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The review is devoted to the pathogenetic substantiation of the use of the activated zinc pyrithione agent in atopic dermatitis. The main mechanisms of formation of the pathological process in atopic dermatitis are explained in more details: hereditary predisposition, violations of the barrier function of the skin and immunological dysfunction leading to the development and persistence of chronic inflammation. The role of zinc ions in the pathogenesis of atopic dermatitis is discussed. The article presents the detailed analysis of the main clinical studies of the activated zinc pyrithione agent in atopic dermatitis, its positive effect on such symptoms as itching, skin manifestations, skin microbioma and severity of the disease course.

The ubiquitin-proteasome system (UPS) plays a central role in various cellular processes through selectively degrading proteins involved in critical cellular functions. Targeting UPS has been validated as a novel strategy for treating human cancer, as inhibitors of the 20S proteasome catalytic activity are currently in clinical use for treatment of multiple myeloma and other cancers, and the deubiquitinase activity associated with the proteasome is also a valid target for anticancer agents. Recent studies suggested that zinc pyrithione, an FDA-approved antidandruff agent, may have antitumor activity, but the detailed molecular mechanisms remain unclear. Here we report that zinc pyrithione (ZnPT) targets the proteasome-associated DUBs (USP14 and UCHL5) and inhibits their activities, resulting in a rapid accumulation of protein-ubiquitin conjugates, but without inhibiting the proteolytic activities of 20S proteasomes. Furthermore, ZnPT exhibits cytotoxic effects against various cancer cell lines in vitro, selectively kills bone marrow cells from leukemia patients ex vivo, and efficiently inhibits the growth of lung adenocarcinoma cancer cell xenografts in nude mice. This study has identified zinc pyrithione, an FDA-approved pharmacological agent with potential antitumor properties as a proteasomal DUB inhibitor.

Nowadays there are various groups of biocidal chemical agents, which can be used in diverse areas, such as personal hygiene, disinfection, antiparasitic action, and also in antifouling mixtures or paints. The versatility and efficacy of some of these agents favors their use and ultimate release into the aquatic environment, where they may still exert toxic activity. Zinc pyrithione is classified as a metal biocide with bactericidal, algicidal, and fungicidal actions. It has been formulated in antifouling paints, which prevent the formation of biofilms in submerged structures, and has also been used for dermocosmetic purposes, in shampoos for the treatment of dandruff and seborrhea. Some of the uses of zinc pyrithione are responsible for its direct release as flakes that reach the bottom sediments, especially in estuarine areas. Considering this fate, the ecotoxicity assessment of its effects towards sediment organisms, namely Polychaetous species, is extremely important. The present study characterized the acute potential toxicity of zinc pyrithione in terms of parameters of oxidative stress (catalase, glutathione S-transferases (GSTs), and thiobarbituric acid reactive substances (TBARS)), and neurotoxicity (acetylcholinesterase) which were evaluated in individuals of the polychaete Hediste diversicolor. Regarding the results obtained, only the activity of GSTs and AChE was significantly altered in relation to non-exposed animals. This set of results indicates that oxidative stress did not occur. published

Zinc pyrithione is ubiquitous in commercial products particularly antidandruff shampoos. For the efficacy of zinc pyrithione therapeutic cleansers to be assessed accurately, the distribution of particles on the scalp needs to be visualized. Currently, no technique is available which provides the chemical specificity and sensitivity required. Here, we report application of fluorescence‐lifetime imaging microscopy (FLIM) for high‐contrast mapping of zinc pyrithione distribution on the scalp. Characterization of the zinc pyrithione emission by using both one‐photon excitation at five specific wavelengths and two‐photon excitation in the range of 740–820 nm revealed its FLIM fingerprint—a characteristic short average time‐weighted emission lifetime of ΤZnPT = 250 ps. Bandpass‐filtering FLIM signals at ΤZnPT enabled an efficient discrimination between the zinc pyrithione and major endogenous skin species in comparison with that of the conventional reflectance confocal microscopy. Our findings provide means for in vivo high‐sensitivity assaying and high‐contrast imaging of zinc pyrithione in biological systems. Refereed/Peer-reviewed

The SOS response is a conserved response to DNA damage that is found in Gram-negative and Gram-positive bacteria. When DNA damage is sustained and severe, activation of error-prone DNA polymerases can induce a higher mutation rate than is normally observed, which is called the SOS mutator phenotype or hypermutation. We previously showed that zinc blocked the hypermutation response induced by quinolone antibiotics and mitomycin C in Escherichia coli and Klebsiella pneumoniae. In this study, we demonstrate that zinc blocks the SOS-induced development of chloramphenicol resistance in Enterobacter cloacae. Zinc also blocked the transfer of an extended spectrum beta-lactamase (ESBL) gene from Enterobacter to a susceptible E. coli strain. A zinc ionophore, zinc pyrithione, was ~100-fold more potent than zinc salts in inhibition of ciprofloxacin-induced hypermutation in E. cloacae. Other divalent metals, such as iron and manganese, failed to inhibit these responses. Electrophoretic mobility shift assays (EMSAs) revealed that zinc, but not iron or manganese, blocked the ability of the E. coli RecA protein to bind to single-stranded DNA, an important early step in the recognition of DNA damage in enteric bacteria. This suggests a mechanism for zinc's inhibitory effects on bacterial SOS responses, including hypermutation.

This study focused on the performance of a marketed antimicrobial polypropylene fibers filter containing zinc pyrithione (PP/ZPT) at the laboratory and compared to those of a similar filter (PP) with same classification F7 (EN779:2002). The filtration performance at laboratory scale of the 2 tested filters during clogging with PM10 particles was quantified in an experimental set-up with filter pressure drop measurement and particle counting up and downstream of the filters. The microbial growth onto new and used filters, both contaminated by aerosolization with a microbial consortium composed of two bacteria (Staphylococcus epidermidis Gram positive, Serratia marcescens Gram negative and fungal spores (Penicillium chrysogenum). The influence of three parameters on the microbial survival onto filters was examined: the air relative humidity, the presence or absence of Zinc pyrithione (ZPT) as antimicrobial substances and the presence of organic particles. Quantitative analyses by colony forming unit were used to determine the survival after 8 days of the bacteria–fungi consortium collected by the filter. The two filters revealed similar filtration performance in terms of change in pressure drop and particle collection efficiency during their clogging with PM10 particles, meaning that the antimicrobial treatment did not degrade the filtration performance of the filter. At low humidity value of conditioning (50% RH), with new or used filters, with or without antimicrobial treatment, the microbial population onto the filters decreases and possibly will not survive (Serratia). At high humidity value of conditioning (90% RH), the bacteria do not grow onto the new filters, and only the fungi was able to develop. The effect of the antimicrobial treatment with zinc pyrithione is confirmed for new filters in particular regarding the fungi Penicillium. For used filters, the results indicate that the antimicrobial treatment is no more efficient with a significant growth of the Penicillium, the endemic species of the micronized rice particles (PM10) collected by the filters; the two populations of bacteria significantly decrease with or without antimicrobial treatment. In a second step, the filtration performances of the 2 filters tested previously was investigated in realistic conditions with a semi-urban outdoor air over a 7 months period. The behavior of the outdoor microorganisms onto the filters (growth/mortality) was observed. Two filtration units were operating at IMT Atlantique location, one containing the PP/ZPT filter and the second the PP filter. Each unit filtered the same semi-urban air. Both filtration units operated continuously and several parameters were monitored throughout the operating period: temperature, relative humidity, filter pressure drop, filter particle collection efficiency, inlet particle mass concentration, and microbial concentrations; in addition, the microbial concentration onto the filters was quantified for 3 times (every 2 months) from an innovative methodology based on media coupons. The filtration performances of the two tested filters in terms of changes in pressure drop and particle collection efficiency were different than those obtained in the Laboratory scale. The methodology of coupons permitted to study the behavior of the microorganisms throughout the study. The antimicrobial effect of the zinc pyrithione was confirmed regarding the inhibition of the fungi cultivated on the DRBC agar with no influence of the level of clogging of the filter (mass of particles deposit).; Cette étude s'est concentrée sur la performance d'un filtre antimicrobien en fibres de polypropylène contenant de la pyrithione de zinc (PP/ZPT) au laboratoire et comparée à celle d'un filtre similaire (PP) avec la même classification F7 (EN779:2002). La performance de filtration à l'échelle du laboratoire des 2 filtres testés pendant le colmatage avec des particules PM10 a été quantifiée dans un dispositif expérimental avec mesure de la perte de charge du filtre et comptage des particules en amont et en aval des filtres. La croissance microbienne sur des filtres neufs et usagés, tous deux contaminés par aérosolisation avec un consortium microbien composé de deux bactéries (Staphylococcus epidermidis Gram positif, Serratia marcescens Gram négatif et spores fongiques (Penicillium chrysogenum). L'influence de trois paramètres sur la survie microbienne sur les filtres a été examinée : l'humidité relative de l'air, la présence ou l'absence de pyrithione de zinc (ZPT) en tant que substances antimicrobiennes et la présence de particules organiques. Des analyses quantitatives par unité formant colonies ont été utilisées pour déterminer la survie après 8 jours du consortium bactéries-champignons collecté par le filtre. Les deux filtres ont présenté des performances de filtration similaires en termes de variation de perte de charge et d'efficacité de collecte des particules pendant leur colmatage avec des particules PM10, ce qui signifie que le traitement antimicrobien n'a pas dégradé les performances de filtration du filtre. A faible valeur d'humidité de conditionnement (50% RH), avec des filtres neufs ou usagés, avec ou sans traitement antimicrobien, la population microbienne sur les filtres diminue et éventuellement ne survivra pas (Serratia). Lorsque l'humidité relative du conditionnement est élevée (90% RH), les bactéries ne se développent pas sur les filtres neufs, et seuls les champignons ont pu se développer. L'effet du traitement antimicrobien avec la pyrithione de zinc est confirmé pour les filtres neufs, en particulier en ce qui concerne les champignons Penicillium. Pour les filtres usagés, les résultats indiquent que le traitement antimicrobien n'est pas plus efficace avec une croissance significative du Penicillium, l'espèce endémique des particules de riz micronisées (PM10) collectées par les filtres ; les deux populations de bactéries diminuent significativement avec ou sans traitement antimicrobien.Dans une deuxième étape, les performances de filtration des 2 filtres testés précédemment ont été étudiées dans des conditions réalistes avec un air extérieur semi-urbain sur une période de 7 mois. Le comportement des microorganismes extérieurs sur les filtres (croissance/mortalité) a été observé. Deux unités de filtration fonctionnaient à IMT Atlantique, l'une contenant le filtre PP/ZPT et l'autre le filtre PP. Chaque unité filtrait le même air semi-urbain. Les deux unités de filtration ont fonctionné en continu et plusieurs paramètres ont été surveillés tout au long de la période d'exploitation : température, humidité relative, chute de pression du filtre, efficacité de collecte des particules du filtre, concentration massique des particules à l'entrée et concentrations microbiennes ; en outre, la concentration microbienne sur les filtres a été quantifiée 3 fois (tous les 2 mois) à partir d'une méthodologie innovante basée sur des coupons de média. Les performances de filtration des deux filtres testés en termes de changement de perte de charges et d'efficacité de collecte de particules étaient différentes de celles obtenues à l'échelle du laboratoire. La méthodologie des coupons a permis d'étudier le comportement des micro-organismes tout au long de l'étude. L'effet antimicrobien de la pyrithione de zinc a été confirmé concernant l'inhibition des champignons sans influence du niveau d'encrassement du filtre (dépôt de masse de particules).

Submitted by ANA MARTA CAVINATO MARCHINI ROLISOLA (anamartarolisola@hotmail.com) on 2018-06-21T22:43:46Z No. of bitstreams: 1 Ana Marta C M Rolisola_Tese de Doutorado.pdf: 4492180 bytes, checksum: d1fdb4a15ef3fdf8d398b1f8be14c005 (MD5) Rejected by Ana Paula Santulo Custódio de Medeiros null (asantulo@rc.unesp.br), reason: - Falta o número do processo FAPESP nos agradecimentos: se você recebeu financiamento da FAPESP, ela exige que nos agradecimentos apareça o número do processo. on 2018-06-22T17:15:12Z (GMT) Submitted by ANA MARTA CAVINATO MARCHINI ROLISOLA (anamartarolisola@hotmail.com) on 2018-06-23T14:11:42Z No. of bitstreams: 1 Ana Marta C M Rolisola_Tese de Doutorado.pdf: 4493139 bytes, checksum: 2980a550f843988e0a8bd31a8ee9ab8d (MD5) Approved for entry into archive by Adriana Aparecida Puerta null (dripuerta@rc.unesp.br) on 2018-06-25T13:41:05Z (GMT) No. of bitstreams: 1 rolisola_amcm_dr_rcla.pdf: 4377095 bytes, checksum: da8491d59c9f3875c68e364b6648d0cf (MD5) Made available in DSpace on 2018-06-25T13:41:05Z (GMT). No. of bitstreams: 1 rolisola_amcm_dr_rcla.pdf: 4377095 bytes, checksum: da8491d59c9f3875c68e364b6648d0cf (MD5) Previous issue date: 2018-05-02 Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) Atualmente, cerca de 18 compostos são utilizados como biocidas de reforço (metálicos) em tintas anti-incrustantes, como por exemplo Piritionato de Zinco (Zn(PT)2), Zineb e Ziram. É relevante o desenvolvimento de um método analítico para determinação das concentrações ambientais de biocidas metálicos. O presente estudo teve como objetivos i)desenvolver uma metodologia de extração em fase sólida (SPE) e cromatografia líquida de alta eficiência acoplada (HPLC) ao espectrômetro de massas com plasma acoplado indutivamente (ICP-MS) para determinação de Zn(PT)2, Zineb e Ziram e ii) quantificar, in lab, a fração lábil total do Piritionato de Zinco, Zineb e Ziram e in situ, a fração lábil total do zinco, utilizando a técnica de difusão em filmes finos por gradiente de concentração (DGT) em solução padrão e água estuarina, respectivamente. Na técnica de SPE foi utilizado o sorbente de sílica funcionalizado com fenil apresentando excelente retenção para Zn(PT)2, Zineb e Ziram (94 ± 0,1%, 85 ± 0,04% e 93 ± 0,1%, respectivamente) e recuperações entre 85% e 110%. Na determinação dos biocidas de zinco utilizando o acoplamento HPLC-VGroove-ICP-MS com diluição pós coluna cromatográfica, a fase móvel composta por metanol e 0,006 mol L-1 de acetato de amônio (50:50, v v-1) apresentou o melhor desempenho na separação do Zn(PT)2, Zineb, Ziram. A curva analítica obtida para o Zn(PT)2 apresentou coeficiente de correlação, LD e LQ satisfatórios para os isótopos 64Zn (0,98, 0,575 mg L-1, 1,916 mg L-1), 66Zn(0,99, 0,480 mg L-1 , 1,600 mg L-1), 68Zn(0,98, 0,602 mg L-1, 2,007 mg L-1). Na técnica DGT foi utilizado o agente ligante resina Chelex® 100 para avaliar a labilidade do Zn(PT)2, Zineb e Ziram em água estuarina. Os resultados demonstraram que a fração lábil total do Zn ficou em torno de 100% para o Zineb (111%) e Ziram (109%), ou seja, estes biocidas formaram espécies totalmente lábeis na amostra de água estuarina e para Zn(PT)2 foi de 75% indicando espécies parcialmente lábeis. Os resultados obtidos na técnica SPE, no acoplamento HPLC-VGroove-ICP-MS e DGT demonstraram que os métodos apresentam desempenho satisfatório para a determinação de Piritionato de Zinco, Zineb e Ziram. About 18 compounds are used as booster biocides (metal) in antifouling paints such as Zinc Pyrithione (Zn(PT)2), Zineb and Ziram. It is important to develop an analytical method for determining of the environmental concentrations of zinc biocides. The present study had as objectives i) to develop a solid phase extraction (SPE) and high performance liquid chromatography (HPLC) coupled to the inductively coupled plasma mass spectrometer (ICP-MS) for the determination of Zn(PT)2, Zineb and Ziram and ii) quantify in lab the total labile fraction of Zn(PT)2, Zineb and Ziram and in situ the total labile fraction of zinc using the diffusive gradient in thin films (DGT) technique in standard solution and estuarine water, respectively. In the SPE technique, the silica sorbent functionalized with phenyl presented excellent retention for Zn(PT)2, Zineb and Ziram (94 ± 0.1%, 85 ± 0.04% and 93 ± 0.1%, respectively) and recoveries between 85% and 110%. In the determination of zinc using the HPLC-VGroove-ICP-MS coupling with post-column chromatographic dilution, the mobile phase composed of methanol and 0.006 mol L-1 of ammonium acetate (50:50, v v-1) of presented the best performance in the separation of Zn(PT)2, Zineb and Ziram. The analytical curve obtained for Zn(PT)2 presented satisfactory correlation coefficient, LD and LQ for the isotopes 64Zn (0.98, 0.575 mg L -1, 1.916 mg L-1), 66Zn (0.99, 0.480 mg L-1, 1.600 mg L-1), 68Zn (0.98, 0.602 mg L-1, 2.007 mg L-1). In the DGT technique, the Chelex® 100 resin binder was used to evaluate the lability of the zinc biocides Zn(PT)2, Zineb and Ziram in estuarine water. The results showed that the total labile fraction of Zn was around 100% for Zineb (111%) and Ziram (109%), that is, these biocides formed totally labile species in the estuarine water sample and for Zn(PT)2 was 75% indicating partially labile species. The results obtained in the SPE technique in the HPLC-VGroove-ICP-MS coupling and DGT demonstrated that the methods present satisfactory performance for the determination of Zn(PT)2, Zineb and Ziram. CNPq: 164326/2015. FAPESP: 2015/03397-4.

New biocides such as the organometallic compound zinc pyrithione (ZnP) have been massively introduced by many countries in formulations of antifouling paints following the ban on tributyltin (TBT). The effects of sublethal concentrations (LC50=82.5 μM, i.e., 26.2 mg/l) on cultured haemocytes of the ascidian Botryllus schlosseri have been investigated and compared with TBT. The percentage of haemocytes with amoeboid morphology and containing phagocytised yeast cells were significantly (p

Zinc pyrithione is an active component incorporated in an extensive range of topically applied commercial products that are used worldwide. Despite its prevalence, no published study has investigated the penetration of zinc from the zinc pyrithione complex into human skin. Zinc is crucial for healthy skin function however an elevated concentration of labile zinc is toxic outside a narrow concentration range. Synchrotron X-ray fluorescence microscopy in conjunction with X-ray absorption near edge structure spectroscopy was used to map the deposition of zinc, quantitate the amount of zinc within the skin and to identify a change in the chemical form of zinc after application. This study has demonstrated a ~3.8 fold increase in zinc concentration within the viable epidermis (VE) after 24 h topical application of zinc pyrithione that increased significantly by ~250 fold after 48 h when compared to control skin. Confocal microscopy using a labile zinc specific dye, ZinPyr-1, showed that zinc pyrithione disrupted the skin cells zinc homeostasis and significantly increased the intracellular zinc concentration leading to cell toxicity. Overall, this study demonstrates that topical application of zinc pyrithione formulations leads to an increase in zinc penetration in human skin, consequently, raising concerns for potential localised toxicity to occur. Refereed/Peer-reviewed

Topical antimicrobial ointments ostensibly mitigate bacterial wound disease and reliance on systemic antibiotics. Yet studies have called into question the therapeutic benefits of several traditional topical antibacterials, accentuating the need for improved next-generation antimicrobial ointments. Yet the development of such agents consisting of a new chemical entity is a time-consuming and expensive proposition. Considering that drug combinations are a mainstay therapeutic strategy for the treatment of other therapeutic indications, one alternative approach is to improve the performance of conventional antimicrobial ointments by the addition of a well-characterized and FDA-approved agent. Here we report data that indicate that the antimicrobial properties of silver sulfadiazine ointments can be significantly improved by the addition of the antifungal zinc pyrithione, suggesting that such combinations may provide an improved therapeutic option for the topical treatment of wound infections., Pseudomonas aeruginosa, Acinetobacter baumannii, and Staphylococcus aureus are commonly associated with biofilm-associated wound infections that are recalcitrant to conventional antibiotics. As an initial means to identify agents that may have a greater propensity to improve clearance of wound-associated bacterial pathogens, we screened a Food and Drug Administration-approved drug library for members that display bactericidal activity toward 72-h-established P. aeruginosa biofilms using an adenylate kinase reporter assay for bacterial cell death. A total of 34 compounds displayed antibiofilm activity. Among these, zinc pyrithione was also shown to reduce levels of A. baumannii and S. aureus biofilm-associated bacteria and exhibited an additive effect in combination with silver sulfadiazine, a leading topical therapeutic for wound site infections. The improved antimicrobial activity of zinc pyrithione and silver sulfadiazine was maintained in an ointment formulation and led to improved clearance of P. aeruginosa, A. baumannii, and S. aureus in a murine model of wound infection. Taken together, these results suggest that topical zinc pyrithione and silver sulfadiazine combination formulations may mitigate wound-associated bacterial infections and disease progression. IMPORTANCE Topical antimicrobial ointments ostensibly mitigate bacterial wound disease and reliance on systemic antibiotics. Yet studies have called into question the therapeutic benefits of several traditional topical antibacterials, accentuating the need for improved next-generation antimicrobial ointments. Yet the development of such agents consisting of a new chemical entity is a time-consuming and expensive proposition. Considering that drug combinations are a mainstay therapeutic strategy for the treatment of other therapeutic indications, one alternative approach is to improve the performance of conventional antimicrobial ointments by the addition of a well-characterized and FDA-approved agent. Here we report data that indicate that the antimicrobial properties of silver sulfadiazine ointments can be significantly improved by the addition of the antifungal zinc pyrithione, suggesting that such combinations may provide an improved therapeutic option for the topical treatment of wound infections.

We performed a whole-transcriptome analysis of miconazole-treated Candida albicans biofilms, using RNA-sequencing. Our aim was to identify molecular pathways employed by biofilm cells of this pathogen to resist action of the commonly used antifungal miconazole. As expected, genes involved in sterol biosynthesis and genes encoding drug efflux pumps were highly induced in biofilm cells upon miconazole treatment. Other processes were affected as well, including the electron transport chain (ETC), of which eight components were transcriptionally downregulated. Within a diverse set of 17 inhibitors/inducers of the transcriptionally affected pathways, the ETC inhibitors acted most synergistically with miconazole against C. albicans biofilm cells. Synergy was not observed for planktonically growing C. albicans cultures or when biofilms were treated in oxygen-deprived conditions, pointing to a biofilm-specific oxygen-dependent tolerance mechanism. In line, a correlation between miconazole’s fungicidal action against C. albicans biofilm cells and the levels of superoxide radicals was observed and confirmed both genetically and pharmacologically using a triple superoxide dismutase mutant and a superoxide dismutase inhibitor N-N′-diethyldithiocarbamate, respectively. Consequently, ETC inhibitors that result in mitochondrial dysfunction and affect production of reactive oxygen species can increase miconazole’s fungicidal activity against C. albicans biofilm cells.

The recent ban on TBT in boat antifouling paints has resulted in a large employment of the biocide zinc pyrithione (ZnPT) as substitute. Despite concerns of its environmental toxicity at ultra-trace concentrations, ZnPT has received little attention, as it was assumed to photo-degrade easily. However, recent evidence has suggested that ZnPT degrades only partially, and persists in the marine environment, especially where the influence of light is limited, such as in harbours. Short-term acute toxicity tests and life table response experiments (LTREs) were performed to evaluate the effects of ZnPT on the polychaete Dinophilus gyrociliatus at both individual and population level. The 96h-LC 50 values for ZnPT on D. gyrociliatus were 7.8 and 11.5 nM under dark and 12 h light/12 h dark conditions, respectively. In LTREs, laboratory cultured cohorts of D. gyrociliatus were exposed to sublethal concentrations of ZnPT (0.5 and 1 nM) and compared to a control cohort. The survival among individuals exposed to the highest concentration decreased already during the 2nd week of life with respect to the control. The effects of the biocide on fecundity were even more evident: ZnPT caused a considerable reduction in both the exposed groups. The demographic approach applied here succeeded in identifying ZnPT effects both on the biological cycle and on the growth potential of polychaete D. gyrociliatus . The net growth rate ( R 0 ) appeared to be the demographic parameter most sensitive to ZnPT, as the biocide exposure was associated with a sharp decline of R 0 in both the 0.5 and the 1 nM groups (−41% and −63%, respectively) in comparison to the control cohort. The population growth rate λ (often used as an index of population fitness) and the life expectancy e 0 were also significantly reduced, while ZnPT exposure did not affect the generation time T . These results highlight the potential ecological threat posed by the biocide ZnPT, even at the very low tested concentrations, which are already detectable in some European marinas.

Commercially formulated anti-dandruff shampoos contain zinc pyrithione (ZPT) as an active ingredient that has antifungal, antibacterial and anti-seborrheic properties. The determination of ZPT concentration in commercial anti-dandruff shampoos by differential pulse polarography (DPP) was based on the electrochemical reduction of zinc ions in ammoniacal buffer pH 10.2, and the linear dependence of the reduction differential pulse peak current at the potential - 1.33 V vs. concentration of zinc. Using the calibration curve method, it was found that the range of linearity for the determination of zinc concentration was from 1.28 x 10-5 to 1.39 x 10-4 mol L‒1 (linear regression equation: I = - 0.097 + 6.635 x 105c). Surface active ingredients and micro-components in the shampoos did not exert a polarographic interference for the determination of zinc and did not affect the indirect determination of the content of the active ingredient ZPT. The concentrations of zinc in the analyzed anti-dandruff shampoo samples were determined by the standard addition method, resulting in 4.20 x 10‒2 mol L‒1, 1.76 x 10‒1 mol L‒1 and 1.82 x 10‒1 mol L‒1. The results of DPP determinations of zinc and ZPT show that the content of ZPT was 0.28%, 1.15% i.e. 1.19% and was below the maximum recommended level of ZPT in anti-dandruff shampoos. This simple and sensitive differential pulse polarography method is suitable for a routine and rapid control of the active ingredient content, as well as for the quality control of anti-dandruff shampoos. Aktivni sastojak komercijalno formulisanih šampona protiv peruti je cink-pirition, koji ima antifungalno, antibakterijsko i antiseboreično dejstvo. Određivanje cink-piritiona u šamponima protiv peruti primenom metode diferencijalne pulsne polarografije zasnivalo se na elektrohemijskoj redukciji jona cinka u amonijačnom puferu pH 10,2 i linearnoj zavisnosti intenziteta struje pika na redukcionom potencijalu - 1,33 V i koncentracije cinka. Metodom kalibracione krive je određen opseg linearnosti za određivanje koncentracije cinka od 1,28 x 10‒5 do 1,39 x 10‒4 mol L-1 i dobijena je linearna regresiona jednačina I = - 0,097 + 6,635 x 105c. Utvrđeno je da površinski aktivne komponente u matriksu šampona ne pokazuju polarografsku interferenciju i ne utiču na određivanje koncentracije cinka i sadržaja cink-piritiona u analiziranim šamponima. Koncentracije cinka u analiziranim uzorcima šampona određene su metodom standardnog dodatka i iznose 4,20 x 10‒2 mol L-1, 1,76 ' 10‒1 mol L-1 i 1,82 x 10‒1 mol L-1. Rezultati polarografskog određivanja cinka i sadržaja cink-piritiona pokazuju da su dobijene vrednosti cink-piritiona 0,28%, 1,15% i 1,19% ispod maksimalno preporučenog sadržaja cink-piritiona u šamponima protiv peruti. Ova jednostavna i osetljiva metoda diferencijalno pulsne polarografije pogodna je za rutinsko i brzo određivanje sadržaja aktivnog sastojka i kontrolu kvaliteta šampona protiv peruti.

Commercially formulated anti-dandruff shampoos contain zinc pyrithione (ZPT) as an active ingredient that has antifungal, antibacterial and anti-seborrheic properties. The determination of ZPT concentration in commercial anti-dandruff shampoos by differential pulse polarography (DPP) was based on the electrochemical reduction of zinc ions in ammoniacal buffer pH 10.2, and the linear dependence of the reduction differential pulse peak current at the potential - 1.33 V vs. concentration of zinc. Using the calibration curve method, it was found that the range of linearity for the determination of zinc concentration was from 1.28 ´ 10 ‒5 to 1.39 ´ 10 -4 mol L ‒1 (linear regression equation: I = - 0.097 + 6.635 ´ 10 5 c). Surface active ingredients and micro-components in the shampoos did not exert a polarographic interference for the determination of zinc and did not affect the indirect determination of the content of the active ingredient ZPT. The concentrations of zinc in the analyzed anti-dandruff shampoo samples were determined by the standard addition method, resulting in 4.20 ´ 10 ‒2 mol L ‒1 , 1.76 ´ 10 ‒1 mol L ‒1 and 1.82 ´ 10 ‒1 mol L ‒1 . The results of DPP determinations of zinc and ZPT show that the content of ZPT was 0.28%, 1.15% i.e. 1.19% and was below the maximum recommended level of ZPT in anti-dandruff shampoos. This simple and sensitive differential pulse polarography method is suitable for a routine and rapid control of the active ingredient content, as well as for the quality control of anti-dandruff shampoos. PRIMENA DP POLAROGRAFIJE ZA ODREĐIVANJE CINKA I SADRŽAJA CINK-PIRITIONA U SAMPONIMA PROTIV PERUTI Aktivni sastojak komercijalno formulisanih sampona protiv peruti je cink-pirition, koji ima antifungalno, antibakterijsko i antiseboreicno dejstvo. Određivanje cink-piritiona u samponima protiv peruti primenom metode diferencijalne pulsne polarografije zasnivalo se na elektrohemijskoj redukciji jona cinka u amonijacnom puferu pH 10,2 i linearnoj zavisnosti intenziteta struje pika na redukcionom potencijalu - 1,33 V i koncentracije cinka. Metodom kalibracione krive je određen opseg linearnosti za određivanje koncentracije cinka od 1,28 ´ 10 ‒5 do 1,39 ´ 10 ‒4 mol L -1 i dobijena je linearna regresiona jednacina I = - 0,097 + 6,635´10 5 c. Utvrđeno je da povrsinski aktivne komponente u matriksu sampona ne pokazuju polarografsku interferenciju i ne uticu na određivanje koncentracije cinka i sadržaja cink-piritiona u analiziranim samponima. Koncentracije cinka u analiziranim uzorcima sampona određene su metodom standardnog dodatka i iznose 4,20 ´ 10 ‒2 mol L -1 , 1,76 ´ 10 ‒1 mol L -1 i 1,82 ´ 10 ‒1 mol L -1 . Rezultati polarografskog određivanja cinka i sadržaja cink-piritiona pokazuju da su dobijene vrednosti cink-piritiona 0,28%, 1,15% i 1,19% ispod maksimalno preporucenog sadržaja cink-piritiona u samponima protiv peruti. Ova jednostavna i osetljiva metoda diferencijalno pulsne polarografije pogodna je za rutinsko i brzo određivanje sadržaja aktivnog sastojka i kontrolu kvaliteta sampona protiv peruti. HIGHLIGHTS Commercially formulated anti-dandruff shampoos contain zinc pyrithione (ZPT) as an active ingredient that has antifungal, antibacterial and anti-seborrheic effects; ZPT is based on the organic entity pyrithione (PT) in which a zinc ion forms a metal complex with PT in a 1 : 2 ratio; Determination of ZPT concentration in commercial anti-dandruff shampoos by differential pulse polarography is based on electrochemical reduction of zinc ions in ammoniacal buffer of pH 10.2; Surface active ingredients (anionic and amphoteric) and micro-components in the shampoos do not show a polarographic interference for determination of zinc and do not affect determination of the content of ZPT active ingredient; A simple and sensitive differential pulse polarography method is suitable for routine and rapid control of the active ingredient content, as well as for quality control of anti-dandruff shampoos.

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Background: Dandruff is a common condition in clinical practice. We undertook a study to evaluate the efficacy and safety of a combination of zinc pyrithione and polytar in a shampoo base for the treatment of dandruff. Methods: A combination of polytar (1%) and zinc pyrithione (1%) was used for 4 weeks to treat 954 patients suffering from mild to severe dandruff. Scoring of dandruff was done on a 0-10 scale for each of the 6 regions of scalp at weeks 0, 2, 4 and 6. Follow up was for 2 weeks. Results: There was consistent improvement in dandruff scores over the treatment and the follow up period. There was significant improvement in signs and symptoms such as erythema and itching, with a negligible adverse event profile. The global assessment by investigators showed good-excellent results in the majority of patients and there was high acceptability for the treatment among the patients. Conclusion: A combination shampoo of polytar (1%) and zinc pyrithione (1%) offers a safe and effective option in the treatment of dandruff and its associated symptoms.

Zinc pyrithione (ZP) is commonly used to prevent dandruff and seborrheic dermatitis. Many consumers are exposed daily to high doses of ZP, causing serious concerns about its toxicity. The reproductive and developmental toxicities were previously reported in pregnant rats. However, the estrogenic activity of ZP at varying degrees of exposure has been rarely studied. Thus, we performed an uterotrophic assay, E-screen assay, and gene expression profiling to assess the estrogenic activity of ZP. For the uterotrophic assay, ZP (2, 10, or 50 mg/kg/d) was subcutaneously administered to ovariectomized rats every day for three days. Uteri were extracted 24 hours after the last dose. Then, wet and blotted uterine weights were measured. For the E-screen essay, MCF-7 cells (a breast cancer cell line) were exposed to 10-9 to 10-6 M of ZP, and cell proliferation was then measured. For the gene expression analysis, changes of gene expression levels in uterine samples taken for the uterotrophic assay were analyzed. In the uterotrophic assay, the concentration of ZP had no significant effect on uterine weight. In the E-screen assay, ZP at any concentration showed no significant increase in MCF-7 cell proliferation, compared to the control group. However, 10-6 M of ZP significantly reduced cell viability. The changes in gene expression slightly differed between the ZP and control groups. The in vivo and in vitro assays, together with gene expression analysis, demonstrated that ZP showed no significant estrogenic activity.

Background: Scalp seborrheic dermatitis is a chronic type of inflammatory dermatosis that is associated with sebum secretion and proliferation of Malassezia species. Ketoconazole or zinc-pyrithione shampoos are common treatments for scalp seborrheic dermatitis. However, shampoos comprising different compounds are required to provide patients with a wider range of treatment options. Objective: This study was designed to evaluate a new-formula shampoo that contains natural ingredients-including extract of Rosa centifolia petals and epigallocatechin gallate (EGCG)-that exert antioxidative, anti-inflammatory, and sebum secretion inhibitory effects, and antifungal agents for the treatment of scalp seborrheic dermatitis. Methods: Seventy-five patients were randomized into three treatment groups; new-formula shampoo, 2% ketoconazole shampoo, and 1% zinc- pyrithione shampoo. The clinical severity scores and sebum levels were assessed by the same dermatologists at baseline (week 0), and at 2 and 4 weeks after using the shampoo. User satisfaction and irritation were also assessed with the aid of a questionnaire. Results: The efficacy of the new-formula shampoo was comparable to that of both the 1% zinc- pyrithione shampoo and the 2% ketoconazole shampoo. Furthermore, it was found to provide a more rapid response than the 1% zinc-pyrithione shampoo for mild erythema lesions and was associated with greater user satisfaction compared with the 2% ketoconazole shampoo. However, the new-formula shampoo did not exhibit the previously reported sebum inhibitory effect. Conclusion: Extract of R. centifolia petals or EGCG could be useful ingredients in the treatment of scalp seborrheic dermatitis. (Ann Dermatol 26(6) 733∼738, 2014)

Antifouling biocide zinc pyrithione (ZnPT) and its biological fate have received little attention because this compound was assumed not to be persistent in marine ecosystems. An analytical procedure was developed that has proved to be efficient and very sensitive in extracting ZnPT and its main secondary products, Zn and ionized pyrithione (PT−), from both seawater and biological samples, namely in the gills and digestive gland of the bioindicator species Mytilus galloprovincialis. Short-term experiments were carried out to investigate ZnPT toxicity and bioaccumulation. The effects on survival and tissue bioaccumulation of ZnPT and its secondary products were studied on adult mussels from a natural population, collected in the harbor area of Porto Santo Stefano (Italy) and exposed to sublethal doses of the biocide for up to 7 d. Zinc pyrithione was shown to be persistent in the experimental seawater in the short term. A basal level of ZnPT and ionized PT− was detected in the mussels, indicating that ZnPT availability in the sampling site is already high enough to induce a detectable accumulation in individuals of the native population. Zinc pyrithione rapidly accumulated in the tissues of the exposed mussels, proportionately to both exposure concentration and time, identifying the gills and digestive gland as important targets in the biological pathway of the contaminants. Even though the 7-d median lethal concentration (LC50) = 8.27 µM established here appears high with respect to reported ZnPT environmental concentrations, the results indicate that this biocide could represent a threat for marine organisms in coastal environments and that further investigations on its biological effects at sublethal doses are needed. Environ. Toxicol. Chem. 2010;29:2583–2592. © 2010 SETAC

The anti-fouling biocide zinc pyrithione (ZnPT) was recently demonstrated to be more persistent than expected in the coastal environment, and to have a potential for bioaccumulation. We investigated the occurrence of adverse effects in the marine mussel Mytilus galloprovincialis when exposed to non-lethal concentrations of the contaminant (0.2 and 0.4 μM ZnPT), through the use of a battery of biomarkers from the molecular to the individual level. In particular, the expression of HSP27, HSP60, HSP70 and the presence of genotoxic damage were investigated in the gills and digestive gland of mussels by means of Western blot and TUNEL procedures, respectively. In addition, a stress on stress response test was performed in order to highlight a possible general stress conditions in the exposed bivalves. A concentration of 0.2 μM ZnPT was found sufficient to trigger a marked stress response in gills and digestive gland, and a concentration-dependent HSP expression was highlighted. Moreover, at the tested concentrations, ZnPT was found able to induce genotoxic effects, as demonstrated by an amplified DNA fragmentation (up to +37% of TUNEL positive cells in comparison to the control group) and by an increased frequency of apoptotic cells (up to +5%) in the tissues of the exposed mussels. In addition, the stress on stress response test demonstrated a heavily decreased tolerance to anoxic conditions in mussels exposed to the higher tested concentration of the biocide (LT 50 = 5.4 days) compared to the control individuals (LT 50 = 10.7 days). Multivariate analyses highlighted a strong correspondence between the observed biological effects in M. galloprovincialis , HSP over-expression and DNA damage in the gills and digestive gland, and the bioaccumulation levels of the biocide. Data presented here indicate the need for further investigations on the ZnPT effects on the key species of marine coastal communities, with the aim of obtaining the necessary information for a sound risk assessment of the impact of this new antifoulant on marine ecosystems.

Background, aim and scope Sources of organic micropollutants occuring in surface waters are often unknown. Regarding environmental risk assessments for surface waters, construction materials have as till now, not been given much consideration, although biocides used as preservatives are known to reach urban storm water runoff. The study focused on biocides for facades coatings and aimed (1) to determine ecotoxicological effect values, (2) to quantify the leaching behaviour and (3) to assess the environmental risk for surface waters using a dynamic transport model. Materials and methods Eight biocides used in resin based facade coatings were investigated. Some biocides are substances known as pesticides for agricultural purposes like diuron, carbendazim and terbutryn. Ecotoxicological effect values for aquatic organisms were determined for every biocide. Leaching of four biocides from a render under UV-irradiation has been investigated in the laboratory including the influence of varying temperatures. Using 80 irrigation intervals over 28 days, facade runoff was sampled and followed by biocide chemical analysis. The total losses were calculated based on the concentration patterns. These data were used for modelling the transport of cybutryn from facades to surface waters. Biocide specific effect values and leaching characteristics have been taken into consideration. Results Acute and chronic effect values as well as predicted no effect concentrations for the investigated biocides indicate their high potential to affect aquatic organisms. The leaching of four biocides (diuron, terbutryn, cybutryn, carbendazim) from the facade render under the experimental conditions delivers high concentrations in the beginning followed by an exponential decrease. Rising temperature increased the concentration of biocides in the runoff. The total losses were between 7 % and 29 % depending on the substances. More than half of the losses occur in the runoff within the first 15 min of runoff from a 60 min irrigation cycle. The modelling result for cybutryn underlines its high environmental risk for small surface waters. Discussion The leaching of the biocides, their potential ecotoxic effects and persistence show clearly that the environmental risk for surface waters and soils seems to be high for certain biocides; whereas for others the risk seems to be significantly lower. With respect water quality criteria, polluted facades runoff has to be diluted before runoff can enter the discharge. Diuron and carbendazim are however also used as pesticides and preservatives for other materials and cybutryn is also used as an antifouling agent. All pathways have to be evaluated in order to identify relevant sources and to act more efficiently with respect to water and soil protection. Conclusions Concentrations with high environmental risk are expected at new facades, especially at facades with thermal insulation. With the given low predicted no effect concentrations in a range of a few ng/L and large amounts of biocides applied in paints and renders, the environmental risk for common biocides used in facade coatings has to be investigated in laboratory and field scale. It seems plausible that source control measures as the most efficient and sustainable precautionary principle need to be evaluated. Recommendations and perspectives Biocides and additives applied in construction materials have to be taken into consideration as relevant sources when evaluating the quality of storm water runoff, discharge into urban areas and the impact to soil and surface waters. A sustainable construction material management and storm water management are required. It is expected that ongoing laboratory and field studies with exterior paints, renders and flat sheets for waterproofing containing biocides and additives will give further insight into their environmental impact. Background, aim and scope Sources of organic micropollutants occuring in surface waters are often unknown. Regarding environmental risk assessments for surface waters, construction materials have as till now, not been given much consideration, although biocides used as preservatives are known to reach urban storm water runoff. The study focused on biocides for facades coatings and aimed (1) to determine ecotoxicological effect values, (2) to quantify the leaching behaviour and (3) to assess the environmental risk for surface waters using a dynamic transport model. Materials and methods Eight biocides used in resin based facade coatings were investigated. Some biocides are substances known as pesticides for agricultural purposes like diuron, carbendazim and terbutryn. Ecotoxicological effect values for aquatic organisms were determined for every biocide. Leaching of four biocides from a render under UV-irradiation has been investigated in the laboratory including the influence of varying temperatures. Using 80 irrigation intervals over 28 days, facade runoff was sampled and followed by biocide chemical analysis. The total losses were calculated based on the concentration patterns. These data were used for modelling the transport of cybutryn from facades to surface waters. Biocide specific effect values and leaching characteristics have been taken into consideration. Results Acute and chronic effect values as well as predicted no effect concentrations for the investigated biocides indicate their high potential to affect aquatic organisms. The leaching of four biocides (diuron, terbutryn, cybutryn, carbendazim) from the facade render under the experimental conditions delivers high concentrations in the beginning followed by an exponential decrease. Rising temperature increased the concentration of biocides in the runoff. The total losses were between 7 % and 29 % depending on the substances. More than half of the losses occur in the runoff within the first 15 min of runoff from a 60 min irrigation cycle. The modelling result for cybutryn underlines its high environmental risk for small surface waters. Discussion The leaching of the biocides, their potential ecotoxic effects and persistence show clearly that the environmental risk for surface waters and soils seems to be high for certain biocides; whereas for others the risk seems to be significantly lower. With respect water quality criteria, polluted facades runoff has to be diluted before runoff can enter the discharge. Diuron and carbendazim are however also used as pesticides and preservatives for other materials and cybutryn is also used as an antifouling agent. All pathways have to be evaluated in order to identify relevant sources and to act more efficiently with respect to water and soil protection. Conclusions Concentrations with high environmental risk are expected at new facades, especially at facades with thermal insulation. With the given low predicted no effect concentrations in a range of a few ng/L and large amounts of biocides applied in paints and renders, the environmental risk for common biocides used in facade coatings has to be investigated in laboratory and field scale. It seems plausible that source control measures as the most efficient and sustainable precautionary principle need to be evaluated. Recommendations and perspectives Biocides and additives applied in construction materials have to be taken into consideration as relevant sources when evaluating the quality of storm water runoff, discharge into urban areas and the impact to soil and surface waters. A sustainable construction material management and storm water management are required. It is expected that ongoing laboratory and field studies with exterior paints, renders and flat sheets for waterproofing containing biocides and additives will give further insight into their environmental impact.

As an assignment from the Swedish Environmental Protection Agency, IVL has during 2006/2007 performed a 'Screening Study' of zinc pyrithione. Also the concentrations of irgarol 1051, zinc (Zn) and lead (Pb) were measured in the study As an assignment from the Swedish Environmental Protection Agency, IVL has during 2006/2007 performed a 'Screening Study' of zinc pyrithione. Also the concentrations of irgarol 1051, zinc (Zn) and lead (Pb) were measured in the study