Photosensitisation by voriconazole-N-oxide results from a sequence of solvent and pH-dependent photochemical and thermal reactions

Morlière, Patrice; Silva, A.M.S.; Seixas, Rafaela; Boscá, Francisco; Mazière, Jean‐Claude; Ferreira, João F.; Santús, René; Filipe, Paulo

doi:10.1016/j.jphotobiol.2018.07.023

Cited by 12 publications

(12 citation statements)

References 26 publications

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“…Carey et al reported a decrease in quantum yield for TFM from 300 to 350 nm within the same range as the current findings . Studies have reported quantum yields for fluoxetine and other pharmaceuticals not included in this study under UV-C wavelengths (255 and 275 nm), and these values are consistently higher than those reported in other studies using solar wavelengths of >290 nm for the same compounds. , …”

Section: Resultssupporting

confidence: 86%

“…39 Studies have reported quantum yields for fluoxetine and other pharmaceuticals not included in this study under UV-C wavelengths (255 and 275 nm), and these values are consistently higher than those reported in other studies using solar wavelengths of >290 nm for the same compounds. 40,41 Unlike quantum yields, the pseudo-first-order rate constants followed the trend of molar absorption by wavelength (Table 1) with only slight differences between 255 and 275 nm. The rate constants were calculated in cm 2 W −1 s −1 (normalized to irradiance) and can be converted to s −1 by multiplying with any individual LED irradiance in W cm −2 .…”

Section: ■ Introductionmentioning

confidence: 92%

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Wavelength-Dependent UV-LED Photolysis of Fluorinated Pesticides and Pharmaceuticals

Bhat

Pomerantz

Arnold

2023

Environ. Sci. Technol.

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The wavelength dependence of photoproduct formation and quantum yields was evaluated for fluorinated pesticides and pharmaceuticals using UV-light emitting diodes (LEDs) with 255, 275, 308, 365, and 405 nm peak wavelengths. The fluorinated compounds chosen were saflufenacil, penoxsulam, sulfoxaflor, fluoxetine, 4-nitro-3-trifluoromethylphenol (TFM), florasulam, voriconazole, and favipiravir, covering key fluorine motifs (benzylic-CF 3 , heteroaromatic-CF 3 , aryl-F, and heteroaromatic-F). Quantum yields for the compounds were consistently higher for UV-C as compared to UV-A wavelengths and did not show the same trend as molar absorptivity. For all compounds except favipiravir and TFM, the fastest degradation was observed using 255 or 275 nm light, despite the low power of the LEDs. Using quantitative 19 F NMR, fluoride, trifluoroacetate, and additional fluorinated byproducts were tracked and quantified. Trifluoroacetate was observed for both Ar-CF 3 and Het-CF 3 motifs and increased at longer wavelengths for Het-CF 3 . Fluoride formation from Het-CF 3 was significantly lower as compared to other motifs. Ar−F and Het-F motifs readily formed fluoride at all wavelengths. For Het-CF 3 and some Ar-CF 3 motifs, 365 nm light produced either a greater number of or different major products. Aliphatic-CF 2 /CF 3 products were stable under all wavelengths. These results assist in selecting the most efficient wavelengths for UV-LED degradation and informing future design of fluorinated compounds.

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Section: Resultssupporting

confidence: 86%

Section: ■ Introductionmentioning

confidence: 92%

Wavelength-Dependent UV-LED Photolysis of Fluorinated Pesticides and Pharmaceuticals

Bhat

Pomerantz

Arnold

2023

Environ. Sci. Technol.

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“…Regular VRC N-oxide blood-level monitoring is not routinely indicated, although determination of the VRC N-oxide/ voriconazole ratio may provide information about the patient's metabolic phenotype and may play a role in VRC-associated toxicity. Exposure-dependent hepatotoxicity has been convincingly shown for VRC only [36], although phototoxicity associated to VRC treatment is probably related to its metabolite [37]. In special circumstancesdsuch as cystic fibrosis (CF) or treatment in children [38]dTDM is required to maintain blood concentrations between 1 and 6 mg/L.…”

Section: Azoles Voriconazole (Vrc)mentioning

confidence: 99%

Antifungal therapeutic drug monitoring: focus on drugs without a clear recommendation

Gómez-López

2020

Clinical Microbiology and Infection

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Background: The goal of therapeutic drug monitoring (TDM) is to determine the appropriate exposure of difficult-to-manage medications to optimize the clinical outcomes in patients in various clinical situations. Concerning antifungal treatment, and knowing that this procedure is expensive and timeconsuming, TDM is particularly recommended for certain systemic antifungals: i.e., agents with a well-defined exposureeresponse relationship and unpredictable pharmacokinetic profile or narrow therapeutic index. Little evidence supports the routine use of TDM for polyenes (amphotericin B), echinocandins, fluconazole or new azoles such as isavuconazole, despite the fact that a better understanding of antifungal exposure may lead to a better response. Aims: The aim of this work is to review published pharmacokinetic/pharmacodynamic data on systemically administered antifungals, focusing on those for which monitoring is not routinely recommended by experts. Sources: A MEDLINE search of the literature in English was performed introducing the following search terms: amphotericin B, fluconazole, itraconazole, voriconazole, posaconazole, triazoles, caspofungin, micafungin, anidulafungin, echinocandins, pharmacokinetics, pharmacodynamics, and therapeutic drug monitoring. Review articles and guidelines were also screened. Content: This review collects different pharmacokinetic/pharmacodynamic aspects of systemic antifungals and summarizes recent threshold values for clinical outcomes and adverse events. Although for polyenes, echinocandins, fluconazole and isavuconazole extensive clinical validation is still required for a clear threshold and a routine monitoring recommendation, particular points such as liposome structure or complex pathophysiological conditions affecting final exposure are discussed. For the rest, their better-defined exposureeresponse/toxicity relationships allow access to useful threshold values and to justify routine monitoring. Additionally, clinical data are needed to better define thresholds that can minimize the development of antifungal resistance. Implications: General TDM for all systemic antifungals is not recommended; however, this approach may help to establish an adequate antifungal exposure for a favourable response, prevention of toxicity or development of resistance in special clinical circumstances.

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“…Importantly, before employing in silico tools in a wider context, e.g., beyond the initial chemical context or even as a decision point in a general phototoxicity screening flowchart, it remains paramount to understand the overall performance in this wider chemical Figure 6. Structure alerts for phototoxicity: chlorpromazine, 43 methoxsalen, 44 hydrochlorothiazide, 45,46 triflusal, 47 lomefloxacin, 48 tetracycline, 49,50 fenofibrate, 51 extended aromatic hydrocarbons, 52 naproxen, 53 chlordiazepoxide, 54 voriconazole, 55 pradigastat, 56 atorvastatin, 57 and flutamide. 58 space.…”

Section: Phototoxicity�convention and Recent Advancesmentioning

confidence: 99%

Phototoxicity─Medicinal Chemistry Strategies for Risk Mitigation in Drug Discovery

Harrison¹,

Chen²,

Yasoshima³

et al. 2023

J. Med. Chem.

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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.

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Photosensitisation by voriconazole-N-oxide results from a sequence of solvent and pH-dependent photochemical and thermal reactions

Cited by 12 publications

References 26 publications

Wavelength-Dependent UV-LED Photolysis of Fluorinated Pesticides and Pharmaceuticals

Wavelength-Dependent UV-LED Photolysis of Fluorinated Pesticides and Pharmaceuticals

Antifungal therapeutic drug monitoring: focus on drugs without a clear recommendation

Phototoxicity─Medicinal Chemistry Strategies for Risk Mitigation in Drug Discovery

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