphologic evaluation of live human tissue. We evaluate the clinical applicability of a fluorescent confocal laser scanning microscope (FLSM) for a systematic evaluation of normal and diseased skin in vivo and in correlation with routine histology. A total of 40 patients were recruited to participate in the study. Skin sites of 10 participants with no prior history of skin disease served as controls and to evaluate topographic variations of normal skin in vivo. Thirty patients with a suspected diagnosis of nonmelanoma skin cancer were evaluated, whereby FLSM features of actinic keratoses (AK) and basal cell carcinoma (BCC) were recorded in an observational analysis. Selected BCCs were monitored for their skin response to topical therapy using Imiquimod as an immune-response modifier. A commercially available fluorescence microscope (OptiScan Ltd., Melbourne, Australia) was used to carry out all FLSM evaluations. Common FLSM features to AK and BCC included nuclear pleomorphism at the level of the granular and spinous layer and increased vascularity in the superficial dermal compartment. Even though the presence of superficial disruption and mere atypia of epidermal keratinocytes was more indicative of AK, the nesting of atypical basal cells, increased blood vessel tortuosity, and nuclear polarization were more typical for BCC. All diagnoses were confirmed by histology. FLSM allowed a monitoring of the local immune response following therapy with Imiquimod and demonstrated a continuous normalization of diseased skin on repeated evaluations over time. This study illustrates potential applications of FLSM in clinical dermatology for the evaluation of dynamic skin conditions and monitoring of cutaneous response to noninvasive therapies. The findings are of preliminary nature and warrant further investigations in the future.

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.

Secondary cicatricial and other permanent alopecias.

Various nonfollicular scalp conditions can cause secondary scarring or permanent alopecia. Possible causes are congenital defects, trauma, inflammatory conditions, infections, and neoplasms (rarely drugs). Associated signs and symptoms and other diagnostic procedures such as histopathology may aid in the diagnosis. Detection of the underlying disorder may be difficult in end-stage lesions. Treatment is specific for active conditions. Surgery and hair transplantation are options for localized scars.

Folliculitis decalvans.

Folliculitis decalvans is a rare inflammatory scalp disorder. The present paper gives a practical approach to diagnosis and patient management and reviews possible pathogenetic factors and treatment options. Folliculitis decalvans is classified as primary neutrophilic cicatricial alopecia and predominantly occurs in middle-aged adults. Staphylococcus aureus and a deficient host immune response seem to play an important role in the development of this disfiguring scalp disease. Lesions occur mainly in the vertex and occipital area. Clinically, the lesions present with follicular pustules, lack of ostia, diffuse and perifollicular erythema, follicular tufting, and, oftentimes, hemorrhagic crusts and erosions. Histology displays a mainly neutrophilic inflammatory infiltrate in early lesions and additionally lymphocytes and plasma cells in advanced lesions. Treatment is focused on the eradication of S. aureus anti-inflammatory agents.

Lichen planopilaris.

Lichen planopilaris is a chronic scarring alopecia characterized by follicular hyperkeratosis, perifollicular erythema, and loss of follicular orifices. The scalp lesions may be single or multiple and commonly involve the vertex and parietal area. The hair follicles at the margin of the alopecic patches reveal perifollicular erythema. Anagen hairs can be pulled out easily in active lesions. Associated cutaneous, nail, and mucous membrane lichen planus may be present. Commonly encountered symptoms and signs are increased hair shedding, itching, scaling, burning, and tenderness. Differentiation from other cicatricial alopecia can be performed through meticulous evaluation of the clinical, histopathologic, and immunohistopathologic findings. Treatment strategies depend on the disease activity and physician expertise. Although there are no definitive curative modalities, some new discoveries and conceptual advances continue to broaden our treatment options of this complex condition.

Pseudopelade of Brocq.

Pseudopelade of Brocq (PPB) is a rare, idiopathic, slowly progressive hair disorder, resulting in cicatricial alopecia. It typically presents in Caucasian adult patients as small, smooth, flesh-toned and slightly depressed alopecic patches with irregular outlines. It primarily involves the parietal and vertex portions of the scalp with a chronic prolonged course. Controversial opinions still exist as to whether PPB is a single entity or an end stage of several cicatricial alopecic disorders. A practical approach to diagnosis of PPB and therapeutic update are discussed in this review.

Diagnosis and management of primary cicatricial alopecia: part II.

The second part of this 2-part article reviews clinical features, histology, management, and treatment of neutrophilic primary cicatricial alopecias (folliculitis decalvans and dissecting folliculitis) and mixed primary cicatricial alopecias (acne keloidalis, acne necrotica, and erosive pustular dermatosis).

Diagnosis and management of primary cicatricial alopecia: part I.

In this 2-part article, the authors review the primary cicatricial alopecias. Primary cicatricial alopecia can be defined as predominantly lymphocytic, neutrophilic, or mixed based on the nature of the follicular infiltrate that is present around affected hair follicles. Lymphocytic primary cicatricial alopecias include chronic cutaneous lupus erythematosus (discoid lupus erythematosus), lichen planopilaris, classic pseudopelade of Brocq, central centrifugal cicatricial alopecia, alopecia mucinosa, and keratosis follicularis spinulosa decalvans. In this first part, the authors summarize the classification, epidemiology, diagnostic approach, and patient management of lymphocytic cicatricial alopecias. In part II, the authors will focus on neutrophilic cicatricial alopecias and mixed cicatricial alopecias.

Androgenetic alopecia.

Androgenetic alopecia (AGA), or male pattern hair loss, affects approximately 50% of the male population. AGA is an androgen-related condition in genetically predisposed individuals. There is no treatment to completely reverse AGA in advanced stages, but with medical treatment (eg, finasteride, minoxidil, or a combination of both), the progression can be arrested and partly reversed in the majority of patients who have mild to moderate AGA. Combination with hair restoration surgery leads to best results in suitable candidates. Physicians who specialize in male health issues should be familiar with this common condition and all the available approved treatment options.

Nanoparticles--an efficient carrier for drug delivery into the hair follicles.

The penetration and storage behavior of dye-containing nanoparticles (diameter 320 nm) into the hair follicles was investigated. The results were compared to the findings obtained with the same amount of dye in the non-particle form. In the first part of the experiments, the penetration of the dye into the hair follicles was investigated in vitro on porcine skin, which is an appropriate model for human tissue. It was found that the nanoparticles penetrate much deeper into the hair follicles than the dye in the non-particle form, if a massage had been applied. Without massage, similar results were obtained for both formulations. Subsequently, the storage behavior of both formulations in the hair follicles was analyzed in vivo on human skin by differential stripping. Using the same application protocol, the nanoparticles were stored in the hair follicles up to 10 days, while the non-particle form could be detected only up to 4 days. Taking into consideration the surface structure of the hair follicles, it was assumed that the movement of the hairs may act as a pumping mechanism pushing the nanoparticles deep into the hair follicles.

Innovative liposomes as a transfollicular drug delivery system: penetration into porcine hair follicles.

Liposomes had been widely used for drug delivery in the past. In this study, five different liposomes were used as a follicular delivery system in pig ear skin. The liposomes mainly differed in their sphere diameter, lipid composition, and surface charge. A novel class of liposomes being amphoteric in their charge behavior are compared to established anionic and cationic liposomes. Two different fluorescent dyes, hydrophilic carboxyfluoresceine or lipophilic curcumin, were enclosed in the liposomes and used as model drugs. The fluorescent dyes were also applied in a standard formulation for reference. The penetration depth of the dyes was measured by laser scanning microscopy in histological sections. One hour, 3, 5, and 7 days after application, biopsies were taken and the penetration depth into the hair follicle was measured in longitudinal sections. The liposomes showed a higher penetration depth compared to the standard formulation. The relative penetration depth of the dyes, applied in the standard formulation, averaged 30% of the full follicle length during the whole observation period, whereas the liposomal formulations penetrated considerably deeper into the hair follicles. Amphoteric and cationic liposomes reached an average relative penetration depth of approximately 70% of the full hair follicle length.

In vivo confocal scanning laser microscopy: comparison of the reflectance and fluorescence mode by imaging human skin.

Optical, noninvasive methods have become efficient in vivo tools in dermatological diagnosis and research. From these promising imaging techniques, only the confocal scanning laser microscopy (CSLM) provides visualization of subsurface skin structures with resolutions similar to those of light microscopy. Skin annexes, as well as cutaneous cells from different epidermal layers, can be distinguished excellently. Currently, two forms of application have been established in dermatological practice: the reflectance mode, predominantly in the clinical field, and the fluorescence mode in dermatological research. Differences in both methods exist in the preparative protocol, in maximum imaging depth and, particularly, in the gain of contrast extraction. The reflectance mode demonstrates naturally occurring tissue components, whereas the fluorescent CSLM achieves contrast by administering fluorescence dye, representing the dynamic distribution pattern of the dye's fluorescent emission. Therefore, the reflectance and fluorescent modes highlight various skin microstructures, providing dissimilar in vivo confocal images of the skin. This permits different predications and information on the state of the tissue. We report the advantages and disadvantages of both optical imaging modes. The comparison was drawn by scanning human skin in vivo. Representative images in varying depths were obtained and analyzed; preparation procedures are shown and discussed.

Variations of hair follicle size and distribution in different body sites.

For the evaluation and quantification of follicular penetration processes, the knowledge of variations of hair follicle parameters in different body sites is basic. Characteristics of follicle sizes and potential follicular reservoir were determined in cyanoacrylate skin surface biopsies, taken from seven different skin areas (lateral forehead, back, thorax, upper arm, forearm, thigh, and calf region). The highest hair follicle density and percentage of follicular orifices on the skin surface and infundibular surface were found on the forehead, whereas the highest average size of the follicular orifices was measured in the calf region. The highest infundibular volume and therefore a potential follicular reservoir was calculated for the forehead and for the calf region, although the calf region showed the lowest hair follicle density. The calculated follicular volume of these two skin areas was as high as the estimated reservoir of the stratum corneum. The lowest values for every other parameter were found on the forearm. The present investigation clearly contradicts former hypothesis that the amount of appendages of the total skin surface represents not more than 0.1%. Every body region disposes its own hair follicle characteristics, which, in the future, should lead us to a differential evaluation of skin penetration processes and a completely different understanding of penetration of topically applied drugs and cosmetics.