WITHDRAWN-a resource for withdrawn and discontinued drugs

Post-marketing drug withdrawals can be associated with various events, ranging from safety issues such as reported deaths or severe side-effects, to a multitude of non-safety problems including lack of efficacy, manufacturing, regulatory or business issues. During the last century, the majority of drugs voluntarily withdrawn from the market or prohibited by regulatory agencies was reported to be related to adverse drug reactions. Understanding the underlying mechanisms of toxicity is of utmost importance for current and future drug discovery. Here, we present WITHDRAWN, a resource for withdrawn and discontinued drugs publicly accessible at http://cheminfo.charite.de/withdrawn. Today, the database comprises 578 withdrawn or discontinued drugs, their structures, important physico-chemical properties, protein targets and relevant signaling pathways. A special focus of the database lies on the drugs withdrawn due to adverse reactions and toxic effects. For approximately one half of the drugs in the database, safety issues were identified as the main reason for withdrawal. Withdrawal reasons were extracted from the literature and manually classified into toxicity types representing adverse effects on different organs. A special feature of the database is the presence of multiple search options which will allow systematic analyses of withdrawn drugs and their mechanisms of toxicity

Intruzje wód morskich do jeziora Gardno

Lake Gardno, as the central object in the hydrographic structure, is under the influence of land and sea waters. This results in the situation where the lake together with its direct catchment forms a unique geoecosystem which differs from other inland reservoirs performing the role of local or regional recipients in hydrographic systems, in terms of the quality of water as well as the rate and dynamics of transformations occurring in it. This is an effect of overlapping influences of waters inflowing from the catchment and intrusions of sea waters. During intrusions, waters of higher salinity occur and remain during the greater part of the year in the whole water body of the lake, which is conditioned by the shape of the basin facilitating the penetration of salty waters. It was established that the water coming from intrusions remains for at least several days. There is also evidence from reconnaissance measurements that the retention is longer. The easiness of penetration and long retention period result in the fact that only periodically the desaltation effect of potamic waters leads to an almost complete desaltation of water in the whole basin of the lake Gardno.W pracy podjęto próbę ustalenia czy w jeziorze Gardno dochodzi do intruzji wód morskich i czy skutki, które mogą one wywoływać są typowe dla jezior przybrzeżnych występujących na polskim wybrzeżu Południowego Bałtyku, czy też pod tym względem jest to jezioro wyjątkowe. Zastosowano metodę wykonywania na jeziorze powtarzalnych zdjęć hydrochemicznych z jednoczesnym określeniem aktualnej sytuacji hydrologicznej. W latach 2002- -2006 wykonano 16 serii pomiarów w 7 punktach zlokalizowanych na jeziorze Gardno. Próbki wody pobierano w warstwie powierzchniowej, naddennej oraz interstycjalnej. Wodę z tej ostatniej warstwy uzyskiwano z powierzchniowego osadu dennego pobranego pobierakiem Kajaka poprzez użycie wirówki Centrifuge. Próbki wody analizowano w laboratorium Katedry Hydrologii Uniwersytetu Gdańskiego. Stężenie chlorków określano metodą miareczkową. Poziom wody w jeziorze odczytywano na wodowskazie IMGW zlokalizowanym w Gardnie Wielkiej, natomiast poziom morza na wodowskazie Urzędu Morskiego w Porcie Rowy bądź w Ustce. Jezioro Gardno jako centralny obiekt w strukturze hydrograficznej jest pod wpływem wód lądowych i morskich. Powoduje to, że jezioro tworzy wraz ze swoja zlewnią bezpośrednią bardzo specyficzny geoekosystem, który wyróżnia od innych zbiorników śródlądowych pełniących w systemach hydrograficznych rolę odbiorników lokalnych czy regionalnych nie tylko jakość wód, ale przede wszystkim tempo i dynamika zachodzących w nim przemian. Jest to efekt nakładających się wpływów z jednej strony wód spływających ze zlewni, a z drugiej intruzji wód morskich. Podczas intruzji pojawiają się wody o podwyższonym zasoleniu. Utrzymuje się ono przez większą część roku w całym akwatorium jeziora, czemu sprzyja kształt misy ułatwiający penetrację wód słonych. Stwierdzono, że woda pochodząca z intruzji zalega co najmniej kilka dni. Są także przesłanki wynikające z przeprowadzonych pomiarów rekonesansowych wskazujące na to, że czas zalegania jest dłuższy. Łatwość penetracji i długi okres zalegania powodują, że tylko okresowo działanie wysładzające wód potamicznych doprowadza do prawie całkowitego wysłodzenia wody w całej niecce jeziora Gardno. Najczęściej to oddziaływanie wyraźnie widoczne jest tylko w południowej części zbiornika

Novel DNA topoisomerase iia inhibitors from combined ligand- and structure- based virtual screening

DNA topoisomerases are enzymes responsible for the relaxation of DNA torsional strain, as well as for the untangling of DNA duplexes after replication, and are important cancer drug targets. One class of topoisomerase inhibitors, ''poisons'', binds to the transient enzyme-DNA complex which occurs during the mechanism of action, and inhibits the religation of DNA. This ultimately leads to the accumulation of DNA double strand breaks and cell death. Different types of topoisomerases occur in human cells and several poisons of topoisomerase I and II are widely used clinically. However, their use is compromised by a variety of side effects. Recent studies confirm that the inhibition of the a-isoform of topoisomerase II is responsible for the cytotoxic effect, whereas the inhibition of the b-isoform leads to development of adverse drug reactions. Thus, the discovery of agents selective for topoisomerase IIa is an important strategy for the development of topoisomerase II poisons with improved clinical profiles. Here, we present a computer-aided drug design study leading to the identification of structurally novel topoisomerase IIa poisons. The study combines ligand- and structure-based drug design methods including pharmacophore models, homology modelling, docking, and virtual screening of the National Cancer Institute compound database. From the 8 compounds identified from the computational work, 6 were tested for their capacity to poison topoisomerase II in vitro: 4 showed selective inhibitory activity for the aover the b-isoform and 3 of these exhibited cytotoxic activity. Thus, our study confirms the applicability of computer-aided methods for the discovery of novel topoisomerase II poisons, and presents compounds which could be investigated further as selective topoisomerase IIa inhibitors

Different binding modes of tropeines mediating inhibition and potentiation of alpha 1 glycine receptors

Tropeines are bidirectional modulators of native and recombinant glycine receptors (GlyRs) and promising leads for the development of novel modulatory agents. Tropisetron potentiates and inhibits agonist-triggered GlyR currents at femto- to nanomolar and micromolar concentrations respectively. Here, the potentiating and inhibitory effects of another tropeine, 3alpha-(3'-methoxy-benzoyloxy)nortropane (MBN) were examined by voltage-clamp electrophysiology at wild type and mutant alpha1 GlyRs expressed in Xenopus laevis oocytes. Several substitutions around the agonist-binding cavity of the alpha1 subunit interface (N46C, F63A, N102A, R119K, R131A, E157C, K200A, Y202L and F207A) were found to reduce or eliminate MBN inhibition of glycine activation. In contrast, the binding site mutations Q67A, R119A and S129A which did not affect MBN inhibition abolished the potentiation of chloride currents elicited by low concentrations of the partial agonist taurine following pre-incubation with MBN. Thus, potentiation and inhibition involve distinct binding modes of MBN in the inter-subunit agonist-binding pocket of alpha1 GlyRs. Homology modelling and molecular dynamics simulations disclosed two distinct docking modes for MBN, which are consistent with the differential effects of individual binding site substitutions on MBN inhibition and potentiation respectively. Together these results suggest that distinct binding modes at adjacent binding sites located within the agonist-binding pocket of the GlyR mediate the bidirectional modulatory effects of tropeines

Computational prediction of immune cell cytotoxicity

Immunotoxicity, defined as adverse effects of xenobiotics on the immune system, is gaining increasing attention in the approval process of industrial chemicals and drugs. In-vivo and ex-vivo experiments have been the gold standard in immunotoxicity assessment so far, so the development of in-vitro and in-silico alternatives is an important issue. In this paper we describe a widely applicable, easy-to use computational approach which can serve as an initial immunotoxicity screen of new chemical entities. Molecular fingerprints describing chemical structure were used as parameters in a machine-learning approach based on the Naïve-Bayes learning algorithm. The model was trained using blood-cell growth inhibition data from the NCI database and validated externally with several in-house and literature-derived data sets tested in cytotoxicity assays on different types on immune cells. Both cross-validations and external validations resulted in areas under the receiver operator curves (ROC/AUC) of 75% or higher. The classification of the validation data sets occurred with excellent specificities and fair to excellent selectivities, depending on the data set. This means that the probability of actual immunotoxicity is very high for compounds classified as immunotoxic, while the fraction of false negative predictions might vary. Thus, in a multistep immunotoxicity screening scheme, the classification as immunotoxic can be accepted without additional confirmation, while compounds classified as not immunotoxic will have to be subjected to further investigation