Phototoxicity─Medicinal Chemistry Strategies for Risk Mitigation in Drug Discovery.

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.

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.

Afamelanotide for prevention of phototoxicity in erythropoietic protoporphyria.

Introduction: In erythropoietic protoporphyria (EPP), an inherited disorder of heme biosynthesis, accumulation of protoporphyrin IX results in acute phototoxicity. EPP patients experience severe burning pain after light exposure, which results in a markedly reduced quality of life. Afamelanotide is the first effective approved medical treatment for EPP, acting on melanocortin-1 receptors. This article aims to review afamelanotide.Areas covered: This review summarizes the chemical properties, pharmacokinetics, safety, preclinical and clinical data on afamelanotide in EPP, and post-marketing surveillance. PubMed search, manufacturers' websites, and relevant articles used for approval by authorities were used for the literature search.Expert opinion: Afamelanotide is an α-melanocyte-stimulating hormone analog. It can activate eumelanogenesis without exposure to UV radiation. Clinical studies in EPP showed that afamelanotide treatment significantly increased exposure to sunlight and QoL. In our clinical experience afamelanotide treatment is much more effective in clinical practice than demonstrated in clinical trials and should be made available for all EPP patients meeting inclusion criteria. The 60-day interval period was not based on effectiveness studies, and therefore for some of the patients the maximum of four implants per year with the 60-day interval is insufficient. Afamelanotide is well tolerated; common adverse events were headache, fatigue, and nausea.

Solanum melongena L. Extract Protects Retinal Pigment Epithelial Cells from Blue Light-Induced Phototoxicity in In Vitro and In Vivo Models.

N-retinylidene-N-retinylethanolamine (A2E) accumulation in the retina is a prominent marker of retinal degenerative diseases. Blue light exposure is considered as an important factor contributing to dry age-related macular degeneration (AMD). Eggplant and its constituents have been shown to confer health benefits, but their therapeutic effects on dry AMD remain incompletely understood. In this study, we showed that an extract of Solanum melongena L. (EPX) protected A2E-laden ARPE-19 cells against blue light-induced cell death via attenuating reactive oxygen species. Transcriptomic analysis demonstrated that blue light modulated the expression of genes associated with stress response, inflammation, and cell death, and EPX suppressed the inflammatory pathway induced by blue light in A2E-laden ARPE-19 cells by inhibiting the nuclear translocation of nuclear factor kappa B and transcription of pro-inflammatory genes (CXCL8 and IL1B). The degradation of intracellular A2E was considered the major mechanism underlying the protective effect of EPX. Moreover, chlorogenic acid isolated from EPX exerted protective effects against blue light-induced cell damage in A2E-laden ARPE-19 cells. In vivo, EPX administration in BALB/c mice reduced the fundus damage and degeneration of the retinal layer in a blue light-induced retinal damage model. Collectively, our findings suggest the potential role of Solanum melongena L. extract for AMD treatment.

The feasibility of using Saffron to reduce the photosensitivity reaction of selected photosensitizers using red blood cells and staphylococcusAureus bacteria as targets.

BACKGROUND: The photosensitivity reaction which appears after a Photodynamic therapy treatment session is a challenge that needs further investigation. The goal of this research is to evaluate the possibility of using saffron to reduce or control this photosensitivity reaction and to present mathematical modeling of the cell survival curves and their dependency on saffron concentration. METHODS: Red blood cells (RBC) and Staphylococcus aureus Bacteria (STB) were used as targets in this study. The Photosensitivity of Rose Bengali, Methylene Blue, and Photofrin independently and incorporated with saffron was investigated for continued irradiation at different Saffron concentrations. Gompertz's function was used to fit the survival curve parameters. The 50% cell survival rate was fit to an empirical formula based on Saffron concentrations. RESULTS: Saffron inhibits the photosensitivity reaction of the three photosensitizers and causes a significant increase in the 50% survival rate time (t50) for RBC`s and STB. Saffron didn't show phototoxicity when incubated alone with RBC`s and STB. The survival curve parameters of the RBCs and STB showed a good fit to the Gompertz function. Saffron concentration is related to the RBC`s t50 based on power dependency of 0.56, 0.38 and 0.31 for Photofrin, Methylene Blue and Rose Bengali respectively and 0.1 on STB for Rose Bengali. CONCLUSION: Saffron can efficiently be used to reduce the photosensitivity reaction of Photosensitizers after a PDT treatment session. Gompertz function was found to be an appropriate mathematical model for survival rate curves. The t50 and the saffron concentration are well related through a power dependence empirical formula.

Modulating cellular cytotoxicity and phototoxicity of fluorescent organic salts through counterion pairing.

Light-activated theranostics offer promising opportunities for disease diagnosis, image-guided surgery, and site-specific personalized therapy. However, current fluorescent dyes are limited by low brightness, high cytotoxicity, poor tissue penetration, and unwanted side effects. To overcome these limitations, we demonstrate a platform for optoelectronic tuning, which allows independent control of the optical properties from the electronic properties of fluorescent organic salts. This is achieved through cation-anion pairing of organic salts that can modulate the frontier molecular orbital without impacting the bandgap. Optoelectronic tuning enables decoupled control over the cytotoxicity and phototoxicity of fluorescent organic salts by selective generation of mitochondrial reactive oxygen species that control cell viability. We show that through counterion pairing, organic salt nanoparticles can be tuned to be either nontoxic for enhanced imaging, or phototoxic for improved photodynamic therapy.

Wilderness Dermatology: Bugs, Plants, and Other Nuisances That May Ruin Your Hike.

Spending time outdoors can be rewarding. However, exposure to the sun, insect bites, and plant exposures may result in a wide range of dermatologic manifestations. In this article, we describe potential cutaneous manifestations of common wilderness exposures in New England including photodermatoses from prolonged sun exposure, phytodermatoses from plant exposures, and arthropod-bite reactions from common insects (mosquitos, spiders, ticks, hymenoptera, mites and chiggers). The article will also address preventive and treatment strategies which may help physicians and their patients better prepare for spending time in the wilderness. [Full article available at http://rimed.org/rimedicaljournal-2019-02.asp].

Photochemical and Pharmacokinetic Characterization of Orally Administered Chemicals to Evaluate Phototoxic Risk.

This study aimed to verify the applicability of a proposed photosafety screening system based on a reactive oxygen species (ROS) assay and a cassette-dosing pharmacokinetic (PK) study to chemicals with wide structural diversity. The orally taken chemicals, erythromycin, gatifloxacin, 8-methoxypsoralen (MOP), pirfenidone (PFD), trifluoperazine (TFP), and voriconazole (VRZ), were selected as test compounds. The ROS assay was conducted to evaluate their photoreactivity, and all test compounds excluding erythromycin generated significant ROS under simulated sunlight exposure. According to the ROS data, TFP had potent photoreactivity, and the photoreactivity of 4 other compounds was judged to be moderate. Regarding the oral cassette-dosing PK test in rats, the skin deposition of MOP, PFD, and VRZ was relatively high, and gatifloxacin and TFP exhibited moderate skin deposition properties. Based on the ROS and PK data of test compounds, PFD and TFP were judged to be potent phototoxic compounds, and MOP and VRZ were deduced to have phototoxic risk. The predicted phototoxic risk of test compounds by proposed screening was mostly in agreement with observed in vivo phototoxicity in the rat skin. The proposed screening system could provide reliable photosafety information on orally administered compounds with wide structural diversity.

A fast and simple FIA-chemiluminescence method for the evaluation of Roselle flowers as scavenger of the free radicals generated by UV irradiated antibiotics.

This work proposes a new method for the in vitro evaluation of the effect of UV irradiation on the production of free radicals and other reactive species during the photodecomposition of drugs. The method was based on the UV irradiation of antibiotics molecules to generate excited states that undergo to homolytic bond cleavages. These reactive species can be detected by their ability to oxidize the luminol, producing the electronically excited aminophtalate, which decays to the ground state releasing electromagnetic radiation in the visible zone of the spectrum. This method was applied to penicillin G, nafcillin, azlocillin and neomycin dissolved in water. It was found that the intensity of the luminol chemiluminescence emission (CL) was proportional to the concentration and dependent on the molecular structure of these drugs. Under the optimized conditions, it was found that penicillin and azlocillin were the most susceptible to photodegradation, while neomycin sulfate was the less affected by the UV light. It was observed that the addition to the antibiotics dissolutions of a hydro-alcoholic extract of petals of calyxes of Roselle reduced the CL intensity, indicating that the extract was able to scavenge the free radicals in the irradiated drugs. This result suggest that its addition to the antibiotics can help in the protection against the radicals formed during the exposition to solar light of patients treated with topic similar antibiotics.

Blocking or enhancing effects of some basic emollients in UVA penetration.

BACKGROUND: Topical agents used in combination with phototherapy or photochemotherapy may have both blocking or enhancing effects in ultraviolet rays. OBJECTIVE: In this in vivo study, the effects of topical petrolatum, basis cream, glycerine, and olive oil on the transmission of ultraviolet A radiation were investigated. METHODS: A test was performed to determine the minimal phototoxic dose on 29 volunteers with only psoralen plus ultraviolet A (PUVA) and then the same test was repeated with white petrolatum, basis cream, glycerine, olive oil, and sunscreen (0.3cc/25cm2). The effects of each agent on the minimal phototoxic dose were determined after 72 h. RESULTS: When compared to pure PUVA, there was a statistically significant increase in the mean minimal phototoxic dose values by the application of white petrolatum (P = 0.011), but there was no significant increase or decrease in the mean minimal phototoxic dose values after the application of basis cream (P = 0.326), glycerine (P = 0.611) or olive oil (P = 0.799). STUDY LIMITATIONS: Low number of patients Conclusion: The application of white petrolatum, which has a blocking effect, and also of basis cream immediately before PUVA therapy should not be recommended. Although we specify that glycerine and maybe olive oil can be used before photochemotherapy, there is a need for further research in larger series.

Blocking or enhancing effects of some basic emollients in UVA penetration

Abstract: Background: Topical agents used in combination with phototherapy or photochemotherapy may have both blocking or enhancing effects in ultraviolet rays. Objective: In this in vivo study, the effects of topical petrolatum, basis cream, glycerine, and olive oil on the transmission of ultraviolet A radiation were investigated. Methods: A test was performed to determine the minimal phototoxic dose on 29 volunteers with only psoralen plus ultraviolet A (PUVA) and then the same test was repeated with white petrolatum, basis cream, glycerine, olive oil, and sunscreen (0.3cc/25cm2). The effects of each agent on the minimal phototoxic dose were determined after 72 h. Results: When compared to pure PUVA, there was a statistically significant increase in the mean minimal phototoxic dose values by the application of white petrolatum (P = 0.011), but there was no significant increase or decrease in the mean minimal phototoxic dose values after the application of basis cream (P = 0.326), glycerine (P = 0.611) or olive oil (P = 0.799). Study limitations: Low number of patients Conclusion: The application of white petrolatum, which has a blocking effect, and also of basis cream immediately before PUVA therapy should not be recommended. Although we specify that glycerine and maybe olive oil can be used before photochemotherapy, there is a need for further research in larger series.

Skin penetration and UV-damage prevention by nanoberries.

BACKGROUND: Ethanolic extract from blueberry (Vaccinium myrtillus) is rich in anthocyanins and thus exhibits antioxidant activity. On the other hand, ultradeformable liposomes are capable of penetrating to the impermeable barrier of skin. Nanoberries are ultradeformable liposomes carrying blueberry extract. OBJECTIVES: In this study, their capacity to penetrate the stratum corneum and photodamage prevention were tested, with the aim of developing a topical formulation for skin protection from environmental damage. METHODS: Nanoberries were prepared by lipid film resuspension with ethanolic extract from blueberry, followed by sonication and incorporation to a gel. Size, zeta potential, deformability, rheology, and viscoelasticity were determined. Toxicity was assessed in vivo in zebrafish model, while in vitro cytotoxicity assay was performed on HaCaT and HEK-293T cell lines. Skin penetration was evaluated with the Saarbrücken penetration model followed by tape stripping, cryosection, or optical sectioning. UV-damage protection and photoprotection were determined by ad hoc methods with UVA, UVB, and UVC radiation on HaCaT cells. Wound assay was performed on HaCaT cells. RESULTS: Nanoberries of about 100 nm, with differential elastic properties, did penetrate the stratum corneum, with low toxicity. When HaCaT cells were exposed to UV radiation in the presence of nanoberries, their viability was maintained. CONCLUSIONS: Nanoberries could be effective to protect the skin from sun photodamage.

Ultraviolet A photosensitivity profile of dexchlorpheniramine maleate and promethazine-based creams: Anti-inflammatory, antihistaminic, and skin barrier protection properties.

BACKGROUND: Unwanted side effects such as dryness, hypersensitivity, and cutaneous photosensitivity are challenge for adherence and therapeutical success for patients using treatments for inflammatory and allergic skin response. AIMS: In this study, we compared the effects of two dermatological formulations, which are used in inflammatory and/or allergic skin conditions: dexchlorpheniramine maleate (DCP; 10 mg/g) and promethazine (PTZ; 20 mg/g). METHODS: We evaluated both formulations for phototoxicity potential, skin irritation, anti-inflammatory and antihistaminic abilities, and skin barrier repair in vitro and ex vivo using the standard OECD test guideline n° 432, the ECVAM protocol n° 78, and cultured skin explants from a healthy patient. Ultraviolet A was chosen as exogenous agent to induce allergic and inflammatory response. RESULTS: Both PTZ and DCP promoted increases in interleukin-1 (IL-1) synthesis in response to ultraviolet A (UVA) radiation compared to control. However, the increase observed with PTZ was significantly greater than the DCP, indicating that the latter has a lower irritant potential. DCP also demonstrated a protective effect on UVA-induced leukotriene B4 and nuclear factor kappa B (NF-κB) synthesis. Conversely, PTZ demonstrates more robust UVA antihistaminic activity. Likewise, PTZ promoted a significantly greater increase in the production of involucrin and keratin 14, both associated with protective skin barrier property. CONCLUSION: In conclusion, these data suggest possible diverging UVA response mechanisms of DCP and PTZ, which gives greater insight into the contrasting photosensitizing potential between DCP and PTZ observed in the patients.

Rational Tuning of Visual Cycle Modulator Pharmacodynamics.

Modulators of the visual cycle have been developed for treatment of various retinal disorders. These agents were designed to inhibit retinoid isomerase [retinal pigment epithelium-specific 65 kDa protein (RPE65)], the rate-limiting enzyme of the visual cycle, based on the idea that attenuation of visual pigment regeneration could reduce formation of toxic retinal conjugates. Of these agents, certain ones that contain primary amine groups can also reversibly form retinaldehyde Schiff base adducts, which contributes to their retinal protective activity. Direct inhibition of RPE65 as a therapeutic strategy is complicated by adverse effects resulting from slowed chromophore regeneration, whereas effective retinal sequestration can require high drug doses with potential off-target effects. We hypothesized that the RPE65-emixustat crystal structure could help guide the design of retinaldehyde-sequestering agents with varying degrees of RPE65 inhibitory activity. We found that addition of an isopropyl group to the central phenyl ring of emixustat and related compounds resulted in agents effectively lacking in vitro retinoid isomerase inhibitory activity, whereas substitution of the terminal 6-membered ring with branched moieties capable of stronger RPE65 interaction potentiated inhibition. The isopropyl derivative series produced discernible visual cycle suppression in vivo, albeit much less potently than compounds with a high affinity for the RPE65 active site. These agents were distributed into the retina and formed Schiff base adducts with retinaldehyde. Except for one compound [3-amino-1-(3-isopropyl-5-((2,6,6-trimethylcyclohex-1-en-1-yl)methoxy)phenyl)propan-1-ol (MB-007)], these agents conferred protection against retinal phototoxicity, suggesting that both direct RPE65 inhibition and retinal sequestration are mechanisms of potential therapeutic relevance.

Pharmacokinetics and Pharmacodynamics of Afamelanotide and its Clinical Use in Treating Dermatologic Disorders.

Afamelanotide, the first α-melanocyte-stimulating hormone (MSH) analogue, synthesized in 1980, was broadly investigated in all aspects of pigmentation because its activity and stability were higher than the natural hormone. Afamelanotide binds to the melanocortin-1 receptor (MC1R), and MC1R signaling increases melanin synthesis, induces antioxidant activities, enhances DNA repair processes and modulates inflammation. The loss-of-function variants of the MC1R present in fair-skinned Caucasians are less effectively activated by the natural hormone. Afamelanotide was the first α-MSH analogue to be applied to human volunteers. Ten daily doses of between 0.08 and 0.21 mg/kg in saline injected subcutaneously resulted in long-lasting skin pigmentation and enabled basic pharmacokinetics. Subcutaneous application had full bioavailability, but neither oral nor transdermal application resulted in measurable plasma concentrations or pigmentation response. Two trials in human volunteers showed that neither MC1R variants nor fair skin reduced the afamelanotide-induced increase in skin pigmentation. A controlled-release formulation optimizes administration in man and is effective at a lower dose than the daily saline injections. Promising therapeutic results were published in polymorphic light eruption, erythropoietic protoporphyria (EPP), solar urticaria, Hailey-Hailey disease and vitiligo. In 2014, afamelanotide was approved by the European Medicines Agency for the prevention of phototoxicity in adult patients with EPP. No late effects were reported in volunteers 25 years after the first exposure or after continuous long-term application of up to 8 years in EPP patients, and an immunogenic potential has been excluded. Generally, adverse effects were benign in all trials.

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.

Oral Administration of Fermented Soymilk Products Protects the Skin of Hairless Mice against Ultraviolet Damage.

The protective effect of isoflavones on skin damage from ultraviolet (UV) radiation and their bioavailability were investigated in ovariectomized hairless mice fed diets composed of fermented soymilk containing aglycone forms of isoflavones or control soymilk containing glucose-conjugated forms of isoflavones. The erythema intensity of dorsal skin was significantly higher in ovariectomized mice than in sham-operated mice (p < 0.05). The erythema intensity and epidermal thickness of dorsal skin were significantly lower in the fermented soymilk diet group than in the control diet group (each p < 0.05). Levels of cyclobutane pyrimidine dimers in dorsal skin were significantly lower in the fermented soymilk diet group than in the control group (p < 0.05). Serum and dorsal skin isoflavone concentrations were significantly higher in the fermented soymilk diet group than in the soymilk diet group (p < 0.05). These results indicate that oral administration of a fermented soymilk diet increases isoflavone concentrations in the blood and skin, effectively scavenging the reactive oxygen species generated by UV irradiation and exerting an estrogen-like activity, with a consequent protective effect on skin photodamage in hairless mice.

Acropigmentación dorsal por elaboración de mojitos: una fitofotodermatosis por lima / Acropigmentation of the Dorsum of the Hands From Preparing Mojitos: A Lime-Induced Phytophotodermatosis

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