Academic literature on the topic 'Pharmaceutically active compounds'

Awareness of residual pharmaceutically active compounds (PhACs) in aquatic ecosystems is growing as research into these pollutants increases and analytical detection techniques improve. For most pharmaceuticals analyzed, the effects on aquatic organisms have usually been investigated by toxic assays in the laboratory. However, little is known about integral analysis of pharmacokinetics in aquatic organisms and specific relations between pharmacokinetic parameters and influence factors. Moreover, the influence of the organisms involved and numerous other external factors complicates development of standard tests for environmental evaluation. Current knowledge about residual pharmaceuticals in the aquatic environment, including status, toxic effects, and pharmacokinetics in aquatic organisms, are reviewed. Based on the above, we identify major gaps in the current knowledge and some directions for future research, such as improvement of techniques to remove residual pharmaceuticals from wastewater, and the establishment of standard pharmaceutical modes of action.

The chemical composition, distribution, and fate of pharmaceutically active compounds (PhACs) present in typical pharmaceutical wastewater treatment plants were investigated with the aim of effectively removing these pollutants while minimizing waste of resources and energy. The results of this study indicate that the relative content of an organic compound class is unrelated to the number of organic compounds in the influent and effluent, yet it is directly proportional to the pollution contribution in pharmaceutical wastewater. In wastewater influent, the organic compound classes with the highest relative contents and pollution contributions were acids (relative content = 63.65%, contribution to pollution = 67.22%), esters (44.96%, 41.24%), and heterocyclic compounds (30.24%, 35.23%); in wastewater effluent, these classes were organic acids (62.54%, 65.13%), esters (52.66%, 59.02%), and organosilicon compounds (42.46%, 37.45%). The different physicochemical characteristics of these pollutants result in different removal efficiencies. For example, N,N-dimethylformamide, 4-methyloctane, N-ethylmorpholine, and 4-amino-N,N- and N,N-diethylbenzamide are refractory and are not degraded by microorganisms; thus, these compounds are discharged into the aquatic environment. Other organic compound classes including organosilicon compounds, acids, esters, heterocycles, and alcohols are mostly biodegraded, which leads to high concentrations of hydrocarbons in the wastewater effluent. The results of this study provide a foundation for the improvement of pharmaceutical wastewater treatment.

The aim of this study was the investigation of photocatalytic degradation of pharmaceutically active compounds using doped TiO2 functionalized zeolite photocatalyst. Diclofenac (DCF), a non-steroidal anti-inflammatory drug, that represents a biorefractory micropollutant, was chosen as model of pharmaceutically active compound. The photocatalyst was Z-TiO2-Ag. The concentration of DCF in the working solutions was 10 mg/L,50 mg/L,100 mg/L and 200 mg/L and of photocatalyst 1 g/L in any experiments. The process was monitored by recording the UV spectra of the treated solutions and total organic carbon (TOC) determination. The UV spectra analysis and TOC removal proved that along the advanced degradation of DCF also a mineralization process occurred. The carried out research provided useful information envisaging the treatment of pharmaceutical effluents by photocatalysis.

Background: Potassium permanganate is a green and versatile industrial oxidizing agent. Due to its high oxidizing ability, it has received considerable attention and has been extensively used for many years for the synthesis, identification, and determination of inorganic and organic compounds. Objective: Potassium permanganate is one of the most applicable oxidants, which has been applied in a number of processes in several industries. Furthermore, it has been widely used in analytical pharmacy to develop analytical methods for pharmaceutically active compounds using chemiluminescence and spectrophotometric techniques. Results: This review covers the importance of potassium permanganate over other common oxidants used in pharmaceuticals and reported its extensive use and analytical applications using direct, indirect and kinetic spectrophotometric methods in different pharmaceutical formulations and biological samples. Chemiluminescent applications of potassium permanganate in the analyses of pharmaceuticals using flow and sequential injection techniques are also discussed. Conclusion: This review summarizes the extensive use of potassium permanganate as a chromogenic and chemiluminescent reagent in the analyses of pharmaceutically active compounds to develop spectrophotometric and chemiluminescence methods since 2000.

Ozonation and ozone-based advanced oxidation processes have been shown to be effective in the oxidation of several pharmaceutically active compounds (PhACs) routinely detected in surface waters. Under typical operating conditions of these processes, most of the parent compound oxidized is expected to lead to the formation of transformation products (TPs). For a target ozone exposure, the resulting hydroxyl radical exposure depends on the water matrix or process chosen (e.g. peroxone) which in turn may influence the degradation pathway and the TPs formed. This study was undertaken to examine the expected impact that varying ozone and hydroxyl radical exposures may have on TP formation from the oxidation of PhACs during typical drinking water ozonation. Two representative PhACs were selected for the study. Carbamazepine was chosen to represent PhACs with a fast reaction rate with ozone (kO3 > 104 M−1 s−1) and bezafibrate was chosen to represent PhACs with a slow to moderate reaction rate with ozone (kO3 < 104 M−1 s−1). The results show that under varying ozone and hydroxyl exposure scenarios examined, the major oxidation pathway for the parent compound was dominated by reaction with ozone for carbamazepine while for bezafibrate it varied.

Pharmazeutisch aktive Stoffe (PhACs) sind in allen anthropogen beeinflussten Oberflächengewässern ubiquitär (> 1 µg/l) nachzuweisen. Mehr als 80 verschiedene PhACs und ihre Metaboliten konnten in Oberflächengewässern vor. Es wurden weltweit verschiedene Substanzen in Flüssen detektiert, welche sich in verschiedene Wirkklassen unterscheiden lassen: Schmerzmittel, Lipidsenker, Antiepileptika, Beta-Blocker (ß-Blocker), Beta-Agonisten, Hormontherapeutika und Antibiotika. Über den Verbleib der PhACs, ihre Akkumulation und ihre biologische Wirksamkeit in Makrophyten, ist bisher wenig bekannt. Ein Ziel dieser Arbeit besteht darin, dem freischwimmenden Makrophyten Ceratophyllum demersum (C. demersum), erstmalig die biologische Wirksamkeit von PhACs darzustellen. In der hier vorgestellten Arbeit wurden folgende Ergebnisse zur Klärung der Fragestellung herausgearbeitet: - Ob und wieviel von den jeweiligen PhACs akkumuliert und von den Makrophyten umgewandelt werden können? IBU und LNG weisen eine Aufnahme in dem Nicht-Ziel-Organismus C. demersum auf. Bei CBZ und MET hingegen kommt es zur Bioakkumulation in der Makrophyte. Die Formation von hydroxy-IBU (OH-IBU) und O-desmethyl MET (O-des MET) können in den freischwimmenden Makrophyte nachgewiesen werden. - Welche Auswirkungen PhACs auf Chlorophyll als Stressmarker haben? Die Chlorophyll Pigmente sind nicht stark beeinflusst worden. CBZ, IBU, LNG und MET wiesen eine Tendenz zur Inhibition auf, wobei die größte Sensitivität bei MET auftrat: - Ob die Enzyme der Zelldetoxifikation auf die Anwesenheit von PhACs reagieren? Die aktuelle Studie demonstriert Vorkommen von physikalischen Veränderungen während der oxidativen Antwort bei den freischwimmenden Makrophyten durch CBZ-, IBU-, LNG- und MET-Expositionen. Das Enzym mGST wurde nicht beeinträchtigt bei der niedrigeren Konzentration der getesteten PhACs.
Pharmaceutically active compounds (PhACs) are detected, in all anthropogenic impacted surface waters (> 1µg/l). More than 80 different PhACs and their metabolites are detected in aquatic ecosystems. PhACs from human medicine or veterinary reach the environment primarily through sewage treatment plants (STP). The relevant substances are analgesic, lipid lowering agents, anti-epileptic drugs, beta-blockers, hormone therapeutics and antibiotics. Therefore, the PhACs which were chosen to be analysed were Carbamazepine (CBZ), Ibuprofen (IBU), Levonorgestrel (LNG) and Metoprolol (MET). In comparison to the amount of available analytical data, little is known about their accumulation and the biologically potency in the aquatic environment. The aim of the study was to assess whether PhACs might cause effects on the aquatic non-target organism, the free-floating macrophyt Ceratophyllum demersum. The following hypotheses were used for clarification: - If and how much of the chosen PhACs are accumulated and metabolized? IBU and LNG were shown to be taken up by C. demersum. CBZ and MET demonstrated incidences of bioaccumulation in C. demersum. The formation of first step metabolites (OH-IBU and O-desmethyl MET) were shown in the submerged macrophyte species C. demersum. - Which effects have PhACs on chlorophylle pigments? In C. demersum, chlorophyll pigments were not significantly affected. The results indicated that PhACs (CBZ, IBU, LNG, and MET) can influence chlorophyll pigments, whereby C. demersum showed a higher sensitivity to MET - If cell detoxification enzymes of C. demersum reacts in response to PhACs? The study demonstrated the occurrence of physiological changes in the oxidative stress response of C. demersum due to CBZ, IBU, LNG, and MET exposure. The enzyme mGST was not strongly affected during the exposure with the low concentrations of the PhACs used.

The increasing concern over potential health effects of pharmaceutically active compounds (PhACs) and endocrine disrupting compounds (EDCs) in drinking water has led to an increase in assessment of drinking water treatment plant efficiencies at removing these emerging micropollutants. For the most part, tight commercial membrane processes such as nanofiltration (NF) and reverse osmosis (RO) successfully eliminate PhACs and EDCs, however these are costly processes and infrequently implemented in North American treatment facilities. The more frequently used microfiltration (MF) and loose ultrafiltration (UF) membranes are ineffective in the removal of these compounds. This thesis focuses on developing tight charged ultrafiltration (UF) membranes which could effectively remove PhACs and EDCs from drinking water without compromising flux and cost. The approach centers on developing the membrane surface charge by incorporating charged surface modifying macromolecules (CSMMs) as additives. Four CSMMs (MDI-PPG-HBS, MDI-PEG200-HBS, MDI-PEG400-HBS, MDI-DEG-NDS) were evaluated at three different casting conditions for poly(ether sulfone) (PES) based membranes. The modified membranes were compared to controls (without CSMMs) and one commercial membrane (NF270, Dow/Filmtec). Membrane properties including flux, molecular weight cut off, surface porosity, charge and hydrophilicity were evaluated and compared to the removal of four representative PhACs and EDCs (sulfamethazine, carbamazepine, bisphenol A and ibuprofen) at the mg/L-level. The experimental membranes only achieved a temporary partial removal of the PhACs and EDC tested, thus further development is required. Given the temporary target compound removal and the large membrane pores, size exclusion and charge repulsion are not the dominant removal mechanism. From the removal pattern, and the fact that removal increased with increasing solute hydrophobicity, it is assumed that initial removal is caused by adsorption to the membrane. The membranes developed were tight by conventional ultrafiltration standards but did not achieve the performance desired. In general, it was found that the CSMM-modified membranes did not significantly outperform the control membranes. CSMM-modified membranes tested generally produced less hydrophilic membranes with increasing pre-gelation time or PES concentration, in comparison to the control membranes. Pre-gelation time (i.e., three minutes versus no pre-gelation time) increases membrane porosity, and therefore flux is increased, without compromising removal. Increased PES concentration (i.e., 20% PES in comparison to 18% PES) yields more distinct effects from the different CSMMs. From these results, the most promising casting condition appears to be 20% PES and the CSMMs achieving the best removal are MDI-PEG 400-HBS and MDI-PPG-HBS. As increased surface porosity was achieved, continuing this line of research by optimizing membrane preparation conditions to decrease the pore size may produce the desired characteristics. It is recommended that further tests be performed at increased PES concentrations and with pre-gelation time to achieve better results.

Els fàrmacs constitueixen un grup gran, important i divers, de compostos químics dissenyats per a causar efectes terapèutics sobre la salut principalment humana, però també animal. Per la seva composició, són bioactius i difícils de degradar encara que presentin una dosi mínima. La seva varietat estructural, de composició i efectes és enorme i mentre que alguns d'ells són eliminats completament a les depuradores, d'altres romanen inalterats o parcialment transformats. A més a més, malgrat ser estrictament regulats per assajos clínics abans de la seva distribució al mercat, no existeixen restriccions específiques per al seu alliberament en el medi ambient, i encara manca un mètode de quantificació estàndard per a detectar-los. Cal implementar tecnologies alternatives en les depuradores per a eliminar aquests principis actius de l'aigua abans de ser abocats al medi ambient. Un possible tractament és l'ús de fongs ligninolítics per a degradar aquests compostos. En relació amb aquest tractament, el fong T. versicolor, membre del grup de fongs de podridura blanca, ha estat àmpliament estudiat en l'eliminació de molts fàrmacs en aigües residuals i condicions no estèrils. Tanmateix, encara hi ha diverses qüestions a resoldre d’entre les quals en destaquen: els compostos recalcitrants, la generació de productes de transformació i colls d'ampolla operacionals. Es consideren recalcitrants aquells fàrmacs que romanen inalterats a causa de la seva estructura estable durant els tractaments d’eliminació. En el cas dels tractaments amb fongs, aquesta estabilitat depèn principalment de factors com el mecanisme de degradació, directament afectat pel metabolisme de les espècies de fong emprades. Per tal de descobrir candidats potencials per a l'eliminació i biodegradació de compostos recalcitrants es va realitzar un experiment de cribatge entre 6 espècies diferents de fongs. Espècies poc estudiades, com ara S. rugosoannulata i G. luteofolius, van permetre obtenir importants eliminacions vinculades amb processos de biodegradació. També es va estudiar l'eliminació de fàrmacs tenint en compte els diferents mecanismes de biodegradació i sorció en cultius submergits. Pel que fa a la sorció, les anàlisis dels fàrmacs presents en la fase líquida i en la biomassa del fong mostren resultats semblants respecte de la sorció estimada a partir de controls amb biomassa de fong inactivats per calor. S'ha demostrat que 6 dies no és temps suficient per al fong per a poder degradar els contaminants adsorbits. Pel que fa a la generació de productes de transformació a partir dels compostos principals, es van identificar o-desmethylvenlafaxine i n-desmethylvenlafaxine com els dos principals productes de transformació biològica generats durant la degradació del compost recalcitrant venlafaxina. D'altra banda, els productes de transformació generats pel fong P. ostreatus en la degradació de diclofenac i ketoprofè coincideixen amb les molècules generades per T. versicolor en el mateix tipus de tractament, segons els seus perfils de ressonància magnètica nuclear. A més a més, estudis sobre dos dels principals mecanismes enzimàtics dels fongs, van demostrar que l'enzim extracel·lular lacasa està implicat en la degradació de compostos recalcitrants com l'atenolol, mentre que el complex enzimàtic intracel·lular citocrom P450 intervé en l’eliminació de diclofenac. Els colls d'ampolla operacionals com la competència de la microbiota nativa pels nutrients en els bioreactors fúngics provoquen diversos problemes en l’aplicació del tractament en continu. Per a prevenir la proliferació de bacteris, es va avaluar la implementació d'un biofiltre de sorra per a la reducció de la càrrega bacteriana en aigües residuals d'hospital. Malgrat aconseguir certa reducció bacteriana, aquest pretractament no va permetre reduir prou la càrrega bacteriana d’entrada del reactor amb el fong. En canvi, la microbiota nativa present en el biofiltre de sorra va ser capaç d’eliminar concentracions de l’antibiòtic ciprofloxacina i l'analgèsic ibuprofè. Això va motivar l’anàlisi molecular mitjançant electroforesi en gel de gradient desnaturalitzant (DGGE) per tal d’analitzar els canvis que es produïen en la microbiota com a conseqüència de l’exposició continuada a fàrmacs i quines poblacions microbianes eren candidats potencials responsables de l’eliminació dels fàrmacs en qüestió. Un altre dels problemes operatius a tractar en reactors amb T. versicolor va ser la necessitat de proveir de carboni el reactor per una banda, i del control del pH per l’altra. En aquesta tesi, P. ostreatus i S. rugosoannulata han demostrat poder-se autoproveir de carboni a partir d'aigües residuals amb alts valors de demanda química d'oxigen (DQO), evitant així la necessitat del seu subministrament. A més a més, S. rugosoannulata també va poder reduir el pH de les aigües residuals hospitalàries al seu nivell òptim i, per tant, va mostrar trets prometedors de cara a la seva futura plena implementació en reactors.
Los fármacos son un grupo grande, importante y diverso, de compuestos químicos diseñados para causar efectos terapéuticos sobre la salud principalmente humana, pero también animal. Por su composición, son bioactivos y difíciles de degradar aunque presenten una dosis mínima. Su variedad estructural, de composición y efectos es enorme y mientras que algunos de ellos son eliminados completamente en las depuradoras, otros permanecen inalterados o parcialmente transformados. Además, a pesar de ser estrictamente regulados por ensayos clínicos antes de su distribución en el mercado, no existen restricciones específicas para su liberación en el medio ambiente, y aún falta un método de cuantificación estándar para detectarlos. Hay que implementar tecnologías alternativas en las depuradoras para eliminar estos principios activos del agua antes de ser vertidos al medio ambiente. Un posible tratamiento es el uso de hongos ligninolíticos. En relación con este tratamiento, el hongo T. versicolor, perteneciente al grupo de hongos de podredura blanca, ha sido ampliamente estudiado en la eliminación de muchos principios activos farmacéuticos en aguas residuales y condiciones no estériles. Sin embargo, aún hay varias cuestiones a resolver entre las cuales destacan: los compuestos recalcitrantes, la generación de productos de transformación y cuellos de botella operacionales. Se consideran recalcitrantes aquellos fármacos que permanecen inalterados debido a su estructura estable durante los tratamientos de eliminación. En el caso de los tratamientos con hongos, esta estabilidad depende principalmente de factores como el mecanismo de degradación, directamente relacionado con el metabolismo de las especies de hongo empleadas. En ese sentido se realizó un experimento de cribado entre 6 especies diferentes de hongos para descubrir candidatos potenciales para tratar compuestos recalcitrantes. Especies hasta ahora poco estudiadas, como S. rugosoannulata y G. luteofolius, proporcionaron importantes eliminaciones, vinculadas a procesos de biodegradación. También se estudió la eliminación de fármacos teniendo en cuenta los diferentes mecanismos de biodegradación y sorción en cultivos sumergidos. En cuanto a la sorción, los análisis de los fármacos presentes en la fase líquida y en la biomasa del hongo muestran resultados similares respecto a la sorción estimada a partir de controles con biomasa de hongo inactivada por el calor. Se ha demostrado que 6 días no es tiempo suficiente para que el hongo pueda degradar los contaminantes adsorbidos. En cuanto a la generación de productos de transformación a partir de compuestos principales, se identificaron o-desmethylvenlafaxine y n-desmethylvenlafaxine como los dos principales productos de transformación biológica generados durante la degradación del compuesto recalcitrante venlafaxina. Por otra parte, los productos de transformación generados por el hongo P. ostreatus en la degradación de diclofenaco y ketoprofeno coinciden con las moléculas generadas por T. versicolor en el mismo tratamiento, según sus perfiles de resonancia magnética nuclear. Además, estudios sobre dos de los principales mecanismos enzimáticos de los hongos, demostraron que enzima extracelular lacasa está implicada en la degradación de compuestos recalcitrantes como el atenolol, mientras que el complejo enzimático intracelular citocromo P450 interviene en la eliminación de diclofenaco. Los cuellos de botella operacionales como la contaminación microbiana y la competencia por los nutrientes en los biorreactores fúngicos provocan varios problemas en el mantenimiento de los mismos. Para prevenir la proliferación de bacterias se evaluó la implementación de un biofiltro de arena para la reducción de la carga bacteriana en aguas residuales de hospital. A pesar de conseguir cierta reducción bacteriana, este pretratamiento no permitió reducir suficientemente la carga bacteriana de entrada del reactor con el hongo. En cambio, la microbiota nativa presente en el biofiltro de arena fue capaz de eliminar concentraciones del antibiótico ciprofloxacina y el analgésico ibuprofeno. Esto motivó el análisis molecular mediante electroforesis en gel de gradiente desnaturalizante (DGGE) para analizar los cambios que se producían en la microbiota como consecuencia de la exposición continuada a fármacos y que poblaciones microbianas eran candidatos potenciales responsables de la elimincación de dichos fármacos. Otro de los problemas operativos a tratar en reactores con T. versicolor es la necesidad de proveer el reactor de carbono por un lado, y del control del pH por el otro. En esta tesis, P. ostreatus y S. rugosoannulata han demostrado poderse autoproveer de carbono a partir de aguas residuales con altos valores de demanda química de oxígeno (DQO), evitando así la necesidad de su suministro. Además, S. rugosoannulata también pudo reducir el pH de las aguas residuales hospitalarias a su nivel óptimo y, por tanto, mostró rasgos prometedores para su futura implementación completa en reactores.
Pharmaceutical active compounds are an important, large and diverse group of chemical compounds designed to cause therapeutic effects on health, mainly human but also animal. Because of their composition, they are bioactive and difficult to be degraded even when present at a minimal dose. Their variety of structure, composition and effects is huge, while some of them are completely removed at wastewater treatment plants, others are only partially or non-removed. Furthermore, despite of being strictly regulated by clinical trials before their market distribution, specific restrictions for their release in the environment are almost non-existent, and there is not a standard quantification method yet. Regarding this situation, there is a need to implement alternative technologies in wastewater treatment plants to remove pharmaceuticals from water before entering the environment. One possible treatment is the use of ligninolytic fungi to degrade these compounds. In relation with this approach, the white-rot fungus T. versicolor has been widely studied in the removal of many pharmaceutical active compounds in wastewater under non-sterile conditions. However, there are still several questions to tackle: recalcitrant compounds unable to be degraded, the generation of transformation products, and operational bottlenecks can be highlighted among many other. Certain pharmaceuticals are considered recalcitrant due to its stable structure when treated for their removal. In fungal treatment, this stability depends mainly on factors such as the degradation mechanism, which is directly affected by the metabolism of the fungal species. A screening experiment among 6 different species of fungi attempted to discover new candidates in the removal and biodegradation of recalcitrant compounds. Scarcely studied species such as S. rugosoannulata and G. luteofolius obtained considerable removals linked to biodegradation processes. The removal of pharmaceutical active compounds has also been studied in terms of biodegradation and sorption mechanisms in submerged cultures. Regarding sorption processes, the analyses of the pharmaceutical active compounds present in liquid phase and in fungal biomass showed similar results respect to the sorption estimated by heat killed control biomass. It has been proven that 6 days is generally insufficient time for fungal biomass to degrade the adsorbed contaminants. Concerning the generation of transformation products from parental compounds, odesmethylvenlafaxine and n-desmethylvenlafaxine were identified as the two main biological transformation products generated during the degradation of the recalcitrant compound venlafaxine. On the other hand, transformation products generated by the fungus P. ostreatus in the degradation of diclofenac and ketoprofen coincide with the molecules generated by T. versicolor in the same treatment according to their nuclear magnetic resonance profiles. Besides, studies on two main fungal enzymatic mechanisms showed that the extracellular enzyme laccase is involved in the degradation of recalcitrant compounds such as atenolol, whereas the intracellular enzymatic complex cytochrome P450 is involved in diclofenac transformation. Operational bottlenecks, such as microbial competition by native microbiota for nutrients in fungal bioreactors, cause several problems in applying continuous treatment. In order to prevent bacteria proliferation, the implementation of a biosand filter for the reduction of a high bacterial load in hospital wastewater was evaluated. This pretreatment was not able to achieve enough reduction in bacterial load of the fungal reactor’s inlet. Instead, the native microbiota present in the biosand filter was able to remove spiked concentrations of the antibiotic ciprofloxacin and the analgesic ibuprofen. This opened the way for a molecular biology study with denaturing gradient gel electrophoresis (DGGE) to analyse which changes in the microbiota could entail the presence of potential candidates for pharmaceutical removal and which could be those microorganisms. Other operational issues to be tackled in T. versicolor reactors were the need for carbon supply and the pH control. In this thesis, P. ostreatus and S. rugosoannulata have proven able to self-obtain its carbon source from wastewaters achieving high chemical oxygen demand (COD) reductions, avoiding the need for carbon supply. Besides, S. rugosoannulata was also able to lower the pH of hospital wastewaters to its optimal, and hence showing promising features to its full implementation in reactors.

Pharmaceutically active compounds (PhACs) and endocrine disrupting compounds (EDCs) can pose a significant risk to the environment and human health, undermining prosperity. Current wastewater treatment plants (WWTPs) cannot efficiently act as barriers to their release and have been identified as main points of discharge and contamination. The present thesis aimed to investigate the fate of five PhACs (ibuprofen, sulfamethoxazole, metoprolol, carbamazepine and venlafaxine) and five EDCs (estrone, 17β-estradiol, estriol, 17α-ethinylestradiol and bisphenol A) in different systems simulating wastewater treatment scenarios and to identify factors triggering their elimination. A comparative assessment was carried out to determine the contribution of the microbial groups (either autotrophic or heterotrophic) present in different lab, pilot and full-scale treatment systems performing different processes in the removal of the selected compounds. The results indicated that the overall efficiency of wastewater treatment systems can be broadened by combining different aerobic and anaerobic conditions and different types of biomass
Els compostos farmacèuticament actius (PhACs) i els pertorbadors endocrins(EDC) poden suposar un risc considerable per al medi ambient i la salut humana. Les estacions depuradores d'aigües residuals (EDAR) no poden actuar de manera eficient com a barreres per al seu alliberament i s'han identificat com a punts principals de descàrrega. La present tesi pretén determinar el destí de cinc PhACs (ibuprofèn, sulfametoxazol, metoprolol, carbamazepina i venlafaxina) i cinc EDCs (estrona, 17β-estradiol, estriol, 17α-etinilestradiol i bisfenol A), en sistemes que simulen escenaris de tractament d'aigües residuals, per identificar els factors claus en la seva eliminació. Es va realitzar una avaluació comparativa per determinar la contribució dels diferents grups bacterians (autòtrofs o heteròtrofs) presents en diferents sistemes a escala de laboratori, pilot i a gran escala. Els resultats indiquen que l'eficiència global dels sistemes de tractament d'aigües residuals es pot ampliar combinant diferents condicions aeròbiques i anaeròbies i tipus de biomassa

Ces travaux de thèse s’insèrent dans le contexte de la contamination du milieu marin par les contaminants émergents, tels que les produits pharmaceutiques (PP), et de leurs effets sur les organismes marins. L’étude des liens de cause à effet entre l’exposition à un ou plusieurs contaminants et la réponse de la moule méditerranéenne, Mytilus galloprovincialis, a été l’axe central des recherches présentées dans cette thèse. Afin de renseigner les mécanismes d’action et les potentiels effets toxiques des PP, données manquantes dans la littérature, les approches –omiques telles que la métabolomique et la protéomique ont été favorisées. Les effets de l’antiépileptique carbamazépine (CBZ), un PP fréquemment détecté dans le milieu marin, ont dans un premier temps été investigués sur M. galloprovincialis à travers une approche intégrée de la métabolomique et de la protéogénomique. La stratégie de fusion des données appliquée a mis en évidence des signatures protéiques et métaboliques corrélées entre elles en réponse à l’exposition. L’utilisation d’outils bioinformatiques remettant les protéines et métabolites dans leur contexte biologique a ainsi révélé des changements concernant la synthèse des protéines, la dégradation des acides gras, la métabolisation des acides aminés et des glucides, et la programmation de la mort cellulaire. Bien que l’étude des effets d’un seul contaminant soit essentielle pour obtenir des informations d’ordre mécanistique, elle s’éloigne en revanche de la pertinence d’une exposition environnementale, les organismes étant exposés simultanément à une multitude de contaminants. Dans le but d’intégrer cette complexité, les moules M. galloprovincialis ont été exposées à un rejet de station d’épuration (STEP), voie d’entrée principale des PP dans le milieu marin. L’analyse des empreintes métaboliques générées a d’abord été effectuée sur les moules mâles afin d’écarter la variabilité biologique liée au sexe (susceptible de masquer la réponse à l’exposition). Plusieurs voies métaboliques ont ainsi été révélées comme impactées (ex. acides aminés, bases puriques et pyrimidiques, cycle de Krebs, neurohormones, etc.) pouvant perturber plusieurs fonctions et processus biologiques (ex. métabolisme énergétique, système immunitaire, osmorégulation, reproduction, formation du byssus, etc.) et avoir des conséquences néfastes sur l’organisme. En se basant sur la littérature, des hypothèses de relation de cause à effet ont pu être établies entre certains contaminants détectés dans le rejet de STEP (38 PP et 4 pesticides) et les effets observés. A partir de cette même expérimentation, le facteur sexe a ensuite été intégré dans le traitement des données issues des individus mâles/femelles et exposés/non-exposés afin de comprendre le rôle du sexe dans la réponse à l’exposition. Pour cela, l’approche statistique Analyse of variance Multiblock Orthogonal Partial Least Square s’est révélée pertinente pour ce genre de design expérimental multifactoriel. Cette approche a ainsi pu associer la variabilité des données métabolomiques à leur(s) facteur(s) d’origine(s). Une réponse commune entre les deux sexes, reliée au facteur exposition, a été mise en évidence à travers la modulation de plusieurs lysophospholipides induite par un stress oxydant. Tandis qu’une réponse sexe-dépendante, reliée à l’interaction entre les facteurs sexe et exposition, a été décrite suite à une modulation de certains lipides polaires selon le sexe et une perturbation de la voie de la kynurénine uniquement chez les mâles. Ces travaux de thèse ont pu renforcer les connaissances sur les effets d’un PP préoccupant pour l’environnement, la CBZ, exclue de tout cadre réglementaire, ainsi que sur les effets d’une exposition proche des conditions environnementales reconstituées à travers un rejet de STEP. Des approches originales d’investigation des effets et d’analyses des données ont été pertinemment appliquées
This PhD thesis takes place in a context of the contamination of marine environment by emerging contaminants, such as pharmaceutical active compounds (PhAC), and their effects on marine organisms. The study of causal relationships between exposure to one or more contaminants and the response of the Mediterranean mussel, Mytilus galloprovincialis, was the central focus of the research presented in this thesis. In order to provide information on the mechanisms of action and potential toxic effects of PhAC, data lacking in the literature, -omic approaches such as metabolomics and proteomics were applied. The effects of the antiepileptic carbamazepine (CBZ), a PhAC frequently detected in the marine environment, were first investigated on M. galloprovincialis through an integrated approach of metabolomics and proteogenomics. The data fusion strategy applied revealed correlated protein and metabolic signatures in response to exposure. The use of bioinformatics tools that put proteins and metabolites into their biological context thus highlighted changes in protein synthesis, fatty acid degradation, amino acid and carbohydrate metabolism, and cell death programming. Although the study of the effects of a single contaminant is essential to obtain mechanistic information, it is far removed from the relevance of environmental exposure, since organisms are exposed simultaneously to a multitude of contaminants. In order to integrate this complexity, mussels M. galloprovincialis were exposed to a wastewater treatment plant (WWTP) effluent, the main pathway of PhAC into the marine environment. Analysis of the metabolic fingerprints generated was first performed on male mussels to rule out gender-related biological variability (which could hide the response to exposure). Several metabolic pathways were thus revealed to be impacted (e.g. amino acids, purines and pyrimidines, Krebs cycle, neurohormones, etc.) which can disrupt several biological functions and processes (e.g. energy metabolism, immune system, osmorregulation, reproduction, byssal formation, etc.) and have adverse consequences on the organism. Based on the literature, hypotheses of causal relationships have been established between certain contaminants detected in the WWTP effluent (38 PPs and 4 pesticides) and the effects observed. Based on the same experiment, the gender factor was then integrated into the processing of data acquired from male/female and exposed/unexposed individuals in order to understand the role of gender in the response to exposure. To this end, the statistical approach of Analysis of Variance Multiblock Orthogonal Partial Least Square proved to be relevant for this kind of multifactorial experimental design. This approach was thus able to characterize and relate the variability of metabolomics data to its different factors of origin. A common response between the two genders, related to the exposure factor, was demonstrated through the modulation of several lysophospholipids induced by oxidative stress. While a gender-specific response, related to the interaction between gender and exposure factors, has been described following a modulation of certain polar lipids according to gender and a disruption of the kynurenin pathway only in males. This thesis work was able to strengthen knowledge on the effects of a PhAC of concern for the environment, CBZ, excluded from any regulatory framework, as well as on the effects of an exposure close to the environmental conditions reconstituted through a WWTP effluent. Original approaches to effects investigation and data analysis have been pertinently applied

The presence of several pharmaceutical active compounds (PhACs) in water bodies has garnered increasing attention and worldwide concern. The effluents from wastewater treatment plants (WWTPs) are one of the main sources of PhACs in aquatic environments. Advanced tertiary treatments are required to improve the quality of WWTP effluents discharged into sensitive receiving water bodies. This thesis has focused on biological activated carbon coupled with ultrafiltration (BAC-UF) and UV-C activated peroxydisulfate and peroxymonosulfate (UV/PDS and UV/PMS). The BAC-UF technology has been evaluated at pilot-scale during one year of operation, assessing the removal of 15 PhACs at environmentally relevant concentration. With respect to UV/PDS and UV/PMS technologies, they were preliminarily assessed with a set of lab-scale experiments and then, validated at pilot-scale simulating real operating conditions. Finally the comprehensive evaluation of these advanced treatment technologies identified some of the practical factors limiting the potential application of BAC-UF, UV/PDS and UV/PMS technologies.
La presencia de varios compuestos activos farmacéuticos (PhACs) en las masas de agua ha ganado una atención creciente y preocupación mundial. Los efluentes de las depuradores son una de las principales fuentes de PhAC en entornos acuáticos. Se requieren tratamientos terciarios avanzados para mejorar la calidad de los efluentes de las depuradoras que abocan en masas de agua receptoras sensibles. Esta tesis se focaliza en la tecnologias de carbón activo biológico combinado con la ultrafiltración (BAC-UF) y el peroxidisulfato y el peroximonosulfato activados por UV-C (UV/PDS y UV/PMS). La tecnología BAC-UF se ha evaluado a escala piloto durante un año de operacion, evaluando la eliminación de 15 PhACs. Con respecto a UV/PDS y UV/PMS, se evaluaron preliminarmente a escala de laboratorio y luego se validaron a escala piloto, simulando condiciones reales de operación. Finalmente, la evaluación integral de estas tecnologías de tratamiento avanzadas identificó algunos de los factores prácticos que limitan la aplicación potencial de las tecnologías BAC-UF, UV/PDS y UV/PMS.

Doutoramento em Restauro e Gestão Fluviais - Instituto Superior de Agronomia. Universidade de Lisboa
Emergent pollutants such as pharmaceutical active compounds (PhACs) have gained attention in the recent years since they can pose a threat to both river ecosystems and human health. The wide variety of pollutants in the market nowadays has overburdened the current wastewater treatment plants (WWTPs). Moreover, due to the increasingly growing society ecological awareness, environment friendly technologies have been more recently explored for wastewater treatment. Constructed wetlands (CWs) systems are an attractive example since they mimic natural processes such as pollutants filtration, phytoremediation and biodegradation but in a controlled form. The present thesis explore the potential of using locally available industry by products and native riparian wetland plants for enhancing the performance and implementation of CWs, for the removal of the highly consumed diuretic drug Furosemide. The state of art on the thesis subject was elaborated taking into account the situation in Portugal and in Brazil. Afterwards the validation of an analytical Furosemide quantification method through high performance liquid chromatography (HPLC-UV) in aqueous solution was performed taking in consideration the thesis projected experiments design. Light expanded clay aggregates and cork granulates were tested in terms of Furosemide adsorption capacity, showing both good removal values although with different adsorption ratio behaviours. A plant uptake experiment was performed with Iris pseudacorus to develop an analytical quantification method through HPLC-MS/MS for Furosemide in plant tissues. The PhAC was detected in the plants at residual concentrations hence limiting plant uptake capacity conclusions. Additionally, an experiment with both Iris pseudacorus and Typha domingensis was performed to study their uptake capacity, having both promoted similar removals of the PhAC. In overall, the tested components showed potential for CWs application and enhancement
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NRs are enzymes that catalyze the reduction of nitroaromatics to their corresponding nitroso, hydroxylamine, and, in limited cases, amine They have gathered interest in many scientific communities, and are currently actively researched bioremediation and prodrug activation. Here we attempt to utilize them for the purpose of synthesizing substituted aromatic amines that are found in a number of active pharmaceutical ingredients (APIs). As NRs described in the literature have varying product distribution ranges (from those that produce hydroxylamine to others that yield amine) several similar and different NRs were studied for their selectivity. Additionally, a quantitative structure-activity relationship (QSAR) was determined to characterize the substrate specificity of NRs. To employ the use of flavoenzymes in synthesis, multiple reaction- and protein-engineering approaches were devised. One scheme was to establish an enzymo-chemical synthesis where NRs were paired with reducing agents for a chemical reduction. Another method was to create a monomeric NR through directed evolution from ER scaffolds for future immobilization applications. Protein engineering techniques were also utilized on NADH oxidases which we characterized and developed for nicotinamide cofactor regeneration. As a whole, this dissertation expands our current understanding on NRs and demonstrates the possibility of using several flavoenzymes in the synthesis of organic molecules.

Pharmaceuticals have been present in our world’s waters since humans began experimenting with medicines; however, product propagation and ready access to pharmaceuticals coupled with burgeoning human population have significantly increased the loading of these compounds into the environment. Pharmaceutically active compounds (PhACs) are considered to produce a biological activity on humans and animals. Drugs manufacturing processes lead to release of toxic organic compounds and their metabolites into the environment. Safety and toxicology studies have used to investigate the side effects of pharmaceuticals on human and animal health. Treatment processes can and do reduce the concentrations of pharmaceuticals in water, however, the degree of efficacy is often a function of chemical structure, cost, and energy. All treatment processes have some degree of side effects, such as generation of residuals or by-products. This paper provides a concise report on removal of PhACs by recent advances oxidation processes (AOPs) where hydroxyl radicals (HO . ) acts as a common oxidant and the improvement of biodegradability to a level amicable for subsequent biological treatment.

Marine fungi are species of fungi which live in estuaries environment and marine environment. These species are found in common habitat. Marine fungi are rich in antimicrobial compounds such as anthrones, cephalosporins, peptides, steroids. These compounds which are derived mainly focused in the area of anti-inflammatory, anti-oxidant, anti-fungal, anti-microbial, anti-fouling activity. Bioactive terpene compounds are produced by marine fungi and marine derived fungi can produce sclerotides, trichoderins. Marine fungi have become the richest sources of biologically active metabolites and structurally novel in the marine environment. In a recent study the marine derived fungi dichotomomyces cejpii exhibits activity towards cannabinoid which is used to treat alzheimer dementia. Aspergillus unguis showed significant acetyl cholinesterase besides its anti-oxidant activity. These acts as a promising intent for discovery of pharmaceutically important metabolites like alkaloids, peptides. Computational (in silico) strategies have been developed and broadly applied to pharmacology advancement and testing. This review summarizes the bioactive compounds derived from marine fungi in accordance with the sources and their biological activities.

Many pharmaceutical compounds are active at very low doses, and a portion of them regularly enters municipal sewage systems and wastewater-treatment plants following use, where they often do not fully degrade. Two such compounds, CBZ and LTG, have been detected in wastewater effluents, surface waters, drinking water, and irrigation water, where they pose a risk to the environment and the food supply. These compounds are expected to interact with organic matter in the environment, but little is known about the effect of such interactions on their environmental fate and transport. The original objectives of our research, as defined in the approved proposal, were to: Determine the rates, mechanisms and products of photodegradation of LTG, CBZ and selected metabolites in waters exposed to near UV light, and the influence of DOM type and binding processes on photodegradation. Determine the potential and pathways for biodegradation of LTG, CBZ and selected metabolites using a white rot fungus (Pleurotusostreatus) and ADP, and reveal the effect of DOM complexation on these processes. Reveal the major mechanisms of binding of LTG, CBZ and selected metabolites to DOM and soil in the presence of DOM, and evaluate the effect of this binding on their photodegradation and/or biodegradation. We determined that LTG undergoes relatively slow photodegradation when exposed to UV light, and that pH affects each of LTG’s ability to absorb UV light, the efficiency of the resulting reaction, and the identities of LTG’sphotoproducts (t½ = 230 to 500 h during summer at latitude 40 °N). We observed that LTG’sphotodegradation is enhanced in the presence of DOM, and hypothesized that LTG undergoes direct reactions with DOM components through nucleophilic substitution reactions. In combination, these data suggest that LTG’s fate and transport in surface waters are controlled by environmental conditions that vary with time and location, potentially affecting the environment and irrigation waters. We determined that P. ostreatusgrows faster in a rich liquid medium (glucose peptone) than on a natural lignocellulosic substrate (cotton stalks) under SSF conditions, but that the overall CBZ removal rate was similar in both media. Different and more varied transformation products formed in the solid state culture, and we hypothesized that CBZ degradation would proceed further when P. ostreatusand the ᵉⁿᶻʸᵐᵃᵗⁱᶜ ᵖʳᵒᶠⁱˡᵉ ʷᵉʳᵉ ᵗᵘⁿᵉᵈ ᵗᵒ ˡⁱᵍⁿⁱⁿ ᵈᵉᵍʳᵃᵈᵃᵗⁱᵒⁿ. ᵂᵉ ᵒᵇˢᵉʳᵛᵉᵈ ¹⁴C⁻Cᴼ2 ʳᵉˡᵉᵃˢᵉ ʷʰᵉⁿ ¹⁴C⁻ᶜᵃʳᵇᵒⁿʸˡ⁻ labeled CBZ was used as the substrate in the solid state culture (17.4% of the initial radioactivity after 63 days of incubation), but could not conclude that mineralization had occurred. In comparison, we determined that LTG does not degrade in agricultural soils irrigated with treated wastewater, but that P. ostreatusremoves up to 70% of LTG in a glucose peptone medium. We detected various metabolites, including N-oxides and glycosides, but are still working to determine the degradation pathway. In combination, these data suggest that P. ostreatuscould be an innovative and effective tool for CBZ and LTG remediation in the environment and in wastewater used for irrigation. In batch experiments, we determined that the sorption of LTG, CBZ and selected metabolites to agricultural soils was governed mainly by SOM levels. In lysimeter experiments, we also observed LTG and CBZ accumulation in top soil layers enriched with organic matter. However, we detected CBZ and one of its metabolites in rain-fed wheat previously irrigated with treated wastewater, suggesting that their sorption was reversible, and indicating the potential for plant uptake and leaching. Finally, we used macroscale analyses (including adsorption/desorption trials and resin-based separations) with molecular- level characterization by FT-ICR MS to demonstrate the adsorptive fractionation of DOM from composted biosolids by mineral soil. This suggests that changes in soil and organic matter types will influence the extent of LTG and CBZ sorption to agricultural soils, as well as the potential for plant uptake and leaching.