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Hepatitis C is a ribonucleic acid (RNA) virus, and its presence in individuals was previously considered to be a chronic condition. However, recent therapeutic advances with virus-directed treatment have resulted in a significant increase in cure rates as demonstrated by an absence of virus on repeat testing. Currently, several individual and combination antiviral therapies are available for the treatment of hepatitis C virus infection. However, each of the hepatitis C antiviral agents is associated with potential adverse skin effects whose incidence varies depending on the agent used for treatment. The cutaneous reactions, including photosensitivity, usually resolve once the antiviral treatment is completed. In this report, we discuss the case of a chronic hepatitis C patient who developed sofosbuvir-velpatasvir (Epclusa)-associated toxicity, while receiving the antiviral therapy. The 57-year-old man developed cutaneous phototoxicity when he started treatment with the drug. The adverse skin reaction promptly resolved once the treatment was completed. Clinicians who manage patients being treated with antiviral agents for hepatitis C infection should consider counseling these individuals regarding photoprotection including avoidance of sun exposure, daily sunscreen use, and wearing photoprotective clothing.

Simultaneous contact allergies are common in individuals with photocontact allergy to ketoprofen. The rate of contact allergy to the fragrance substances oxidized linalool and oxidized limonene in ketoprofen-photo-allergic individuals were investigated in comparison with the corresponding rates in individuals without photo-contact allergy to ketoprofen, using Fisher's exact test. A total of 4,021 patients were routinely tested with oxidized linalool; of whom 190 (4.7%) tested positively. For oxidized limonene the numbers were 3,797 patients and 111 positive reactions (2.9%). A total of 19 contact allergic reactions to oxidized linalool were noted in 29 patients (65.5%) who also had photocontact allergy to ketoprofen (p

The novel group of immunological agents used for solid tumors has importantly improved the quality of life and the survival rate of oncologic patients. Compared to conventional chemotherapy agents, they are more effective and less toxic. However, adverse cutaneous effects are commonly observed, and in some cases, they may induce treatment discontinuation, with heavy impact on patient prognosis. Among these, photosensitive reactions, either phototoxic or photoallergic, are increasing. Much remains to be clarified on the understanding of their prevention, diagnosis, and management. We have reviewed the literature about photosensitive reactions occurring during oncologic immunotherapies. Early dermatological diagnosis and adequate management, with oncologist's cooperation, is fundamental.

Drug-induced photosensitivity reactions are significant adverse effects. Ketoprofen is one of the most common drugs that can cause skin rash in sun-exposed areas. Non-steroidal anti-inflammatory drugs (NSAIDs), such as ketoprofen, are often used for a variety of symptoms, including pain and fever. An understanding of the presentation and clinical course of ketoprofen-induced photosensitivity is necessary to correctly diagnose and manage this condition. Ketoprofen-induced photosensitivity reactions usually present as photoallergic dermatitis, which is a cell-mediated immune process. The benzophenone moiety in ketoprofen plays a major role in ketoprofen's ability to act as a photosensitizer. Several agents, such as fenofibrate and octocrylene have been found to be associated with aggravation of ketoprofen-induced photoallergic dermatitis or cross-photosensitization, and these reactions result from structural similarities with ketoprofen. Treatment of ketoprofen-induced photoallergic dermatitis includes discontinuation of ketoprofen, topical or systemic corticosteroids and avoidance of sun exposure and agents known to exacerbate dermatitis. In conclusion, photoallergic dermatitis is a significant adverse effect of ketoprofen. Some agents known to worsen dermatitis may be found in sun protection products (notably, octocrylene in sunscreen). Educating the patient to avoid these products is critical to treatment. Since NSAIDs, such as ketoprofen, are used commonly for a variety of illnesses, drug-induced photoallergic dermatitis should be high on the differential in individuals using these medications who present with acute onset of a rash in sun-exposed areas.

Antecedentes: La dermatitis por contacto fotoalérgica (DCFA) a oxibenzona fue por primera vez documentada en 1980, siendo hoy el principal fotoalérgeno de Estados Unidos de América, Canadá y el cuarto en Europa. En Argentina no existen datos ni publicaciones con respecto a esta reacción cutánea. Objetivo: Conocer el porcentaje de pacientes con fotosensibilidad afectados con fotoalergia a oxibenzona. Metodología: Estudio descriptivo de corte transversal. Un total de 35 pacientes con reacciones fotosensibles con prueba del fotoparche en el Centro de investigación del Hospital Público San Martín, en la ciudad de La Plata, fueron estudiados durante los anos ˜ 2015 y 2016. Resultados: Se observó el 17,14% de DCFA, presentando 5 (14,28%) pacientes al menos una reacción positiva a oxibenzona en el test de fotoparche, 4 pacientes solo en la zona irradiada con 5 J/cm2 (de UVA) y solo un paciente tanto en la zona irradiada como en la no irradiada. Conclusiones: La DCFA a protectores solares compuestos por oxibenzona es frecuente y se presume infradiagnosticada debido a la falta de estudios confirmatorios como la prueba del fotoparche. El porcentaje de sensibilización varía de acuerdo con cada región, sobre todo por las distintas composiciones y costumbres de uso en protectores solares, cosméticos y tratamiento tópico. Background: Photoallergic contact dermatitis (PACD) to oxybenzone was reported for the first time in 1980. Oxybenzone is the most common photoallergen in the United States and Canada and the fourth most common.in Europe. There are no studies or data on the prevalence of oxybenzone PACD in Argentina. Objective: To determine the proportion of photosensitive patients with PACD to oxybenzone. Methods: We conducted a descriptive cross-sectional study of 35 patients with photosensitivity reactions confirmed by photopatch testing at the Research Center of Hospital Público San Martín in La Plata, Argentina, in 2015 and 2016. Results: PACD was identified in 6 patients (17.14%). Five of these (14.28%) had at least one positive reaction to oxybenzone in the photopatch test; 4 had a reaction at irradiated sites only (5 J/cm 2 UVA) and one had a reaction at both irradiated and nonirradiated sites. Conclusions: PACD to sunscreens containing oxybenzone is common and is probably underdiagnosed due to a lack of confirmation by photopatch tests or other diagnostic tools. Sensitization rates vary according to region and are influenced by sunscreen ingredients and variations in the use of sunscreen products, cosmetics, and topical drugs. Fil: Alejandra Isabel, Lo Russo. Provincia de Entre Rios. Hospital San Martin; Argentina Fil: Ipiña Hernandez, Adriana. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Física de Rosario. Universidad Nacional de Rosario. Instituto de Física de Rosario; Argentina Fil: Cannavó, A.B.. Sociedad Argentina de Dermatología; Argentina Fil: Piacentini, Ruben Dario Narciso. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Física de Rosario. Universidad Nacional de Rosario. Instituto de Física de Rosario; Argentina Fil: Niklasson, B.. Chemotechnique Diagnostics; Suecia

Titel, Inhaltsverzeichnis 1\. Einleitung und Zielstellung 1 2\. Theoretischer Teil 3 3\. Ergebnisse und Diskussion 21 4\. Zusammenfassung 120 Summary 122 5\. Experimenteller Teil 124 6\. Anhang 132 7\. Literaturverzeichnis 133 Publikation, Das Ziel dieser Arbeit, die Kopplung der Photochemie im rein wässrigen Milieu mit der Hochleistungsflüssigchromatographie, wurde erfolgreich umgesetzt. Unter Verwendung einer Säulenschaltung konnte der Photoreaktor mit dem chromatographischen System gekoppelt werden. Die Anreicherung und Chromatographie erfolgte mit zwei speziellen Aqua Säulen. Die im Rahmen dieser Arbeit erstmals entwickelte HPLC online Methode konnte erfolgreich zu Photostabilitätsprüfungen bei variablen pH-Werten und mit unterschiedlichen Lichtquellen eingesetzt werden. Diese Methode ermöglicht die Untersuchung von verschiedensten Arzneistoffen. So konnten sowohl polare als auch lipophile Arzneistoffe untersucht werden. Besonders hervorzuheben ist die Anwendung dieser Methode zum Screening auf phototoxische oder photoallergene Reaktionen von Arzneistoffen. Zur Testung auf phototoxische Reaktionen wurde die DNA-Base Guanosinmonophosphat als Modellsubstanz verwendet. Die Arzneistoffe Chlorpromazin und Ofloxacin zeigten unter Belichtung mit UV-A Licht Wechselwirkungen und Reaktionen mit der DNA-Base und die phototoxische Wirkung dieser Stoffe konnte mit dieser Methode bestätigt werden. Auf der anderen Seite zeigte das Diuretikum Hydrochlorothiazid keine Reaktion mit GMP, obwohl der Stoff in der Literatur als phototoxisch beschrieben wurde. Durch die Verwendung eines kurzen DNA-Einzelstranges anstatt der Base GMP konnte eine Reaktion von Hydrochlorothiazid unter Belichtung mit dem DNA-antisense-Strang nachgewiesen werden. In Versuchen mit dem DNA-sense-Strang konnte hingegen keine Wechselwirkung festgestellt werden. Zur Testung auf photoallergische Reaktionen erwies sich das Dipeptid Alanyltryptophan als Modellsubstanz für besonders geeignet. Die Versuchsergebnisse zum Screening auf Photoallergenität korrelierten gut mit den Angaben aus der Literatur. Die Photoallergenität konnte für die Phenothiazine, Hydrochlorothiazid, Ofloxacin und Mefloquin durch die Wechselwirkung oder Reaktion mit dem Dipeptid bestätigt werden. Bestätigt wurde die Theorie, dass häufig halogenierte Arzneistoffe an photochemischen Reaktionen mit Biomolekülen beteiligt sind. Die halogenierten Arzneistoffe Chlorpromazin, Hydrochlorothiazid, Ofloxacin und Mefloquin erwiesen sich als besonders reaktiv in Gegenwart von Biomolekülen. Die nicht halogenierten Arzneistoffe Etodolac und Nifedipin zeigten zum Vergleich kaum Reaktionen mit den Biomolekülen. Insgesamt hat sich in den durchgeführten Untersuchungen eine ausgeprägte pH-Abhängigkeit gezeigt. Dabei ist das Spektrum der resultierenden Photoprodukte stark vom pH-Wert abhängig und somit auch die Reaktivität der Photoprodukte mit den Biomolekülen. Mit den Untersuchungsergebnissen lässt sich eine sequenzabhängige Schädigung der DNA- Einzelstränge belegen. Die Chromatogramme von dem DNAa-Strang zeigten in Anwesenheit von Hydrochlorothiazid, Eosin und Protoporphyrin eine Schädigung der DNA, während vergleichend die Untersuchungsergebnisse zu dem DNAs-Strang eine größere Stabilität zeigten. Im Vordergrund steht die Nutzung dieser Methode zum Screening auf ein mögliches phototoxisches und photoallergenes Potential von Arzneistoffen. Bei Arzneistoffen, die sich in der Entwicklung befinden, könnte frühzeitig ein phototoxisches oder photoallergenes Potential erkannt werden. Mit dieser Methode steht eine kostengünstige Alternative zu herkömmlichen Methoden zur Verfügung. Im Vergleich sind Tierversuche sehr zeitaufwendig und damit auch kostenintensiv. Ausgehend von den vorgestellten Ergebnissen ergeben sich zahlreiche weitere Anwendungsmöglichkeiten. Mit dieser Methode könnten neue Erkenntnisse zu Wirkungsmechanismen von Photosensibilisatoren in der Photodynamischen Therapie gewonnen werden., The purpose of this work, the coupling of the photochemistry in the purely watery environment with the high performance liquid chromatography, was moved successfully. The HPLC on-line method was developed by using a hyphenated technique comprising a photoreactor and HPLC separation. The enrichment and chromatography occurs with two special aqua columns. The developed HPLC on- line method was used successfully for photostability testing with variable pH factors and with different sources of light. The described method allows the investigation of the most different drugs. Thus, polar as well as lipophilic drugs could be investigated with this method. Especially the application of this method the screening on phototoxic or photoallergic reaction by drugs is to be emphasised. For screening phototoxic reactions the DNA base guanosinemonophosphate was used as model substance. The drugs chlorpromazine and ofloxacine showed under exposure with UVA light interaction and reaction with the DNA base and the phototoxic effect of these drugs could be confirmed with this method. On the other side the diuretic drug hydrochlorothiazide showed no reaction with GMP, although the drug was described in the literature as phototoxic. A reaction of hydrochlorothiazide could be proved by the use of short DNA antisense single-strand instead of the base GMP under exposure with UVA light. However, in attempts with the DNA sense single-strand no interaction could be ascertained. For the screening on photoallergic reaction of drugs the dipeptide alanyltryptophan was used as model substance. The test results to the screening on photoallergy well correlated with the information from the literature. The photoallergic potential could be confirmed for the phenothiazines, hydrochlorothiazide, ofloxacine and mefloquine by the interaction or reaction with the dipeptide. The theory was confirmed that often halogenated drugs are involved in photochemical reactions with biomolecules. The halogenated drugs chlorpromazine, hydrochlorothiazide, ofloxacine and mefloquine turned out especially reactive in present of biomolecules. The not halogenated drugs etodolac and nifedipine showed to the comparison weak reaction with biomolecules. All together distinctive pH dependence has appeared in the carried out investigations. A damage dependent on sequence of the DNA single-strand can be booked with the investigation results. The chromatograms of the DNA antisense strand showed in presence of hydrochlorothiazide, eosine and protoporphyrine a damage or structure change of the DNA antisense strand, while the comparative investigation results showed higher stability to the DNA sense strand. The main application of the described HPLC on-line method is the screening on photoallergic and phototoxic potential of drugs. Drugs in development could be tested with this method in early stage. This method is a low cost alternative to conventional methods. In comparison animal experiments are very time-consuming and are also cost- intensive with it. Outgoing from the introduced results numerous other application possibilities arise. With the developed method new knowledge could be won to understand mechanisms by photosensitizers in photodynamic therapy.

Regulatory requirements: According to the current Notes for Guidance of the Scientific Committee on Cosmetic Products and Non-Food Products (SCCNFP), cosmetic ingredients and mixtures of ingredients absorbing UV light (in particular UV filter chemicals used, for example, to ensure the light stability of cosmetics or used in sun protection products) should be tested for acute phototoxic and photogenotoxic potential. Testing for photosensitisation (immunological photoallergy) potential is not specifically required, but it is nevertheless often performed. Acute phototoxicity: Due to a thorough multi-stage and multi-centre validation trial (1992-1998) the In Vitro 3T3 Neutral Red Uptake Phototoxicity Test (3T3-NRU-PT) had already gained acceptance by the SCCNFP in 1998, and it is recommended by the EMEA/CPMP as a basic preclinical test for acute phototoxicity. It was accepted as Method No. 41 in Annex V to Directive 67/548/EEC in the year 2000, and was accepted as the new Test Guideline 432 by the OECD in 2002. The 3T3-NRU-PT is regarded as a basic screen for identifying acute phototoxic potential. Two additional in vitro tests, formally evaluated in controlled blind trials, the RBC Phototoxicity Test (RBC-PT) and the Human 3-D Skin Model Phototoxicity Test (H3D-PT), are regarded as useful and important adjunct tests to overcome some limitations of the 3T3-NRU-PT, namely the fairly low UVB tolerance of the 3T3 fibroblasts and the inability to model the bioavailability of test materials topically applied to the skin. In addition, the RBC-PT permits an evaluation of the phototoxic mechanisms involved. In conclusion, the identification of acute phototoxic hazards is now regarded as being sufficiently covered by in vitro tests, so that animal testing for that endpoint can now be 100% replaced. Photogenotoxicity: In the area of photogenotoxicity, almost the whole battery of in vitro genetic toxicity tests have been (or are currently being) converted into test protocols of photogenotoxicity tests. Tests exclusively predictive for gene mutation, for example, the Photo-Ames (P-Ames) Test and the Photo-Thymidine Kinase Test (P-TKT), have become less important than tests for clastogenic effects (for example, the Photo-Chromosome Aberration Test [P-CAT] and the Photo-Micronucleus Test [P-MNT]). In addition, a number of promising indicator tests, such as the Photo-Comet Assay (P-Comet) have been developed. Although routinely used, to date none of the new photogenotoxicity tests have been formally validated. Therefore, the P-MNT and the P-Comet are currently being evaluated in a formal interlaboratory validation study. It is expected that these in vitro photogenotoxicity test methods may become available as validated and accepted methods within the next five years. Photoallergy (Photosensitisation): In the area of photoallergy (photosensitisation), as development of predictive in vitro tests for delayed contact sensitisation (allergenicity) potential without the involvement of light, due to a lack of ability to model the complex mechanisms underlying allergy, no promising in vitro methods to predict photo-sensitisation potential are currently in sight (see the section on skin sensitisation). One in vitro screening method, which models the covalent binding of a light activated chemical to human serum albumin, may become relevant. However, while the binding of an excited chemical to proteins is a prerequisite for photoallergy, this is not a sufficient predictor on its own. The only promising alternatives currently under development are in vivo refinements, like the Photo Local Lymph Node Assay (PLLNA). Once a reliable and predictive in vitro test battery and strategy for the assessment of "dark" sensitisation potential have been developed and accepted, their adaptation into similar photosensitisation testing will become possible.