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BACKGROUND Little is known about the aetiologies and relevant allergens in paediatric patients with hand eczema (HE). OBJECTIVES To characterize the aetiologies and determine the proportion of positive and currently relevant allergens in children/adolescents (age

Patients with atopic dermatitis (AD) have skin barrier impairment in both lesional and nonlesional skin. They are typically exposed daily to emollients and intermittently to topical anti-inflammatory medicaments, thereby increasing the risk of developing contact allergy and systemic exposure to chemical ingredients found in these topical preparations. We systematically searched for studies that investigated skin absorption of various penetrants, including medicaments, in patients with AD, but also in animals with experimentally-induced dermatitis. We identified 40 articles: 11 human studies examining model penetrants, 26 human studies examining AD drugs, and three animal studies. We conclude that patients with AD have almost twofold increased skin absorption compared with healthy controls. There is a need for well-designed epidemiological and dermatopharmacokinetic studies that examine to what extent AD causes patients to be systemically exposed to chemicals compared with nonatopic dermatitis.

To understand the action of Cathepsin G (Cat G) and matrix metalloproteases (MMPs) on the β/Smad pathway of transforming growth factor β (TGF-β) in chronically photodamaged human fibroblasts. Cat G plays a significant role in the process of skin photoaging and in collagen synthesis and degradation which is induced by UV irradiation it could interact with TGF-β/Smad signaling. No available studies have thoroughly explored its molecular mechanisms of photoaging regulation.Fibroblasts were divided into 4 groups: (1) control, (2) UVA irradiation of 25 J/cm2, (3) UVA irradiation of 25 J/cm2 + MMPs inhibitor, and (4) 25 J/cm2 UVA irradiation + Cat G inhibitor. All treatments were repeated daily for 21 days. Western blot and ELISA was employed to detect Protein levels for Cat G, MMPs, and several smads.Compared to UVA-irradiated cells, the addition of MMPs inhibitor downregulated the expression of smad2, smad3, and smad4 as well as TGF-β. The addition of Cat G inhibitor downregulated the expression of smad2, smad3, and smad4 as well as TGF-β. These data suggest that TGF-β/Smad signaling was decreased by inhibition of MMPs and Cat G decreased in chronically human fibroblasts which are photo-damaged.These results may help expand our knowledge of mechanisms mediating photoaging and is possibly instrumental to the exploration of novel anti-photoaging treatments.

Human skin provides a partially effective barrier against potentially toxic chemicals. Much of this barrier protection can be attributed to the stratum corneum (SC), the uppermost and nonviable layer of the epidermis because the rate-limiting step for the penetration of most substances is diffusion through the SC.

Background: Topical use of α-hydroxy acid (AHA) may increase skin photosensitivity, as demonstrated by increased numbers of sunburst cells. However, effects of AHA on tanning have not been studied. Objective: Our purpose was to study whether short-term use of glycolic acid hastens resolution of pre-existing light-induced pigmentation and whether the skin becomes tan more easily in Asian and Caucasian subjects after such treatment. Methods: Six Asian and six Caucasian volunteers received separate irradiations of UVB and UVA to both sides of the lower back. In a double-blind fashion, patients then applied a 10% glycolic acid gel, pH 3.52, to one side of the back, including the irradiated area, and the contralateral extensor forearms once daily for 7 days and then twice daily for 2 weeks. A placebo gel, pH 5.75, was applied to the opposite sides. The subjects returned for measurement of residual tanning with a colorimeter and received additional irradiation to forearms and a second site on the back. Resulting pigmentation was measured immediately after irradiation, at 2 hours, and at 1 week. Results: Increased UVB-induced skin tanning occurred on the forearm and the lower back in both races in areas pretreated with glycolic acid. UVA also caused increased tanning, but only on the extensor forearms in Asian subjects. Treatment with glycolic acid for 3 weeks had no effect on pre-existing light-induced pigmentation. Conclusion: Short-term topical treatment of glycolic acid caused an increase in UVB tanning as well as in UVA tanning in some subjects, even in the absence of overt irritation. The inclusion of UVB, and even UVA, sunscreen in AHA products may be warranted. (J Am Acad Dermatol 2000;43:238-43.)

The local kinetics of percutaneous absorption provide information of relevance to the treatment of skin diseases and to the potential efficacy of transdermally delivered chemotherapy for systemic effect. This paper describes two non-invasive procedures (laser Doppler velocimetry and photopulse plethysmography) which permit pharmacodynamic measurements of methyl nicotinate skin penetration to be made in vivo in man. The methods are sensitive to the local vasodilative action elicited by the nicotinic acid ester. Dose-response behavior as a function of time has been monitored (1) over the concentration range 5-100 mM, and (2) by variation of drug application time and administration area. At the higher concentrations used, the magnitude of the erythemal response is saturable, and the effect is then progressively prolonged by further increasing the applied dose. Analysis of the data permits assessment of (a) the kinetics of drug delivery to and depletion from the site of action, and (b) the hypothetical level of steady state drug input necessary to sustain 50 % of the maximum detected response. Measurements of the type described here may prove useful, therefore, for elucidating otherwise inaccessible aspects of transcutaneous kinetics in vivo.

The literature addressing determination of the bioavailability of dermatological and other topically administered drugs has been reviewed. The various methods employed, their advantages and drawbacks, have been identified and evaluated. The state of the art and the success of topical bioavailability assessment are discussed in the light of the information presented. It is concluded that, although current methodology ensures the responsible use of topical medicaments, the techniques are, on the whole, quantitatively inadequate. A number of recommendations are proposed as possible improvements to the approaches now undertaken, and specific measurements for drugs in different therapeutic categories are suggested. The ultimate objective of this survey is to catalyze the establishment of straightforward, objective, quantitative, and reproducible methods to evaluate topical bioavailability and to reduce significantly, thereby, the incidence of bioinequivalence and pharmacological inactivity observed following drug dosing to the skin.

This work uses the approach of compartmental analysis to describe the time course of solutes in plasma following transdermal iontophoresis.

Transdermal drug delivery allows for a constant rate of drug administration and prolonged action, which can be beneficial to elderly patients who are often polymedicated. Several studies have compared dermatopharmacokinetics in the young and elderly with conflicting results. Despite the potential limitations of age-related changes in skin factors and cutaneous metabolism, marketed transdermal products generally do not report age-related differences in pharmacokinetics. This overview discusses the current data, summarizes marketed product findings and highlights the importance of further studies to evaluate age-related dermatopharmacokinetics.

Changes in the skin that occur in the elderly may put them at increased risk for altered percutaneous penetration from pharmacotherapy along with potential adverse effects. Skin factors that may have a role in age-related percutaneous penetration include blood flow, pH, skin thickness, hair and pore density, and the content and structure of proteins, glycosaminoglycans (GAGs), water, and lipids. Each factor is examined as a function of increasing age along with its potential impact on percutaneous penetration. Additionally, topical drugs that successfully overcome the barrier function of the skin can still fall victim to cutaneous metabolism, thereby producing metabolites that may have increased or decreased activity. This overview discusses the current data and highlights the importance of further studies to evaluate the impact of skin factors in age-related percutaneous penetration.

There is a need to better define how the efficacy of investigational drugs is affected by study design, implementation, and placebo responses in randomized controlled trials. The improvements observed in placebo groups within trials examining psoriasis treatments may be partially due to study design and implementation. We conducted a systematic review of randomized placebo-controlled trials assessing the efficacy of biologics in the treatment of psoriasis and psoriatic arthritis to evaluate rates of placebo and active drug responders to determine specific factors within study design that may contribute to placebo responses. We included randomized, placebo-controlled trials of etanercept, infliximab, adalimumab, golimumab, ustekinumab, alefacept, and efalizumab that utilized Psoriasis Area Severity Index as an outcomes measure. We compared the rates of the placebo treatment arm versus the active drug arm achieving 75 % improvement of Psoriasis Area Severity Index. 31 trials involving 8285 active treatment and 3999 placebo patients were included. Rates of placebo responders (4.14 %) were significantly lower than active drug responders (48.4 %). The overall odds ratio calculated was 23.94 (p < 0.0001, 95 % CI 16.02–35.76). Binomial regression models showed that treatment indication, randomization fraction, a PASI inclusion requirement, and the time period of outcomes measure documentation affect placebo responses. Placebo responses seen in randomized controlled trials evaluating biologics in the treatment of psoriasis are not likely due to a physiologic mechanism, but may be secondary to chronic disease course and factors of clinical trial design and implementation.

Repeated contact of skin with surfactants causes irritation often characterized by dryness, erythema and scaliness. Morphologically healed skin after preexposure can still evoke a stronger reaction to any subsequent exposure of an irritant. Cumulative irrtancy using the overlap phenomenon was studied. The effects of repeated and prolonged application of sodium lauryl sulfate (SLS) on human skin in vivo (healthy adult volunteers) were evaluated using non-invasive techniques of TEWL and skin capacitance measurements and visual scoring. The inability of TEWL and skin capacitance to achieve pretreatment values 2 weeks post SLS treatment suggests the possible detrimental effects of SLS on skin lipids. The surfactant effect was cumulative and dehydrating effects on prolonged and repeated application were observed.

We document evidence that the major rate-limiting step in iontophoretic drug delivery of low molecular weight charged solutes can be dermal perfusion at the site of application; for high molecular weight solutes, on the other hand, transport to the site of microcirculation uptake may, in some circumstances, become the slowest step.

Allergic complications following insertion of metallic orthopaedic implants include allergic dermatitis reactions but also extracutaneous complications. As metal-allergic patients and/or surgeons may ask dermatologists and allergologists for advice prior to planned orthopaedic implant surgery, and as surgeons may refer patients with complications following total joint arthroplasty for diagnostic work-up, there is a continuous need for updated guidelines. This review presents published evidence for patch testing prior to surgery and proposes tentative diagnostic criteria which clinicians can rely on in the work-up of patients with putative allergic complications following surgery. Few studies have investigated whether subjects with metal contact allergy have increased risk of developing complications following orthopaedic implant insertion. Metal allergy might in a minority increase the risk of complications caused by a delayed-type hypersensitivity reaction. At present, we do not know how to identify the subgroups of metal contact allergic patients with a potentially increased risk of complications following insertion of a metal implant. We recommend that clinicians should refrain from routine patch testing prior to surgery unless the patient has already had implant surgery with complications suspected to be allergic or has a history of clinical metal intolerance of sufficient magnitude to be of concern to the patient or a health provider. The clinical work-up of a patient suspected of having an allergic reaction to a metal implant should include patch testing and possibly in vitro testing. We propose diagnostic criteria for allergic dermatitis reactions as well as noneczematous complications caused by metal implants.

Synopsis Transepidermal water loss (TEWL), skin surface water loss (SSWL) and water content of the stratum corneum are utilized to assess the hydration effects of moisturizers and soaps. The relationship among these parameters may help differentiating hydration obtained via occlusion or by water-holding in the stratum corneum. Furthermore, skin function (hydration, dehydration, barrier damage) can be studied comparing the data obtained with these techniques. In this study, the effects of glycerol, petrolatum, soaps and commercial moisturizers on the skin are investigated and discussed.

Patch testing remains the milestone of testing procedures in the diagnosis of allergic contact dermatitis and related diseases, in which a delayed-type (type IV) hypersensitivity is suspected (see Chap. 2). As explained in Chaps. 3–6, the technique has its own limitations and cannot by itself solve all situations encountered in environmental dermatology. Fortunately, patch testing has some undisputed “allies” to improve and prolong its performance. These additional testing procedures are discussed in the following sections.

Photosensitivity is defined as responsiveness to light exposure. For many common dermatologic drugs, proper storage conditions are essential for maintaining drug activity. Degradation and loss of activity can occur with exposure to light, temperature, and/ or moisture. For example, ketoconazole degrades after 24 hours of light exposure. In this article storage guidelines for common dermatology drugs are provided. We suspect that drug degradation is common due to improper storage and that improved patient instruction regarding storage will reduce degradation and alleviate some of the danger associated with improper storage and usage patterns.

Background: The North American Contact Dermatitis Group (NACDG) has members who assess subjects with suspected allergic contact dermatitis (ACD) and patch tests them with the same screening allergens using a standardized procedure permitting analysis of long-term trends in patch test reactions. Objective: This study reports the trends in prevalence patch test positivity of allergens by pooling data collected by the NACDG between 1970 and 2002. Patients/Methods: Patients were tested with the screening series of allergens, using a standardized technique. Data from these patients were recorded on a standard computer entry form and analysed. More than 100 allergens were tested on over 34 000 patients during several patch studies between the period. The Cochran-Armitage test of trend is used to evaluate changes in prevalence over time. Results: 4 trends are noticed: (1) The incidence of presumed allergic nickel (P < 0.0001) and quaternium-15 (P < 0.0001) reactions rose with consistency over the years. (2) While that of cinnamic aldehyde (P = 0.21) and p-phenylenediamine (P < 0.0001) decreased. (3) The prevalence of positive reactions for potassium dichromate (P < 0.0001) shows an initial steady decrease but then a sharp increase starting from the 1996 period. (4) In contrast, thiuram (P = 0.0008) and neomycin (P < 0.0001) show an initial general increase, with a sharp decrease between 1998 and 2002. Conclusion: Implications for opportunities to prevent ACD by utilizing less-allergenic alternatives appear robust; however, we do not wish to over generalize interpretations because of important limitations.

To investigate differences in response to irritation according to age and site seven young-adult and eight elderly females were exposed to 0.25% sodium lauryl sulphate (SLS) under patch-test occlusion for 24 h. Ten anatomical regions were tested: forehead, upper arm, volar and dorsal forearm, postauricular, palm, abdomen, upper back, thigh, and ankle. The skin responses were evaluated 24 h post-patch removal by visual scoring and by transepidermal water loss measurements (TEWL). Non-treated symmetrical anatomical regions served as controls. SLS induced a mild erythematous reaction on most anatomical regions except the palm and TEWL was significantly increased as compared with controls. The elderly group demonstrated significantly less susceptibility to SLS-induced irritation for most regions of the body as indicated by visual scores and TEWL measurements. In addition, evaluation of the stratum corneum water content following SLS irritation demonstrated lower responses in the old age group for most regions. The thigh had the highest reactivity and the palm the lowest, in both age groups. These data suggest that young adult skin is more sensitive to SLS than old skin and that SLS irritation varies considerably with respect to region. Moreover, objective TEWL measurements seem to be a better indicator of irritant susceptibility, especially in the elderly, than clinical evaluation by visual scoring.

The effect of daily topical application on the in vivo percutaneous absorption of benzoic acid, parathion and salicylic acid in rhesus monkeys has been investigated. The study was designed to test further the hypothesis that topical bioavailability, or body burden, of a chemical following chronic exposure may be accurately predicted from the result of a single acute-dose experiment. No significant change in percutaneous absorption from that following the initial dose was observed following the eighth daily dose of a 14-day multidose regimen for each of the three penetrants considered. The results are consistent with those of recent experiments in humans with malathion and steroids, but not entirely consistent with the results of other animal studies.

Exposure of the skin to surfactant-based products can result in irritation. To control this effect researchers are probing mechanisms of surfactant action. In vitro studies show that mixing surfactants often results in less denaturation (swelling) of stratum corneum. We have explored the in vivo human irritation response (using a 21-day cumulative irritation test) to two of these surfactants – sodium lauryl sulfate (SLS) and (C12–C14) alkyl, 7-ethoxy sulfate (AEOS-7EO). Results demonstrate that addition of AEOS-7EO to a constant dose of SLS results in a significant reduction in erythema, hence producing a milder system. The reason for the synergism is unclear, but may relate to experimentally determined alterations in the micellar solution properties of the SLS upon addition of AEOS-7EO.

Psoriasis is a chronic relapsing disease characterized by variable clinical features. Several factors may exacerbate its manifestations, or even trigger the disease, such as traumatic injury to the skin, physical and psychological stress, cold weather, excessive alcohol intake, and drugs such as lithium and Beta-blockers. We describe the most common features of psoriasis and the exogenous factors that may induce, trigger or exacerbate the disease.

Barrier creams (BC) are used in hand care to protect the user against damage from surfactants and other irritants; their clinical value remains debatable; some reports indicate that inappropriate BC application might induce a deleterious rather than a beneficial effect. Since many cosmetic formulations contain 'skin protectants', we review concept, application, and efficacy from the pertinent scientific literature.

With cutaneously applied local anesthetic bases various effects may be observed, such as a decrease in pricking pain and a change in burning, itch, and thermal sensations. These effects occur after skin penetration and may be attributed to the action of the anesthetics on nociceptors and thermoreceptors, i.e., on C and A delta nerve fibers, respectively. As little is known about the pharmacodynamic response of nonionic surfactants with a potentially anesthetic action such as polidocanol, this study characterizes nonionic surfactants pharmacodynamically by measuring thermal thresholds with a thermal sensory analyzer after cutaneous application. The results obtained with the nonionic surfactants were compared with data resulting from the cutaneous application of local anesthetic bases such as mepivacaine, bupivacaine, prilocaine, lidocaine, the 1:1 mixture of lidocaine and prilocaine contained in EMLA and a triple mixture consisting of lidocaine, prilocaine and tetracaine (1:1:1). The results show that none of the investigated surfactants affect thermal thresholds probably due to their high molecular weight. The same was observed with the anesthetics mepivacaine and bupivacaine. In contrast, prilocaine, lidocaine, the 1:1 mixture of lidocaine and prilocaine and the triple mixture consisting of lidocaine, prilocaine and tetracaine (1:1:1) proved to be potent local anesthetics. However, their pharmacodynamic responses do not differ significantly from each other.

Irritant contact dermatitis (ICD) is a common dermatological diagnosis in which endogenous and exogenous factors have been implicated. This review explores ethnicity as a possible endogenous factor. While there is a clinical consensus that blacks are less reactive and Asians are more reactive than Caucasians, the data supporting this hypothesis rarely reaches statistical significance. The studies reviewed do not provide sufficient evidence to determine that race is a predisposing factor to the degree of irritation in ICD. We conclude that race could be a factor in ICD, which has practical consequences regarding topical product testing requirements, an ever-expanding global market, occupational risk assessment, and the clinical thinking about ICD. Pitfalls in defining differences are discussed.

Cutaneous adverse drug reactions (CADRs) to systemically administered drugs have increased in number during the last few years. This is due to the expanding number of new active molecules used in the treatment of a variety of diseases. CADR are varied and described in full detail in oriented manuals of dermatology [1–3].

Prick tests are primarily used to detect antigens (allergens) involved in the occurrence of type I immediate skin reactions. The classic (but not exclusive) example of such reactions is immunological contact urticaria (see Fig. 10.1). This is caused by an antigen antibody, type I, immunoglobulin E (IgE)-mediated hypersensitivity reaction. The antigen is the chemical contactant that binds to specific IgE antibodies on the surface of dermal mast cells. This triggers degranulation and liberation of vasoactive substances, primarily histamine, that cause dermal oedema surrounded by an erythematous flare. Elevated serum levels of specific IgE antibodies have been demonstrated in response to contact urticariogens such as natural latex.

Contact sensitivity to plants containing 1 or more sesquiterpene lactones (SLs) is difficult to diagnose. The mixture of SLs (SL mix) has been shown to detect only about 60% of sensitized individuals. In order to improve the diagnosis of sensitization to plants containing SLs, we have tested a mixture of frullanolides contained in Frullania dilatata and Frullania tamarisci at 3 different concentrations (0.01%, 0.033% and 0.1% in petrolatum). 8605 consecutive eczema patients in 1 North American and 15 European dermatology departments were tested with this mix, and 0.35% of positive cases to the different concentrations were found. Routine use of this mix permitted detection of only a small percentage of extra cases and did not improve the SL mix score. The frullanolide mix should therefore be restricted to investigations in particular geographical zones and/or in particular occupations.