An approach to evaluate metabolite-related phototoxicity with combined use of photochemical properties and skin deposition.

Some chemicals have been reported to cause metabolite-related phototoxicity, and this study aimed to verify the applicability of photosafety assessment based on photochemical and pharmacokinetic properties to evaluate the metabolite-related phototoxicity risk. The phototoxic risk of imipramine (IMI) and its metabolite, desipramine (DMI), was evaluated by photochemical and pharmacokinetic analyses. IMI and DMI were found to have similar photoreactivities based on the generation of reactive oxygen species. The skin concentrations of IMI and DMI reached maximal levels at approximately 1 and 4 h, respectively, after oral administration of IMI (10 mg/kg), and DMI showed high skin deposition compared with IMI. According to the results, DMI was identified as a contributor to phototoxicity induced by orally-taken IMI. In in vivo phototoxicity testing, ultraviolet A irradiation from 3 to 6 h after oral administration of IMI (100 mg/kg) caused more potent phototoxic reactions compared with that from 0 to 3 h, and DMI yielded by metabolism of IMI would be associated with phototoxic reactions caused by orally-administered IMI. In addition to the data on IMI, a parent chemical, photochemical and pharmacokinetic profiling of its metabolite, DMI, led to reliable phototoxicity prediction of orally-administered IMI. Thus, characterization of the photosafety of metabolites would generate reliable information on the phototoxicity risk of parent chemicals, and the proposed strategy may facilitate comprehensive photosafety assessment of drug candidates in pharmaceutical development.

Insight into immunocytes infiltrations in polymorphous light eruption.

Polymorphous light eruption (PLE) which is one of the most common photodermatoses has been demonstrated to be immune-mediated disorder. Resistance to UV-induced immunosuppression resulting from differential immune cells infiltration and cytokines secretion has been highlighted in the pathogenesis of PLE. In this study, we reviewed differential patterns of immune cells infiltrations and cytokines secretion that may contribute to PLE occurrence and development.

Evidence and conjecture about mechanisms of cutaneous disease in photodermatology.

Photosensitivity disorders are caused by a variety of mechanisms. Three common themes are as follows: excess chromophore allowing visible light energy to cause photodynamic damage, reduced DNA repair capacity to UV-induced DNA damage, and enhanced sensitivity to light-induced allergens mediated immunologically. Although the cause of each condition may be known, the precise pathogenesis underlying the photosensitivity has taken longer to understand. By focussing on three clinical disorders under each of these themes, we have explored the following: why erythropoietic protoporphyria differs so markedly from the other cutaneous porphyrias; how a DNA repair defect was eventually revealed to be the underlying cause of the vitamin B3 deficiency disorder of pellagra; an immunological explanation for the over reactivity to photoallergens in chronic actinic dermatitis.

Photopatch testing in Asians: a 5-year experience in Singapore.

BACKGROUND: Photopatch testing is important for diagnosing photoallergic contact dermatitis. We aimed to evaluate the use of photopatch test at the National Skin Centre, Singapore. METHODS: All patients who had photopatch tests done between 2007 and 2011 at the National Skin Centre were included. RESULTS: Twenty-two patients were included. The mean age was 40.2. Female : male ratio was 3.4. The ethnic groups were Chinese (68%), Malay (4%), Indian (14%) and others (14%). Ten out of 22 patients (45.5%) had a positive photopatch test. There were 20 positive photopatch test reactions found in these 10 patients, and all 20 positive reactions were of current relevance. The frequencies of the positive photopatch test reactions were 2-hydroxy-4-methoxybenzophenone (oxybenzone) (n = 6), 2-hydroxymethoxymethylbenzophenone (mexenone) (n = 3), 2-ethylhexyl-4-dimethylaminobenzoate (n = 1), ketoprofen gel (n = 1) and the patient's own product (n = 9). CONCLUSIONS: Our study suggests that sunscreen is the most common photoallergen to date as opposed to musk ambrette, which was the most common photoallergen in our earlier study in 1991-1993. This finding is similar to the recent European Multicentre Photopatch Test Study.

Normal minimal erythema dose responses in patients with suspected photosensitivity disorders.

PURPOSE: Our study identified the most common diagnoses in patients with a history of photosensitivity or with a photodistributed eruption and normal minimal erythema dose (MED) responses. METHODS: We retrospectively reviewed the diagnoses and phototest results of 319 patients who were phototested at the New York University Photomedicine Section of the Charles C. Harris Skin and Cancer Pavilion from 1993 to 2009. Patients were phototested if they had a history of photosensitivity or had an eruption with a distribution that suggested photosensitivity. RESULTS: The majority of patients with normal MEDs were diagnosed with polymorphous light eruption, followed by contact or photocontact dermatitis, photodistributed dermatitis not otherwise specified (idiopathic), solar urticaria and photoexacerbated atopic dermatitis. DISCUSSION: The clinical history of photosensitivity and physical findings remain as important metrics in the diagnosis of patients with photodistributed dermatoses and normal MEDs.

First reported case of tenofovir-induced photoallergic reaction.

A 50-year-old man, a known case of human immunodeficiency virus infection for the past 1 year, was on antiretroviral therapy in the form of stavudine, lamivudine, and nevirapine. Three days after replacing stavudine with tenofovir, he developed redness on the face and neck and within 48 h the rash became generalized. Dermatological examination revealed involvement of photoexposed areas of the face in the form of erythema and ill-defined hyperpigmented plaques, with mild periorbital edema. There was specific involvement of V and nape of the neck. Extensive erythema and scaling were also present on buttocks, thighs, and upper third of legs. A diagnosis of photoallergic dermatitis to tenofovir was considered and confirmed by histopathology and photopatch test. He responded well to the stoppage of the drug and oral corticosteroids. This is the first report of a photoallergic reaction to tenofovir in the literature.

Heracleum Sosnowskyi Manden.

Heracleum Sosnowskyi was discovered in 1772 and described as a separate species in 1944 by I. P. Mandenova. Its name is derived from the surname of a botanist studying Caucasian flora, Prof. D.I. Sosnowski. In the area of the Caucasus foothills, the plant reaches approximately 1-1,5 m in height, whereas in Poland its size is significantly larger, up to 3-3.5 m. Heracleum blooms from mid-June to the end of July. The flowers are arranged in umbels and last for 2-3 weeks. In Central Europe, the species colonizes mostly neglected green areas, ruins and riversides. Heracleum poses a serious threat to the human population due to its photoallergic properties, resulting from the presence of intensely toxic furanocoumarin in its sap. Furanocoumarins are found in small hairs that cover the leaves and stem, and are the components of the essential oil. They may penetrate the skin through the epithelial layer, posing a direct threat to human health. Contact with the plant, followed by sun exposure, may lead to the development of large blisters and symptoms of burns. Heracleum, in the event of consumption, is also harmful to farm animals, causing, among others, internal bleeding and diarrhea. Although the toxic properties of Heracleum have been known for many years, every summer people who had contact with the plant present at physicians of different medical specialties.

[Eczematous skin diseases]. / Ekzemás megbetegedések.

The skin, as one of the most important barriers of the human body, protects the inner homeostasis from the harmful environmental influences as well as physical, chemical and biological factors. When the impact of these factors exceeds the tolerance and reproducing capacity of the skin, pathological alterations will develop. If follows from this that dermatology can surely be considered to be a part of environmental medicine. Eczematous diseases are mostly pathological pictures of varied mechanisms developing as a result of environmental influences (irritants, contact allergens, microbes). Since their clinical appearance is similar, it is a serious professional challenge to diagnose them. In this article we present the clinical features, provoking factors of these skin diseases as well as therapeutical possibilities.

Sunscreen allergy: A review of epidemiology, clinical characteristics, and responsible allergens.

Although allergy to sunscreen represents a small proportion (< 1%) of allergic contact dermatitis reactions in North America, it is one of the most common causes of photoallergy. The epidemiology and clinical characteristics of sunscreen allergy are summarized in this review. In addition, a detailed discussion of specific chemical sunscreen allergens is provided.

Can a positive photopatch test be elicited by subclinical irritancy or allergy plus suberythemal UV exposure?

Photopatch test (PhPT) interpretation is difficult and clinical relevance is not always apparent. A positive PhPT may reflect photocontact allergy or phototoxicity. We hypothesized that it may also reflect the additive or synergistic effects of a suberythemal reaction to a contact irritant [e.g. sodium lauryl sulfate (SLS)] or allergen (e.g. nickel) and suberythemal UV exposure. 10 nickel allergic volunteers had duplicate SLS and nickel series applied on either side of the back for 24 h and 48 h, respectively. After removal, one side was irradiated with 5 J/cm(2) UVA or the dose below the minimal erythema dose for solar-simulated radiation (SSR). The minimal irritancy dose (MID) for SLS and the minimal allergenic dose (MAD) for nickel were determined visually and objectively by erythema meter. While photoaugmentation of subclinical contact allergy or irritancy occurred in some subjects, photosuppression occurred in roughly an equal number. UVA changed the nickel MAD at 48 h in 2 of 5 volunteers but not the SLS MID. SSR changed the nickel MAD in 4 of 5 and the SLS MID in 3 of 5. 2 subjects (none after UVA) showed erythema only in the irradiated set of patches, which could have been interpreted as a positive PhPT. We have demonstrated photoaugmentation and photosuppression of contact allergy and irritancy, which could result in false-positive or false-negative interpretation of PhPTs.

Investigation of photosensitive disorders.

Investigation of photodermatosis is based primarily on the history and clinical findings, histological, immunological and biochemical findings are variably helpful depending on the clinical picture. Formal testing for photosensitivity may be the only definitive test proving photosensitivity on occasion. This article delineates the important features which allow classification of patients which then enables appropriate treatment.

Photosensitivity to exogenous agents.

OBJECTIVE: To better understand cutaneous photosensitivity reactions, a review of its etiologic factors, clinical characteristics, pathogenesis, and treatment modalities was undertaken. METHODS: Articles discussing the above aspects of phototoxic and photoallergic reactions were used to demonstrate what is currently known about photoinduced reactions and how to treat them. RESULTS: Upon interaction of solar UV radiation with the chemical that is present in significant levels on the skin, one of two known reactions may occur in susceptible patients: a phototoxicity and/or photoallergy. Phototoxic and photoallergic reactions can be diagnosed separately on the basis of pathogenesis, clinical characteristics, and histology. Examples of drugs capable of inducing a phototoxic reaction include amiodarone, retinoids, nonsteroidal antiinflammatory agents, diuretics, and antibiotics. Substances known to cause a photoallergic response are fragrances, sunscreens, topical antimicrobials, NSAID, and psychiatric medications, such as chlorpromezine. CONCLUSION: Photoinduced reactions produced by exogenous chemicals are common skin disorders. Definitive therapy requires identifying and removing the offending agent, either the photosensitizing chemical or light. The use of fully protective clothing and a sunscreen of high SPF are important measures when light exposure is inevitable.

Management of polymorphous light eruption : clinical course, pathogenesis, diagnosis and intervention.

Optimal management of patients with polymorphous light eruption (PLE), the most frequent photodermatosis, requires knowledge of the individual clinical course of the disease and pathogenic factors. As PLE often causes problems during leisure-time activities and holidays, resulting in a substantial loss of quality of life, prophylaxis is the most important therapeutic approach. Management of PLE must, therefore, focus on basic preventative measures and additional therapeutic approaches, depending on the clinical condition. PLE can be classified into four severity groups (mild, moderate-to-severe, severe and therapy-resistant), which are useful for determining appropriate prophylactic measurements. No specific laboratory tests are available for the diagnosis of PLE, therefore, a clinician must rely on the clinical appearance of the disorder (e.g. clinical symptoms, the location of the lesions, the relationship of the occurrence of the lesions with sun exposure and the time course of the lesions) as well as a patient's medical history in order to make a diagnosis. Basic preventative management of PLE consists of adequate sun protection comprising avoidance of sun exposure, the use of textile sun protection and the application of broadband sunscreens with high UVA protection potential. Other supportive measurements have to be managed individually and are dependent on the patient's medical history and the severity of the disease. Topical antioxidants, systemic immunomodulation, photo(chemo)therapy and systemic immunosuppression may be required in some cases of PLE. Topical antioxidants represent a new treatment approach for moderate-to-severe PLE and are an effective and well tolerated option for this patient population. Severe PLE also requires photo(chemo)therapy. Phototherapy can be in the form of 311 nm UVB or UVA1 irradiation. In cases where 311 nm UVB or UVA1 are ineffective, psoralen plus UVA (PUVA) bath therapy may be used. However, PUVA bath therapy must be used with caution because it is associated with acute and long-term adverse effects. In rare exceptions we would consider using oral PUVA therapy. However, in our outpatient department, quality of life of most patients is improved with the treatment regimens that are recommended for patients with moderate-to-severe PLE, without the need for photo(chemo)therapy.

Antibodies directed to drug epitopes to investigate the structure of drug-protein photoadducts. Recognition of a common photobound substructure in tiaprofenic acid/ketoprofen cross-photoreactivity.

Drug-induced photoallergy is an immune adverse reaction to the combined effect of drugs and light. From the mechanistic point of view, it first involves covalent binding of drug to protein resulting in the formation of a photoantigen. Hence, determination of the structures of drug-protein photoadducts is of great relevance to understand the molecular basis of photoallergy and cross-immunoreactivity among drugs. Looking for new strategies to investigate the covalent photobinding of drugs to proteins, we generated highly specific antibodies to drug chemical substructures. The availability of such antibodies has allowed us to discriminate between the different modes by which tiaprofenic acid (TPA), suprofen (SUP), and ketoprofen (KTP) photobind to proteins. The finding that the vast majority of the TPA photoadduct can be accounted for by means of antibody anti-benzoyl strongly supports the view that the drug binds preferentially via the thiophene ring, leaving the benzene ring more accessible. By contrast, selective recognition of SUP-protein photoadducts by antibody anti-thenoyl evidences a preferential coupling via the benzene ring leaving the thiophene moiety more distant from the protein matrix. In the case of KTP, photoadducts are exclusively recognized by antibody anti-benzoyl, indicating that the benzene ring is again more accessible. As a result of this research, we have been able to identify a common substructure that is present in TPA-albumin and KTP-albumin photoadducts. This is remarkable since, at a first sight, the greatest structural similarities can be found between TPA and SUP as they share the same benzoylthiophene chromophore. These findings can explain the previously reported observations of cross-reactivity to KTP (or TPA) in patients photosensitized to TPA (or KTP).

Phototoxicity and photoallergy.

Photosensitivity may be phototoxic or photoallergic. Phototoxicity is much more common. There are 2 types of phototoxicity: photodynamic, which requires oxygen, and nonphotodynamic, which does not. Reactions induced by porphyrin molecules, coal tar derivatives, and many drugs are photodynamic. The reaction induced by psoralens, for the most part, is nonphotodynamic. Acute phototoxic reactions are characterized by erythema and edema followed by hyperpigmentation. Long-term ultraviolet phototoxicity results in chronic sun damage and skin cancer formation. Also, certain chemicals such as psoralen molecules and coal tar are photocarcinogenic. Phototoxic reactions to certain drugs produce unusual clinical patterns, that is lichenoid eruptions, dyschromia, photo-onycholysis, and pseudoporphyria. Photoallergy is an uncommon acquired altered reactivity dependent on an immediate antibody or a delayed cell mediated reaction. Solar urticaria is an example of the former, whereas photoallergy to exogenous chemicals is an example of the latter. Photoallergy to systemic drugs does occur but is difficult to characterize. The action spectrum for photoreactions to exogenous agents usually at least includes the ultraviolet A rays for both phototoxicity and photoallergy.

Phytophotodermatitis associated with parsnip picking.

Phytophotodermatitis to certain plant groups is a well recognised entity. The combination of sunlight exposure and contact with plants of the umbelliferae family leads to the development of painful, erythematous, and bullous lesions and later to cutaneous hyperpigmentation. Agricultural workers and many clinicians often fail to make this link when patients present with these lesions. An incident involving 11 patients is presented to high-light this problem.