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JAAD Case Reports Dec 2023
PubMed: 38077162
DOI: 10.1016/j.jdcr.2023.08.019 -
Journal of Medicinal Chemistry Jul 2023Phototoxicity is a common safety concern encountered by project teams in pharmaceutical research and has the potential to stop progression of an otherwise promising... (Review)
Review
Phototoxicity is a common safety concern encountered by project teams in pharmaceutical research and has the potential to stop progression of an otherwise promising candidate molecule. This perspective aims to provide an overview of the approaches toward mitigation of phototoxicity that medicinal chemists have taken during the lead optimization phase in the context of regulatory standards for photosafety evaluation. Various strategies are laid out based on available literature examples in order to highlight how structural modification can be utilized toward successful mitigation of a phototoxicity liability. A proposed flowchart is presented as a guidance tool to be used by the practicing medicinal chemist when facing a phototoxicity risk. The description of available tools to consider in the drug design process will include an overview of the evolution of in silico methods and their application as well as structure alerts for consideration as potential phototoxicophores.
Topics: Humans; Drug Discovery; Drug Design; Dermatitis, Phototoxic; Chemistry, Pharmaceutical
PubMed: 37450689
DOI: 10.1021/acs.jmedchem.3c00749 -
Molecules (Basel, Switzerland) Aug 2023Indocyanine green (ICG) is an important kind of near infrared (NIR) photosensitive molecules for PTT/PDT therapy as well as imaging. When exposed to NIR light, ICG can... (Review)
Review
Indocyanine green (ICG) is an important kind of near infrared (NIR) photosensitive molecules for PTT/PDT therapy as well as imaging. When exposed to NIR light, ICG can produce reactive oxygen species (ROS), which can kill cancer cells and pathogenic bacteria. Moreover, the absorbed light can also be converted into heat by ICG molecules to eliminate cancer cells. In addition, it performs exceptionally well in optical imaging-guided tumor therapy and antimicrobial therapy due to its deeper tissue penetration and low photobleaching properties in the near-infrared region compared to other dyes. In order to solve the problems of water and optical stability and multi-function problem of ICG molecules, composite nanomaterials based on ICG have been designed and widely used, especially in the fields of tumors and sterilization. So far, ICG molecules and their composite materials have become one of the most famous infrared sensitive materials. However, there have been no corresponding review articles focused on ICG molecules. In this review, the molecular structure and properties of ICG, composite material design, and near-infrared light- triggered anti-tumor, and antibacterial, and clinical applications are reviewed in detail, which of great significance for related research.
Topics: Humans; Indocyanine Green; Dermatitis, Phototoxic; Coloring Agents; Anti-Bacterial Agents; Hot Temperature
PubMed: 37630337
DOI: 10.3390/molecules28166085 -
Pharmaceuticals (Basel, Switzerland) Jul 2021Photosensitivity is one of the most common cutaneous adverse drug reactions. There are two types of drug-induced photosensitivity: photoallergy and phototoxicity.... (Review)
Review
Photosensitivity is one of the most common cutaneous adverse drug reactions. There are two types of drug-induced photosensitivity: photoallergy and phototoxicity. Currently, the number of photosensitization cases is constantly increasing due to excessive exposure to sunlight, the aesthetic value of a tan, and the increasing number of photosensitizing substances in food, dietary supplements, and pharmaceutical and cosmetic products. The risk of photosensitivity reactions relates to several hundred externally and systemically administered drugs, including nonsteroidal anti-inflammatory, cardiovascular, psychotropic, antimicrobial, antihyperlipidemic, and antineoplastic drugs. Photosensitivity reactions often lead to hospitalization, additional treatment, medical management, decrease in patient's comfort, and the limitations of drug usage. Mechanisms of drug-induced photosensitivity are complex and are observed at a cellular, molecular, and biochemical level. Photoexcitation and photoconversion of drugs trigger multidirectional biological reactions, including oxidative stress, inflammation, and changes in melanin synthesis. These effects contribute to the appearance of the following symptoms: erythema, swelling, blisters, exudation, peeling, burning, itching, and hyperpigmentation of the skin. This article reviews in detail the chemical and biological basis of drug-induced photosensitivity. The following factors are considered: the chemical properties, the influence of individual ranges of sunlight, the presence of melanin biopolymers, and the defense mechanisms of particular types of tested cells.
PubMed: 34451820
DOI: 10.3390/ph14080723 -
RIFM fragrance ingredient safety assessment, phenylethyl anthranilate, CAS Registry Number 133-18-6.Food and Chemical Toxicology : An... Oct 2020The existing information supports the use of this material as described in this safety assessment. Phenylethyl anthranilate was evaluated for genotoxicity, repeated dose... (Review)
Review
The existing information supports the use of this material as described in this safety assessment. Phenylethyl anthranilate was evaluated for genotoxicity, repeated dose toxicity, developmental and reproductive toxicity, local respiratory toxicity, phototoxicity/photoallergenicity, skin sensitization, and environmental safety. Data from phenylethyl anthranilate and the read-across analog cinnamyl anthranilate (CAS # 87-29-6) show that phenylethyl anthranilate is not expected to be genotoxic. The skin sensitization endpoint was completed using the DST for non-reactive materials (900 μg/cm); exposure is below the DST. The reproductive and local respiratory toxicity endpoints were evaluated using the TTC for a Cramer Class II material, and the exposure to phenylethyl anthranilate is below the TTC (0.009 mg/kg/day and 0.47 mg/day, respectively). Data on read-across analogs phenethyl alcohol (CAS # 60-12-8) and anthranilic acid (CAS # 118-92-3) provide a calculated MOE >100 for the repeated dose and developmental toxicity endpoints. The phototoxicity/photoallergenicity endpoints were evaluated based on UV spectra; phenylethyl anthranilate is not expected to be phototoxic/photoallergenic. The environmental endpoints were evaluated; phenylethyl anthranilate was found not to be PBT as per the IFRA Environmental Standards, and its risk quotients, based on its current volume of use in Europe and North America (i.e., PEC/PNEC), are <1.
Topics: Animals; Dermatitis, Phototoxic; Humans; Mutagenicity Tests; Perfume; Registries; Risk Assessment; ortho-Aminobenzoates
PubMed: 32640364
DOI: 10.1016/j.fct.2020.111470 -
Molecules (Basel, Switzerland) Dec 2021Polyphenols are a large family of natural compounds widely used in cosmetic products due to their antioxidant and anti-inflammatory beneficial properties and their...
Polyphenols are a large family of natural compounds widely used in cosmetic products due to their antioxidant and anti-inflammatory beneficial properties and their ability to prevent UV radiation-induced oxidative stress. Since these compounds present chromophores and are applied directly to the skin, they can react with sunlight and exert phototoxic effects. The available scientific information on the phototoxic potential of these natural compounds is scarce, and thus the aim of this study was to evaluate the photoreactivity and phototoxicity of five phenolic antioxidants with documented use in cosmetic products. A standard ROS assay was validated and applied to screen the photoreactivity of the natural phenolic antioxidants caffeic acid, ferulic acid, -coumaric acid, 3,4-dihydroxyphenylacetic acid (DOPAC), and rutin. The phototoxicity potential was determined by using a human keratinocyte cell line (HaCaT), based on the 3T3 Neutral Red Uptake phototoxicity test. Although all studied phenolic antioxidants absorbed UV/Vis radiation in the range of 290 to 700 nm, only DOPAC was able to generate singlet oxygen. The generation of reactive oxygen species is an early-stage chemical reaction as part of the phototoxicity mechanism. Yet, none of the studied compounds decreased the viability of keratinocytes after irradiation, leading to the conclusion that they do not have phototoxic potential. The data obtained with this work suggests that these compounds are safe when incorporated in cosmetic products.
Topics: Animals; Antioxidants; Biological Assay; Biological Products; Cell Line; Cell Survival; Dermatitis, Phototoxic; Humans; Mice; Molecular Structure; Polyphenols; Reactive Oxygen Species
PubMed: 35011420
DOI: 10.3390/molecules27010189 -
The Study on Timolol and Its Potential Phototoxicity Using Chemical, In Silico and In Vitro Methods.Pharmaceuticals (Basel, Switzerland) Jan 2024Timolol (TIM) is a non-selective ß-adrenergic receptor antagonist used orally for the treatment of hypertension and heart attacks, and topically for treating glaucoma;...
Timolol (TIM) is a non-selective ß-adrenergic receptor antagonist used orally for the treatment of hypertension and heart attacks, and topically for treating glaucoma; lately, it has also been used in some specific dermatological problems. In the present study, its photodegradation and potential risk of phototoxicity were examined using chemical, in silico and in vitro methods. The UV/VIS irradiated solutions of TIM at pH 1-13 were subjected to LC-UV and UPLC-HRMS/MS analyses showing pseudo first-order kinetics of degradation and several degradation products. The structures of these photodegradants were elucidated by fragmentation path analysis based on high resolution (HR) fragmentation mass spectra, and then used for toxicity evaluation using OSIRIS Property Explorer and Toxtree. Potential risk of phototoxicity was also studied using chemical tests for detecting ROS under UV/VIS irradiation and in vitro tests on BALB/c 3T3 mouse fibroblasts (MTT, NRU and Live/Dead tests). TIM was shown to be potentially phototoxic because of its UV/VIS absorptive properties and generation ROS during irradiation. As was observed in the MTT and NRU tests, the co-treatment of fibroblasts with TIM and UV/VIS light inhibited cell viability, especially when concentrations of the drug were higher than 50 µg/mL.
PubMed: 38256931
DOI: 10.3390/ph17010098 -
Journal of Medicinal Chemistry May 2021Photodynamic therapy (PDT) is used to treat various cancerous diseases. Recently, we have demonstrated that platinated pyridyl-substituted porphyrins are potent agents...
Photodynamic therapy (PDT) is used to treat various cancerous diseases. Recently, we have demonstrated that platinated pyridyl-substituted porphyrins are potent agents for PDT with very high phototoxicity (IC down to 17 nM) and excellent phototoxic indices of higher than 5800 (p.i. = IC(dark)/IC(light)) [Rubbiani, R. ., 2020, 56, 14373]. However, the absorption of porphyrins is not ideal for the treatment of larger tumors because they essentially do not absorb light between 650 and 850 nm. Herein, we report stable conjugates of a novel bacteriochlorin with cisplatin and transplatin. They exhibit extremely high phototoxicity (IC values down to 6 nM, irradiated with a 750 nm LED at a fluence of 5 J/cm), very low dark toxicity, and thereby extremely high phototoxic indices up to 8300. Based on these exciting results, we believe that platinated bacteriochlorins are promising candidates for further investigation as novel PDT anticancer agents.
Topics: Cell Line, Tumor; Cell Nucleus; Cell Survival; Cisplatin; Crystallography, X-Ray; Drug Resistance, Neoplasm; Humans; Light; Microscopy, Fluorescence; Molecular Conformation; Photosensitizing Agents; Porphyrins; Reactive Oxygen Species
PubMed: 33988998
DOI: 10.1021/acs.jmedchem.1c00052 -
Food and Chemical Toxicology : An... Mar 2021The existing information supports the use of this material as described in this safety assessment. 4,5,6,7,8,9,10,11,12,13-Decahydrocyclododecaoxazole was evaluated for... (Review)
Review
The existing information supports the use of this material as described in this safety assessment. 4,5,6,7,8,9,10,11,12,13-Decahydrocyclododecaoxazole was evaluated for genotoxicity, repeated dose toxicity, reproductive toxicity, local respiratory toxicity, phototoxicity/photoallergenicity, skin sensitization, and environmental safety. Data show that 4,5,6,7,8,9,10,11,12,13-decahydrocyclododecaoxazole is not genotoxic. The repeated dose, reproductive, and local respiratory toxicity endpoints were evaluated using the Threshold of Toxicological Concern (TTC) for a Cramer Class III material, and the exposure to 4,5,6,7,8,9,10,11,12,13-decahydrocyclododecaoxazole is below the TTC (0.0015 mg/kg/day, 0.0015 mg/kg/day, and 0.47 mg/day, respectively). The skin sensitization endpoint was completed using the Dermal Sensitization Threshold (DST) for non-reactive materials (900 μg/cm); exposure is below the DST. The phototoxicity/photoallergenicity endpoints were evaluated based on ultraviolet (UV) spectra; 4,5,6,7,8,9,10,11,12,13-decahydrocyclododecaoxazole is not expected to be phototoxic/photoallergenic. The environmental endpoints were evaluated; 4,5,6,7,8,9,10,11,12,13-decahydrocyclododecaoxazole was found not to be Persistent, Bioaccumulative, and Toxic (PBT) as per the International Fragrance Association (IFRA) Environmental Standards, and its risk quotients, based on its current volume of use in Europe and North America (i.e., Predicted Environmental Concentration/Predicted No Effect Concentration [PEC/PNEC]), are <1.
Topics: Animals; Humans; Odorants; Quantitative Structure-Activity Relationship; Reproduction; Risk Assessment; Toxicity Tests
PubMed: 33460695
DOI: 10.1016/j.fct.2021.111983 -
Molecular Genetics and Metabolism Nov 2019Erythropoietic Protoporphyria (EPP) and X-linked Protoporphyria (XLP) are rare, genetic photodermatoses resulting from defects in enzymes of the heme-biosynthetic... (Review)
Review
Erythropoietic Protoporphyria (EPP) and X-linked Protoporphyria (XLP) are rare, genetic photodermatoses resulting from defects in enzymes of the heme-biosynthetic pathway. EPP results from the partial deficiency of ferrochelatase, and XLP results from gain-of-function mutations in erythroid specific ALAS2. Both disorders result in the accumulation of erythrocyte protoporphyrin, which is released in the plasma and taken up by the liver and vascular endothelium. The accumulated protoporphyrin is activated by sunlight exposure, generating singlet oxygen radical reactions leading to tissue damage and excruciating pain. About 2-5% of patients develop clinically significant liver dysfunction due to protoporphyrin deposition in bile and/or hepatocytes which can advance to cholestatic liver failure requiring transplantation. Clinically these patients present with acute, severe, non-blistering phototoxicity within minutes of sun-exposure. Anemia is seen in about 47% of patients and about 27% of patients will develop abnormal serum aminotransferases. The diagnosis of EPP and XLP is made by detection of markedly increased erythrocyte protoporphyrin levels with a predominance of metal-free protoporphyrin. Genetic testing by sequencing the FECH or ALAS2 gene confirms the diagnosis. Treatment is limited to sun-protection and there are no currently available FDA-approved therapies for these disorders. Afamelanotide, a synthetic analogue of α-melanocyte stimulating hormone was found to increase pain-free sun exposure and improve quality of life in adults with EPP. It has been approved for use in the European Union since 2014 and is not available in the U.S. In addition to the development of effective therapeutics, future studies are needed to establish the role of iron and the risks related to the development of hepatopathy in these patients.
Topics: 5-Aminolevulinate Synthetase; Anemia; Clinical Trials as Topic; Dermatitis, Phototoxic; Disease Management; Genes, X-Linked; Heme; Humans; Liver Diseases; Porphyrias, Hepatic; Protoporphyria, Erythropoietic
PubMed: 30704898
DOI: 10.1016/j.ymgme.2019.01.020