Phototoxic Drug Research Articles

Photoprotection and its implications for drug safety

Appropriate photoprotection plays a key role in the safety of using medicinal preparations whose active substances may induce photosensitivity reactions. This aspect applies not only to drugs applied topically to the skin, but also systemically. Drug-induced photosensitivity reactions to light depend on the active substance contained in the medicinal product and its dose, which translates into the concentration in the skin, the type of ultraviolet radiation, its intensity and exposure time. The chemical structure of phototoxic drugs contains unsaturated chemical bonds and aromatic groups, which are responsible for the absorption of radiation, the formation of degradation products and/or free radicals and hypersensitivity reactions. Therefore, in order to prevent hypersensitivity reactions, it is necessary to use appropriate sun protection and/or avoid exposure to solar radiation during pharmacotherapy with selected groups of drugs. The paper presents the latest research results on the impact of drug-induced photohypersensitivity on the increased likelihood of skin cancer. Drugs with the potential to induce photohypersensitivity reactions are discussed, including information on the relationship between their long-term use and the incidence of skin cancer. Based on the data contained in the Product Characteristics, exemplary indications regarding the appropriate photoprotection method to ensure the safe use of the medicinal product are presented. Med Pr Work Health Saf. 2024;75(5).

Photoreactivity of the Non-Steroidal Anti-inflammatory Drug Oxaprozin

Oxaprozin is a phototoxic, non-steroidal anti-inflammatory drug (NSAID) which is generally used in the treatment of inflammation, swelling, stiffness, and joint pain associated with osteoarthritis and rheumatoid arthritis. In addition to these beneficial properties some adverse phototoxic effects are also associated with this drug. For this reason here in we have investigate the photochemical behavior of selected phototoxic drug Oxaprozin. In the present study the methanolic solution of Oxaprozin was irradiated with UVA light under different experimental conditions such as aerobic and anaerobic conditions. The reaction progress was strictly monitored by using thin layer chromatography which confirms the formation of three photoproducts. The isolation of the photoproduct was done by column chromatography. The structural morphology of the isolated photoproducts was established by various spectroscopic techniques such as IR, NMR, 13C NMR mass spectroscopy and High Resolution Mass Spectrometry (HRMS). On the basis of structure the photoproducts are identified as 2-(4,5diphenyl oxazol-2-yl) acetaldehyde (2), 2-(4,5diphenyl oxazol-2yl) ethanol (3), 2ethyl-4,5diphenyl Oxazole (4) by spectral studies.

Phototoxic drug reaction induced by hydroxychloroquine

Phototoxic drug reaction induced by hydroxychloroquine

The phenomenon of phototoxicity and long-term risks of commonly prescribed and structurally diverse drugs

Photosensitivity to structurally diverse drugs is a common but under-reported adverse cutaneous reaction and can be classified as phototoxic or photoallergic. Phototoxic reactions occur when the skin is exposed to sunlight after administering topical or systemic medications that exhibit photosensitizing activity. These reactions depend on the dose of medication, degree of exposure to ultraviolet light, type of ultraviolet light, and sufficient skin distribution volume. Accurate prediction of the incidence and phototoxic response severity is challenging due to a paucity of literature, suggesting that phototoxicity may be more frequent than reported. This paper reports an extensive literature review on phototoxic drugs; the review employed pre-determined search criteria that included meta-analyses, systematic reviews, literature reviews, and case reports freely available in full text. Additional reports were identified from reference sections that contributed to the understanding of phototoxicity. The following drugs and/or drug classes are discussed: amiodarone, voriconazole, chlorpromazine, doxycycline, fluoroquinolones, hydrochlorothiazide, nonsteroidal anti-inflammatory drugs, and vemurafenib. In reviewing phototoxic skin reactions, this review highlights drug molecular structures, their reactive pathways, and, as there is a growing association between photosensitizing drugs and the increasing incidence of skin cancer, the consequential long-term implications of photocarcinogenesis.

Management of Melasma: Emerging Facts

Melasma is a dark or tan discoloration of the skin, whose exact cause is still unclear however sun exposure, hormonal influences, phototoxic drugs, and genetic factors are some of attributing factors. It is more common in females; with an 80% distribution is Centro-facial. Pathophysiologically, melasma shows the surge in dermal and epidermal pigmentation along with melanosomes, perivascular lymphohistiocytic infiltrates, and expansion of melanocytes. The latest treatment regimens include oral, topical, and procedural therapies. Conventional treatment of melasma includes hydroquinone, tretinoin, corticosteroids, and triple combination creams; Tranexamic acid, Polypodium leucotomos, and glutathione are newer drugs that have shown propitious effects. Techniques such as chemical peels, micro-needling, radiofrequency, and laser are also widely used as first-line or complementary treatments for melasma. Combing different treatment modalities have shown better efficacy than monotherapy. The objective of this review is to update the current emerging treatment modalities of melasma.

Phototoxic drug eruption induced by vandetanib used for the treatment of metastatic medullary thyroid cancer

Phototoxic drug eruption induced by vandetanib used for the treatment of metastatic medullary thyroid cancer

Study of Clinicodemographic Profile of Adverse Cutaneous Drug Reactions in Indian Perspective

Background: Cutaneous adverse drug reactions are an important group of disorders which pose considerable amount of diagnostic and therapeutic challenges. The incidence of CADRs is estimated to be 1–2% in the general population. Newer insights have been developing in the field of factors affecting CADRs and the need for studies in the Indian population regarding the newer trends in cutaneous adverse effects. Materials and Methods: A prospective and observational study was conducted in the Department of Pharmacology and Collaboration with Department of Dermatology in MGM Medical College and LSK Hospital. All cases of suspected CADRs in patients with systemically administered drugs were actively screen by a senior dermatologist. Causality assessment was done by a Pharmacologist using WHO UMC scale. Only those cases where the causality was certain probable/likely were recorded. Results: This sampling comprised of 77 CADRs over a period of 1 year from June 2012 to May 2013. The clinical pattern and spectrum of CADRs were studied in 77 subjects. A wide clinical spectrum of CADRs ranging fixed drug eruptions to serious Stevens Johnson syndrome (SJS) was observed. The predominant pattern of reactions observed was fixed drug eruptions FDE (35.1%) followed by acneiform eruptions (23.4%), erythema multiforme (9.1%), and phototoxic drug reactions (7.8%). The antimicrobials causing FDE were macrolides, cephalosporins, and fluoroquinolones. Among the NSAIDs causing FDE, most were due to diclofenac (70%). CADRs were seen most commonly in the 31–40 (26%) years age group followed by 11–20 (24.7%) years and 41–50 (19.5%) years with mean age 32.09 years. Only 5.2% patients were more than 60 years, oldest being 67 years. Antimicrobials were the most common drug group incriminated in 34% patients followed by NSAIDs in 29% cases and steroids in 25% cases. Among NSAIDs, maximum number of CADRs were caused by ibuprofen (40.9%) followed by diclofenac (36.4%), paracetamol (9%), aceclofenac (9%), and nimesulide (4.5%). Serious reactions were infrequent. Conclusion: Most of the reactions were mild (53%) to moderate (42%) requiring no major medical intervention. However, a larger and multi-centric study needs to be conducted across the state to obtain more information about CADRs among the state population.

The Assessment of Meloxicam Phototoxicity in Human Normal Skin Cells: In Vitro Studies on Dermal Fibroblasts and Epidermal Melanocytes.

Meloxicam (MLX), which belongs to the oxicam nonsteroidal anti-inflammatory drug derivatives, is an inhibitor of the cyclooxygenase-2 (COX-2) enzyme. Cutaneous adverse effects caused by interaction between UVA radiation and exogenous factors can manifest as phototoxic reactions. Phototoxicity may be a reason for the accumulation of genetic and molecular changes in long-lived cells with low proliferation potential, leading to tumor development. There are several potentially phototoxic drugs, the active component of which is meloxicam. The research aimed to evaluate the influence of MLX and UVAR on skin cells—fibroblasts and melanocytes homeostasis. The obtained results indicated that co-treatment with MLX and UVAR inhibited skin cell proliferation, proportionally to the drug concentration. The observation was confirmed by cytometric analysis of the cell number and viability. The phototoxic effect of MLX was revealed in morphological changes. It was stated that MLX with UVAR lowered the mitochondrial transmembrane potential and changed the cell cycle profile. Additionally, MLX and UVAR caused the disruption of redox homeostasis by lowering the intracellular level of reduced thiols. The presented study revealed that the phototoxic activity of MLX is associated with oxidative stress induction and disruptions in cell homeostasis. The differences in the phototoxic effects of MLX at the cellular level may be related to the different content of melanin pigments.

Hypoxia-Responsive Azobenzene-Linked Hyaluronate Dot Particles for Photodynamic Tumor Therapy

In this study, we developed ultra-small hyaluronate dot particles that selectively release phototoxic drugs into a hypoxic tumor microenvironment. Here, the water-soluble hyaluronate dot (dHA) was covalently conjugated with 4,4′-azodianiline (Azo, as a hypoxia-sensitive linker) and Ce6 (as a photodynamic antitumor agent), producing dHA particles with cleavable Azo bond and Ce6 (dHA-Azo-Ce6). Importantly, the inactive Ce6 (self-quenched state) in the dHA-Azo-Ce6 particles was switched to the active Ce6 (dequenched state) via the Azo linker (–N=N–) cleavage in a hypoxic environment. In vitro studies using hypoxia-induced HeLa cells (treated with CoCl2) revealed that the dHA-Azo-Ce6 particle enhanced photodynamic antitumor inhibition, suggesting its potential as an antitumor drug candidate in response to tumor hypoxia.

Severe Sunburn-Like Adverse Cutaneous Drug Reaction in a Patient on Treatment with Rifaximin: A Rare Case of Acute Phototoxic Drug Reaction

This paper describes an unreported case of a rifaximin-induced phototoxic reaction in an otherwise healthy 24-year-old female (skin type: V). The patient developed malaise, chills, and facial swelling with accompanying redness and itching that began within a day of initiating treatment with rifaximin (200 mg twice daily), and progressively increased over the next 3–4 days. The patient revealed that they had been lying in the sun for hours due to the chills they were experiencing. Over the next 10 days they developed an exaggerated, acute, sunburn-like phototoxic reaction, with blistering over the exposed skin. A skin biopsy showed no evidence of vasculopathy, endothelial damage, or extravasation of red blood cells. The patient was treated successfully with oral prednisolone (30 mg per day for a week), topical mometasone furoate (0.1%) cream applied twice daily, levocetirizine (5 mg per day taken orally), zinc oxide (20.0%) cream applied every 3 hours during daytime, and strict sun avoidance. The possible pathomechanism of rifaximin-induced sunburn is also discussed here.

Melasma and its Association with Serum Iron Levels and Complete Blood Count

Objective: To observe association of Melasma with serum Iron and complete blood count indices Study Design: Case-control cross-sectional study Place and Duration of Study: Department of Dermatology, HIT Hospital Taxila from 1st May 2021 to 1st October 2021 Methodology: Fifty seven females having melasma were taken as cases and 48 non-pregnant females without melasma as control between 12-50 years of age. Women with pregnancy, history of cardiac or thyroid disease and usage of hormone therapy, phototoxic drugs or anti-convulsant drugs were not included. History and examination was done by a dermatologist. Modified MASI (m Melasma Area and Severity Index) score was used for assessing severity of melasma. Blood samples were collected and send for serum Ferritin level, TIBC and Complete blood count in both groups. Results: The mean age of females were 35±7.4 years, and 48 female patients with no melasma were selected as controls with mean age of 25.7±8.4 years. We also analyzed the effect of different hematological and general factors on mMASI score within group of melasma patient but again found no statistically significant effect of any of these on MASI score. Conclusion: There is no direct association between melasma, serum iron levels and blood indices. Keywords: Melasma, Serum ferritin levels, Complete blood count

Evaluation of the skin phototoxicity of systemically administered pharmaceuticals in Sprague-Dawley rats.

In vivo phototoxicity testing is important for predicting drug-induced phototoxicity in humans. Currently, there is no internationally validated in vivo test method for the photosafety evaluation of pharmaceuticals. In this study, we evaluated the phototoxicity of systemically administered drugs using SD rats. We first determined the appropriate ultraviolet A (UVA) dose using 8-methoxypsoralen, a well-known phototoxic drug. Compared to lower and higher UVA doses, we found that a UVA dose of 10J/cm2 allowed for the detection of phototoxic responses in both a dose- and time-dependent manner. We next performed a phototoxicity study using seven pharmaceutical drugs which included known phototoxic and non-phototoxic drugs using a UVA dose of 10J/cm2. In order to improve the accuracy of our assessment, we evaluated both gross skin findings as well as histopathological findings. Using gross skin findings alone resulted in an accuracy of 85.7% which could be increased to 100% accuracy when the gross skin findings were combined with histopathological findings. This study suggests that the inclusion of histopathological findings increases the accuracy of the phototoxicity evaluation of systemically administered drugs in SD rats. In conclusion, we found that for studying drug-induced phytotoxicity, a 10J/cm2 UVA dose serves as the optimal radiation dose, and that the inclusion of histopathological findings increases the accuracy of the phototoxicity evaluation of the drugs.

Red Ginseng Oil Attenuates Oxidative Stress and Offers Protection against Ultraviolet-Induced Photo Toxicity.

Ginseng (Panax ginseng Meyer) is a well-known herbal medicine that has been used for a long time in Korea to treat various diseases. This study investigated the in vitro and in vivo protective effects of red ginseng extract (RGE) and red ginseng oil (RGO). Liver injury was produced in BALB/c mice by 400 mg/kg of acetaminophen intraperitoneal injection. The antioxidant effects of RGE and RGO on the free radicals 2,2-diphenyl-1-picryl-hydrazyl-hydrate (DPPH) and 2,2′-azino-bis-3-ethylbenzothiazoline-6-sulfonic acid (ABTS) were measured. In addition, the hepatoprotective activities of RGE and RGO on liver markers, including alanine aminotransferase (ALT), aspartate aminotransferase (AST), and oxidative stress markers, including superoxide dismutase (SOD), catalase (CAT) enzyme activity, and 8-hydroxy-2-deoxyguanosine (8-OHdG) in serum and histopathological analysis, were evaluated. The protective effect of RGO on UV-induced phototoxicity was also evaluated in Balb/c 3T3 mouse fibroblast cell line. RGE and RGO effectively inhibited the radicals DPPH and ABTS compared with ascorbic acid and trolox, respectively. Moreover, RGE and RGO significantly decreased the liver enzyme (ALT and AST) levels, increased the antioxidant enzyme (SOD and CAT) levels, and decreased the DNA oxidation product (8-OHdG) content in mice serum. RGO also exhibited protective effect against UV irradiation compared with chlorpromazine hydrochloride, a known phototoxic drug, in Balb/c 3T3 cell line. RGE and RGO possess antioxidant and hepatoprotective properties in mice, and RGO exerts nonphototoxic activity in Balb/c 3T3 cells.

Evaluation of skin phototoxicity of transdermally administered pharmaceuticals in Sprague-Dawley rats

Some drugs cause phototoxicity in humans when exposed to light, thus there is a need for an in vivo phototoxicity test to evaluate them. However, an in vivo phototoxicity test method to evaluate this has not been established. This study aimed to establish an in vivo phototoxicity test method for transdermally administered drugs. For this, we evaluated the phototoxicity using Sprague-Dawley (SD) rats for transdermal administered drugs and we studied the appropriate UVA dose using 8-methoxypsalen, which is a well-known phototoxic drug. We found that a UVA dose of 15 J/cm2 was dose and time dependent response compared to other UVA doses. We performed the Minimum Erythema Dose (MED) test because UVB can cause skin irritation by itself and selected 0.01 J/cm2 as an appropriate dose of UVB. Using the selected UVA and UVB doses, we performed a phototoxicity study of 6 pharmaceutical drugs, which included phototoxic and non-phototoxic drugs. As a result of the phototoxicity test, 100% accuracy was obtained when compared with previous studies. In addition, we performed histopathology to confirm the new findings. We found that histopathology can be used as an additional indicator of phototoxicity test for transdermally administered drugs.

Computational Investigation of Drug Phototoxicity: Photosafety Assessment, Photo-Toxophore Identification, and Machine Learning.

One of the most appreciated capabilities of computational toxicology is to support the design of pharmaceuticals with reduced toxicological hazard. To this end, we have strengthened our drug photosafety assessments by applying novel computer models for the anticipation of in vitro phototoxicity and human photosensitization. These models are typically used in pharmaceutical discovery projects as part of the compound toxicity assessments and compound optimization methods. To ensure good data quality and aiming at models with global applicability we separately compiled and curated highly chemically diverse data sets from 3T3 NRU phototoxicity reports (450 compounds) and clinical photosensitization alerts (1419 compounds) which are provided as supplements. The latter data gives rise to a comprehensive list of explanatory fragments for visual guidance, termed phototoxophores, by application of a Bayesian statistics approach. To extend beyond the domain of well sampled fragments we applied machine learning techniques based on explanatory descriptors such as pharmacophoric fingerprints or, more important, accurate electronic energy descriptors. Electronic descriptors were extracted from quantum chemical computations at the density functional theory (DFT) level. Accurate UV/vis spectral absorption descriptors and pharmacophoric fingerprints turned out to be necessary for predictive computer models, which were both derived from Deep Neural Networks but also the simpler Random Decision Forests approach. Model accuracies of 83-85% could typically be reached for diverse test data sets and other company in-house data, while model sensitivity (the capability of correctly detecting toxicants) was even better, reaching 86%-90%. Importantly, a computer model-triggered response-map allowed for graphical/chemical interpretability also in the case of previously unknown phototoxophores. The photosafety models described here are currently applied in a prospective manner for the hazard identification, prioritization, and optimization of newly designed molecules.

Functionalized Superparamagnetic Iron Oxide Nanoparticles (SPIONs) as Platform for the Targeted Multimodal Tumor Therapy.

Standard cancer treatments involve surgery, radiotherapy, chemotherapy, and immunotherapy. In clinical practice, the respective drugs are applied orally or intravenously leading to their systemic circulation in the whole organism. For chemotherapeutics or immune modulatory agents, severe side effects such as immune depression or autoimmunity can occur. At the same time the intratumoral drug doses are often too low for effective cancer therapy. Since monotherapies frequently cannot cure cancer, due to their synergistic effects multimodal therapy concepts are applied to enhance treatment efficacy. The targeted delivery of drugs to the tumor by employment of functionalized nanoparticles might be a promising solution to overcome these challenges. For multimodal therapy concepts and individualized patient care nanoparticle platforms can be functionalized with compounds from various therapeutic classes (e.g. radiosensitizers, phototoxic drugs, chemotherapeutics, immune modulators). Superparamagnetic iron oxide nanoparticles (SPIONs) as drug transporters can add further functionalities, such as guidance or heating by external magnetic fields (Magnetic Drug Targeting or Magnetic Hyperthermia), and imaging-controlled therapy (Magnetic Resonance Imaging).

Drug and chemical induced photosensitivity from a clinical perspective.

Drug photosensitivity is a relatively common occurrence and a range of mechanisms may be involved. Some of these mechanisms will be discussed, including the most common, that of drug phototoxicity. Different types of photosensitivity are addressed with respect to clinical presentation, mechanisms and additionally the contribution to our understanding through clinically directed investigations and regulatory requirements. Repeated controlled therapeutic use of drug phototoxicity, with psoralen-UVA (PUVA) photochemotherapy and photodynamic therapy (PDT) will also be discussed. Finally, the potential for drug-induced photocarcinogenesis will also be covered.

Phototoxicity of traditional chinese medicine (TCM).

Phototoxicity can cause toxic responses such as edemas and lesions, and is one of the severe adverse effects that largely limit the use of these phototoxic drugs. Some traditional Chinese medicines (TCMs) and their constituents have been reported to be phototoxic. However, to date, their phototoxicity information is still very limited, and lacks systemic investigation. This article presents the phototoxicity potential of various types of TCMs and their active components in an effort to provide valuable information for drug research and discovery to mitigate phototoxicity concerns. Some potential mechanisms of action (MoAs) of phototoxicity are discussed. In addition, in vivo and in vitro phototoxicity assays are summarized this review.

Protective effect of Thai silk extracts on drug-induced phototoxicity in human epidermal A431 cells and a reconstructed human epidermis model

Bombyx mori silk extracts, derived from the cocoon degumming process of draw and dye silk in the textile industry, are mainly composed of sericin protein. To add value to the Thai silk extracts, and hence the silk industry, a simple enrichment process was recently developed and the enriched silk extracts were then applied in nano-cosmeceutical products and nano-delivery systems. In this study, the protective effect of Thai silk extracts from three different strains of Bombyx mori on the drug-induced phototoxicity was evaluated in vitro using chlorpromazine (CPZ), a commonly used antipsychotic drug, as a representative phototoxic drug. The human epidermal A431 cell line and reconstructed human epidermis (RhE) model were used as the in vitro skin model. The silk extracts significantly improved the viability of A431 cells after CPZ exposure and ultraviolet A (UVA) irradiation, as shown by the significantly increased CPZ and UVA IC50 values and the decreased proportion of apoptotic cells. The protective effect of these silk extracts against the CPZ-induced UVA-phototoxicity in A431 cells was associated with the attenuation of intracellular oxidative stress via an increased intracellular glutathione level. Likewise, the silk extracts exhibited a protective effect on the CPZ-induced UVA-phototoxicity in the RhE model, in terms of an improved tissue viability and attenuation of the released inflammatory cytokine, interleukin-1α. These findings support the potential usefulness of silk extracts in novel applications, especially in the protection of drug-induced phototoxicity.

Sun Exposure and Melanoma, Certainties and Weaknesses of the Present Knowledge.

Sun exposure is the main risk factor for cutaneous malignant melanoma (CMM). However, the UV-related pathogenetic mechanisms leading to CMM are far to be fully elucidated. In this paper we will focus on what we still don't fully know about the relationship between UVR and CMM. In particular, we will discuss: the action spectrum of human CMM, how different modalities of exposure (continuous/ intermittent; erythemal/ suberythemal) relate to different CMM variants, the preferential UVR induced DNA mutations observed in different CMM variants, the role of UV-related and UV-unrelated genetic damages in the same melanoma cells. Moreover, we will debate the importance of UVA induced oxidative and anaerobic damages to DNA and other cell structures and the role of melanins, of modulation of innate and acquired immunity, of vitamin D and of chronic exposure to phototoxic drugs and other xenobiotics. A better understanding of these issues will help developing more effective preventative strategies and new therapeutic approaches.