What is the relationship between photosensitizing drugs and skin cancer?

ABSTRACT: Many medications are associated with phototoxicity or photoallergy, the two types of photosensitivity. Recently, a warning related to increased skin cancer risk was added to the labeling of the popular diuretic hydrochlorothiazide. This article reviews some photosensitizing medications and describes patient education on preventing and recognizing photosensitivity reactions and skin cancer.

[Current problems of polypharmacy in geriatric patients when taking drugs with a risk of photosensitivity.]

The article presents an overview of the current problems of polypharmacy in geriatric patients when taking drugs with a risk of photosensitivity. The article contains information about emerging adverse drug reactions, as well as methods for diagnosing, correcting and preventing phototoxic and photoallergic reactions in patients of older age groups. The main aspects of dermatological support in the system of long-term care for geriatric patients when taking drugs with a risk of photosensitivity are outlined. Clinical signs of senile xerosis and skin manifestations of adverse drug reactions were studied when taking drugs with the risk of photosensitization before and after the use of a photoprotector in elderly patients.

Drug-Induced Photosensitivity - a Continuing Diagnostic Challenge.

When taking different drugs, their possible side effects on the skin should be considered, including skin reactions connected to photosensitivity. This photosensitivity caused by drugs can appear as phototoxic reactions (which occur more often) or photoallergic reactions (which occur less often and include allergic mechanisms). The following drugs stand out as medications with a high photosensitivity potential: nonsteroidal anti-inflammatory drugs (NSAIDs), cardiovascular drugs (such as amiodarone), phenothiazines (especially chlorpromazine), retinoids, antibiotics (sulfonamides, tetracyclines, especially demeclocycline and quinolones), etc. In recent years, photosensitive reactions to newer drugs have appeared, e.g., targeted anticancer therapies such as BRAF kinase inhibitors (vemurafenib, dabrafenib), EGFR inhibitors, VEGFR inhibitors, MEK inhibitors, Bcr-Abl tyrosine kinase inhibitors, etc. In patients taking drugs over a longer period of time (e.g., NSAIDs, cardiovascular drugs, etc.), a particular problem arises when an unrecognized drug-induced photosensitivity on the skin manifests in summer months. When taking patient histories, the physician/dermatovenereologist should bear in mind that any drug the patient is currently taking may be the cause of skin reactions. Therefore, patients who use potentially photosensitive drugs and treatments on a long term basis should be warned of the possibility of these side effects on their skin and advised to avoid direct exposure to sunlight and to use adequate photoprotection. If patients carefully protect themselves from the sun, it is often not necessary to stop treatments that include photosensitive drugs. If such reactions appear, anti-inflammatory and antiallergic therapies should be introduced.

Molecular mechanisms of drug photodegradation and photosensitization.

Drug-induced photosensitivity of the skin is drawing increasing attention. In past few decades, photosensitivity has been reported with an array of drugs, and is now recognized as a noteworthy medical problem by clinicians, regulatory authorities and pharmaceutical industry. The photosensitivity is of two types i.e., phototoxicity and photoallergy. Phototoxic disorders have a high incidence, whereas photoallergic reactions are much less frequent in human population. Several hundred substances, chemicals, or drugs may invoke phototoxic and photoallergic reactions. In order to avoid photosensitive reactions, it is essential to understand the mechanism behind the photosensitizing properties of such substances before these drugs are introduced in clinical settings. Photosensitization is inter-related to photochemical reaction, through the knowledge of which the photosensitivity of a drug can be anticipated. This review highlights the current research status on photosensitizing drugs and its correlation to phototoxicity. Different mechanisms of photodegradation of photolabile drugs have also been discussed.

Photoallergy.

Abstract Photoallergic contact dermatitis (PACD) is a hypersensitivity reaction mounting from skin exposure to generally harmless amounts of ultraviolet and/or visible light in the presence of a photoreactive allergen. These reactions are typically delayed type (Gell and Coombs type IV) reactions and require pre-sensitization to photoallergens. Phototoxic reactions are clinically similar and often difficult to differentiate from photoallergies, but they are caused by interaction of light with photoirritants and do not require sensitization. The main investigative technique to diagnose PACD is photopatch testing, which is not commonly used; therefore, PACD may be overlooked in many patients. Currently, leading contact photosensitizers are sunscreens and topical non-steroidal anti-inflammatory drugs. This article provides an overview on photocontact allergies.

Elimination of ketoprofen from the stratum corneum after topical administration with ketoprofen formulations in human subjects.

PURPOSE: To assess the drug concentrations and elimination rate of ketoprofen in the stratum corneum following topical administration of two different formulations in human subjects for reference in the risk management of photocontact dermatitis caused by topical ketoprofen. METHODS: Ketoprofen tape and gel were used as test formulations. The stratum corneum at the application sites was removed by tape-stripping at scheduled times after removal of the formulations. The ketoprofen concentration in the stratum corneum was determined by liquid chromatography with tandem mass spectrometry. RESULTS: The ketoprofen concentration in the stratum corneum decreased and the elimination half-life in the stratum corneum was comparable between tape and gel after removal of the test formulations. The ketoprofen concentration in the stratum corneum decreased more rapidly after the subjects took a shower. Ketoprofen was not detected in the stratum corneum adjacent to the tape application sites. CONCLUSIONS: Ketoprofen in the stratum corneum appears to reach the lower limit of quantitation (0.005 µg) 12-16 days after removal of tape or gel. This period is similar to that recommended for avoiding ultraviolet light after removal of topical ketoprofen formulations in the Summary of Product Characteristics for topical ketoprofen in the European Union.

[Phototoxic and photoallergic reactions]. / Phototoxische und photoallergische reaktionen.

Many artificial or naturally occurring substances are included under the term photosensitizer. After ultraviolet (UV) exposure such agents can lead to increased photosensitivity and subsequently to phototoxic or photoallergic reactions in the skin. From clinical observations and comprehensive studies typical reaction patterns can be deduced which can clarify the difference between phototoxic and photoallergic dermatitis.An illuminated epicutaneous test based on conventional epicutaneous tests, the photopatch test, was developed as a screening method for identification of photosensitizers. The diagnostic specificity and sensitivity of the test is comparable to conventional epicutaneous testing. If possible photosensitizers do not cause any relevant reactions with the photopatch test, other test procedures, such as the photoprick, photoscratch and illuminated intracutaneous tests are available. If the actual photosensitizer is not the test substance but a metabolite of the test substance, a systemic photoprovocation test can be indicated.

Drug-induced photosensitivity: culprit drugs, management and prevention.

Photo-induced drug eruptions are cutaneous adverse events due to exposure to a drug and either ultraviolet or visible radiation. Based on their pathogenesis, they can be classified as phototoxic or photoallergic drug eruptions, although in many cases it is not possible to determine whether a particular eruption is due to a phototoxic or photoallergic mechanism. In this review, the diagnosis, prevention and management of drug-induced photosensitivity are discussed. Diagnosis is based primarily on the history of drug intake and the clinical appearance of the eruption, primarily affecting sun-exposed areas of the skin. Phototesting and photopatch testing can be useful adjuncts in making a diagnosis. The mainstay of management is prevention, including informing patients of the possibility of increased sun sensitivity and the use of sun protective measures. However, once the eruption has occurred, it may be necessary to discontinue the culprit medication and treat the eruption with a potent topical corticosteroid. Drugs that have been implicated in causing photosensitive eruptions are reviewed. Tetracycline, doxycycline, nalidixic acid, voriconazole, amiodarone, hydrochlorothiazide, naproxen, piroxicam, chlorpromazine and thioridazine are among the most commonly implicated medications. We review the medical literature regarding evidence for the culpability of each drug, including the results of phototesting, photopatch testing and rechallenge testing.

Randomized double-blinded placebo-controlled intra-individual trial on topical treatment with a 1,25-dihydroxyvitamin D3 analogue in polymorphic light eruption.

BACKGROUND: Polymorphic light eruption (PLE) is a very frequent photodermatosis whose pathogenesis may involve resistance to ultraviolet (UV)-induced immune suppression. Similar to UV radiation, calcitriol (1,25-dihydroxyvitamin D3) and its analogues such as calcipotriol have been shown to exhibit immunosuppressive properties. OBJECTIVES: We performed a randomized double-blinded placebo-controlled intraindividual half-body trial (NCT00871052) to investigate the preventive effect of a calcipotriol-containing cream in PLE. METHODS: Thirteen patients with PLE (10 women, three men; mean age 37 years) pretreated their skin on two symmetrically located test fields with calcipotriol or placebo cream twice daily for 7 days before the start of photoprovocation testing with solar-simulated UV radiation. We established a specific PLE test score [AA + SI + 0·4 P (range 0-12), where AA is affected area score (range 0-4), SI is skin infiltration score (range 0-4) and P is pruritus score on a visual analogue scale (range 0-10)] to quantify PLE severity. RESULTS: Photoprovocation led to PLE lesions in 12/13 (92%) patients. As shown by the PLE test score, compared with placebo calcipotrial pretreatment significantly reduced PLE symptoms in average by 32% (95% confidence interval 21-44%; P = 0·0022, exact Wilcoxon signed-rank test) throughout the observation period starting at 48 h until 144 h after the first photoprovocation exposure. At 48, 72 and 144 h calcipotriol pretreatment resulted in a lower PLE test score in 7 (58%), 9 (75%) and 10 (83%) of the 12 cases, respectively. Considering all time points together, calcipotriol diminished the PLE test score in all 12 photoprovocable patients (P = 0·0005; Wilcoxon signed-rank test). CONCLUSIONS: These results suggest a potential therapeutic benefit of topical 1,25-dihydroxyvitamin D3 analogues as prophylactic treatment in patients with PLE.

Severe phototoxicity associated with long-term voriconazole treatment.

Voriconazole is a second-generation triazole antifungal approved for the treatment of invasive fungal infections, particularly with Aspergillus, Candida, Fusarium, and Scedosporium spp. Frequently reported adverse effects of voriconazole include visual disturbance (21 %), elevated liver enzymes (15.6 %) and rashes (7 %), which are largely attributable to drug-induced photosensitivity. We report a case of serious phototoxicity in a 8 year old boy who underwent chemotherapy for AML. He received voriconazole for the treatment and subsequent re-infection prophylaxis after pulmonary aspergillosis. One year after the start of therapy he developed blistering eruptions on his face after minimal sunlight exposure. Recent reports about the development of squamous cell carcinoma and melanoma, respectively, in children during and after oral therapy with voriconazole seem to warrant systematic follow-up investigations of all voriconazole-treated patients.

Protective effects of platinum nanoparticles against UV-light-induced epidermal inflammation.

Intracellular reactive oxygen species (ROS) and apoptosis play important roles in the ultraviolet (UV)-induced inflammatory responses in the skin. Metal nanoparticles have been developed to increase the catalytic activity of metals, which is because of the large surface area of smaller particles. Platinum nanoparticles (nano-Pt) protected by poly acrylic acid were manufactured by reduction with ethanol. A marked increase in ROS production was observed in UV-treated HaCaT keratinocytes cell lines, while a decrease in ROS production was observed in nano-Pt-treated cells. Pretreatment of the cells with nano-Pt also caused a significant inhibition of UVB- and UVC-induced apoptosis. Furthermore, we found that mice treated with nano-Pt gel prior to UV irradiation showed significant inhibition of UVB-induced inflammation and UVA-induced photoallergy compared to UV-irradiated control mice. These results suggest that nano-Pt effectively protects against UV-induced inflammation by decreasing ROS production and inhibiting apoptosis in keratinocytes.

A new ecamsule-containing SPF 40 sunscreen cream for the prevention of polymorphous light eruption: a double-blind, randomized, controlled study in maximized outdoor conditions.

Polymorphous light eruption (PMLE) is an idiopathic photodermatosis elicited by UV radiation (UVR). The objective of this double-blind, randomized, controlled, intraindividual, bilateral comparison was to determine the efficacy of the UVA filters (ecamsule, avobenzone) present in the new sun protection factor (SPF) 40 sunscreen cream in preventing PMLE in maximized outdoor conditions (ie, exaggerated sun exposure). Safety also was assessed. Each participant was treated with SPF 40 sunscreen cream containing ecamsule 3%, octocrylene 10%, avobenzone 2%, and titanium dioxide 5% (tetrad) on one side of the body and either an ecamsule-deprived (triad-E) or avobenzone-deprived (triad-A) cream on the other side. Participants were subsequently exposed to incremental doses of sunlight for up to 6 days. The primary efficacy assessment was a composite relative success rate with 3 components. Success was defined as either a delayed time to onset of PMLE or a lower global severity of PMLE comparing one side of the body to the other side in the same participant. Safety evaluations included systemic adverse events (AEs). Of the 144 participants enrolled and randomized, 22 did not experience PMLE during the study duration under these maximized sun exposure conditions. A significantly greater number of successes were detected on the tetrad-treated side compared with either triad: 41 of 73 participants (56%) versus 8 of 73 participants (11%; P<.001) in the triad-E treatment group and 26 of 71 participants (36%) versus 11 of 71 participants (16%; P=.02) in the triad-A treatment group. Polymorphous light eruption appeared later with the tetrad than with either triad. The global severity of the PMLE flares was significantly lower with the tetrad than with both triads at end point (P<.001 and P=.02 for tetrad vs triad-E and tetrad vs triad-A, respectively). In this study, the SPF 40 sunscreen cream containing ecamsule 3%, octocrylene 10%, avobenzone 2%, and titanium dioxide 5% prevented PMLE flares significantly better than similar formulations with only one of the UVA filters (triad-E treatment group, P<.001; triad-A treatment group, P=.02). The inclusion of both ecamsule and avobenzone provides clinical benefit to patients with PMLE compared with formulations containing only one UVA filter.

Protection afforded by sunscreens containing inorganic sunscreening agents against blue light sensitivity induced by aminolevulinic acid.

BACKGROUND: Application of aminolevulinic acid (ALA) for photodynamic therapy induces significant sensitivity to visible light. OBJECTIVE: To determine whether sunscreens containing inorganic agents are effective against sensitivity to blue light induced by ALA application. METHODS & MATERIALS: Twenty subjects received application of ALA on the arm. Thirty minutes before blue light exposure, two sun protection factor 50 inorganic-based sunscreens containing iron oxide 3.2% and 0.2% were applied on separate areas where ALA was applied; a third area received no sunscreen. Small areas of skin were exposed to increasing fluences of blue light 3 or 18 hours later, and the minimal phototoxic dose (MPD) was noted. RESULTS: Three hours after ALA application MPD was 29.2 and 22.6 J/cm(2) for skin protected with sunscreen containing iron oxide 3.2% and 0.2%, respectively, and 10.6 J/cm(2) for unprotected skin (p=.003 and .0497 respectively). At 18 hours after ALA application, MPD for sunscreen containing iron oxide 3.2% was 5.78, compared with 0.33 for unprotected skin (p<.001) with a blue light protection factor of 21. CONCLUSION: The sunscreen containing iron oxide 3.2% afforded significant protection against blue light sensitivity induced by ALA application.

Disabling work-related persistent photosensitivity following photoallergic contact dermatitis from chlorpromazine and olaquindox in a pig breeder.

The use of veterinary medicines and medicated feed has a potential for the exposure of agricultural workers to pharmaceuticals with phototoxic and photoallergic side-effects. We present a 67-year-old self-employed farmer and pig breeder with a 22-year history of severe persistent photosensitivity following photoallergic contact dermatitis due to direct occupational dermal and airborne contact to chlorpromazine (sedative) and olaquindox (antibiotic and animal growth promoter, AGP). His first dermatitis symptoms appeared at the age of 45 when the pig breeding was intensified. He showed erythematous, scaly, and pruritic plaques localized symmetrically on the sun-exposed backs of his hands, fingers, and forearms, spreading to his face and other sun-exposed body sites. Without protective measures, he injected the animals with chlorpromazine. Besides, for several years he mixed by hand a powder containing olaquindox into the pigs' dry food. Epicutaneous and photo-patch tests showed positive reactions to promethazine, chlorpromazine, and olaquindox. In spite of the complete avoidance of the identified photoallergens for several years, his life is still extremely disabled due to the persistent photosensitivity. Our case report stresses the observation that olaquindox and chlorpromazine as phototoxic agents and photoallergens are capable of inducing a persistent and severe photosensitivity for many years, even after termination of exposure. Although the use of phenothiazine derivates and APGs for animals has meanwhile been banned in the European Union (EU), AGPs are still widely used in Asia. Physicians, especially occupational physicians, should be still aware of these phototoxic and photoallergic agents to reduce the burden of skin disease at work.

Scientific problems of photosensitivity.

Photosensitive skin reactions occur when human skin reacts to ultraviolet radiation or visible light abnormally. The forms of photosensitivity are phototoxicity and photoallergy. Phototoxic disorders have a high incidence, whereas photoallergic reactions are much less frequent in human population. Several hundred substances, chemicals, or drugs may invoke phototoxic and photoallergic reactions. In order to avoid photosensitive reactions it is essential to determine the photosensitizing properties of such substances before drugs are introduced in therapy or products made available on the market. The article reviews the mechanisms of photosensitization, explains the most important differences between phototoxic and photoallergic reactions, summarizes the most common photosensitizers, and presents the clinical features and diagnostic procedures of phototoxic and photoallergic reactions.

[Polymorphic light eruption: prophylaxis using a topical combination of antioxidants and UVA protection formulations]. / Lucite estivale bénigne: prévention par un topique associant des filtres anti-UVA et des antioxydants.

BACKGROUND: In a recent randomized, double-blind, placebo-controlled clinical study, the efficacy of a combination consisting of 0.25% alpha-glucosyl-rutin, 1% vitamin E and a broad-spectrum, highly UVA-protective sunscreen (sun protector factor 15 - persistent pigmentation darkening 6) regarding prevention of polymorphous light eruption was well demonstrated. We evaluated this combination under real solar exposure conditions. PATIENTS AND METHODS: Patients with three previous typical polymorphous light eruptions (including one in the last year) were included in an open prospective multicenter study. The preparation was applied every two hours after the first summer exposure. No topical or systemic treatments presumed to be effective against polymorphous light eruption were given concomitantly. Evaluation was performed after the summer by a dermatologist. RESULTS: Two of the 54 patients dropped out of the study, one for an adverse effect (contact dermatitis). At the end of the study following application of the test preparation, no eruption was seen for 35 patients (67%), with minor eruption for 10 patients (19%) and an marked eruption for 7 patients (13%). Pruritus (present in all patients the year before) was not seen in 36 patients (69%), was considered bearable for 36 patients and unbearable for only 3 patients compared to 27 before inclusion. For the dermatologists, efficacy was excellent for 35 patients and good for 7 patients, giving global efficacy of around 80%, with inadequate results in 10% of cases (5 patients). Concerning protection against erythema, the test product reduced sunburn by 60% compared with the previous year. DISCUSSION: Because of the high clinical efficacy of the product noted after UVA challenge tests and verified by this clinical study under actual conditions of exposure, it may be proposed as a new prophylactic treatment for polymorphous light eruption.