Ecotoxicology of polychlorinated biphenyls in fish—a critical review

Polychlorinated biphenyls (PCBs) are widespread persistent anthropogenic contaminants that can accumulate in tissues of fish. The toxicity of PCBs and their transformation products has been investigated for nearly 50 years, but there is a lack of consensus regarding the effects of these environmental contaminants on wild fish populations. The objective of this review is to critically examine these investigations and evaluate publicly available databases for evidence of effects of PCBs in wild fish. Biological activity of PCBs is limited to a small proportion of PCB congeners [e.g., dioxin-like PCBs (DL-PCBs)] and occurs at concentrations that are typically orders of magnitude higher than PCB levels detected in wild fish. Induction of biomarkers consistent with PCB exposure (e.g., induction of cytochrome P450 monooxygenase system) has been evaluated frequently and shown to be induced in fish from some environments, but there does not appear to be consistent reports of damage (i.e., biomarkers of effect) to biomolecules (i.e., oxidative injury) in these fish. Numerous investigations of endocrine system dysfunction or effects on other organ systems have been conducted in wild fish, but collectively there is no consistent evidence of PCB effects on these systems in wild fish. Early life stage toxicity of DL-PCBs does not appear to occur at concentrations reported in wild fish embryos, and results do not support an association between PCBs and decreased survival of early life stages of wild fish. Overall, there appears to be little evidence that PCBs have had any widespread effect on the health or survival of wild fish.     

P27 The Establishment of a New Experiment in Clinical Pharmacology Teaching

Clinical pharmacology is a newly emerging subject which is based on basic pharmacology and clinical medicine. It＇ s very important for training valid and good doctors and pharmaceutists. Rencently many universities in China have required clinical pharmacology as a special necessary course for medical and pharmacy students. But the experimental teaching in clinical pharmacology is not so wide till now in China. We have established a new clinical experiment as ＂Determination of the pharmacokinetic parameters of Ciprofloxacin in healthy young volunteers＂. The experiment was carried out with 10 healthy young volunteers after single oral administration of lOOmg Ciprofloxacin. Urine samples were collected then centrifuged at different time after administration. UV-spectrophotometry method was used to determine the concentration of Ciprofloxacin in urine. The pharmacokinetic parameters following oral administration of tested Ciprofloxacin in healthy young volunteers can be obtained by the formula that the elimination of Ciprofloxacin is conformed to one-compartment model. This method is rapid, accurate, sensitive and the most important, very convenient, it＇ s very suitable for experimental teaching in clinical pharmacology. This new clinical experiment can be widely spread through all the medical and pharmaceutical universities.     

P14 Analyse of effect with using PBL in Pharmacology in our school in the near future

To seek more science and perfect way of teaching in pharmacology, it is different with tradition teaching that we give priority to students when we use PBL, and emphasize to study initiatively. These persons qualified to teach make up of base medicine subject and clinic subject. There are 10 students in a group, and then spread to study, to discuss. At first, we found problem （NOTICE： The students already master important some knowledge of basic medicine, but they do not study knowledge of clinic medicine. ） The problem make them working hard for gaining correlative data through network, library, teaching hospital, then teacher explain these problems in the classroom. Our task is to complete emphase content of teaching according to the brief of teaching. This way lead to student finding problem and to settle problem, in the same time, we must innovate about experiment class. The experiment teachers only to bring forward standard of this experiment . The students planned the step of experiment, argument it, then actualize it. This course need to plentiful for energy and time for teachers and students. On the side, we must set up taking as an elective course that handpick some interest, representative clinic cases to analyze it. It would blaze students interesting of leaning, but their amount inadvisable overabundance. In the near future we found the students work hard than before, their basic receive that observe problem, solve problem, work together and cooperation, but their examination result is not difference with tradition distinctness. For the future effect that the students use many drugs in clinic practice and clinic works is not observed now. This ways that using PBL is beneficial to teach in pharmacolo.gy, but the step must correct gradually. It is importance sense to build network in our school perfect, to handpick cases of PBL, and to learn more clinic knowledge. That will give us science and perfect way of teaching in pharmacology.     

Discovery of a brain-penetrant S1P₃-sparing direct agonist of the S1P₁ and S1P₅ receptors efficacious at low oral dose

2-Amino-2-(4-octylphenethyl)propane-1,3-diol 1 (fingolimod, FTY720) has been recently marketed in the United States for the treatment of patients with remitting relapsing multiple sclerosis (RRMS). Its efficacy has been primarily linked to the agonism on T cells of S1P(1), one of the five sphingosine 1-phosphate (S1P) G-protein-coupled receptors, while its cardiovascular side effects have been associated with activity at S1P(3). Emerging data suggest that the ability of this molecule to cross the blood-brain barrier and to interact with both S1P(1) and S1P(5) in the central nervous system (CNS) may contribute to its efficacy in treating patients with RRMS. We have recently disclosed the structure of an advanced, first generation S1P(3)-sparing S1P(1) agonist, a zwitterion with limited CNS exposure. In this Article, we highlight our strategy toward the identification of CNS-penetrant S1P(3)-sparing S1P(1) and S1P(5) agonists resulting in the discovery of 5-(3-{2-[2-hydroxy-1-(hydroxymethyl)ethyl]-5-methyl-1,2,3,4-tetrahydro-6-isoquinolinyl}-1,2,4-oxadiazol-5-yl)-2-[(1-methylethyl)oxy]benzonitrile 15. Its exceptional in vivo potency and good pharmacokinetic properties translate into a very low predicted therapeutic dose in human (<1 mg p.o. once daily).     

Fish drug analysis—Phish-pharm: A searchable database of pharmacokinetics data in fish

Information about drug residues and pharmacokinetic parameters in aquatic species is relatively sparse. In addition, it is difficult to rapidly compare data between studies due to differences in experimental conditions, such as water temperatures and salinity. To facilitate the study of aquatic species drug metabolism, we constructed a Fish Drug/Chemical Analysis Phish-Pharm (FDA-PP) database. This database consists of more than 400 articles that include data from 90 species (64 genera) of fish. Data fields include genus, species, water temperatures, the average animal weight, sample types analyzed, drug (or chemical) name, dosage, route of administration, metabolites identified, method of analysis, protein binding, clearance, volume of distribution in a central compartment (Vc) or volume of distribution at steady-state (Vd), and drug half-lives (t((1/2))). Additional fields list the citation, authors, title, and Internet links. The document will be periodically updated, and users are invited to submit additional data. Updates will be announced in future issues of The AAPS Journal. This database will be a valuable resource to investigators of drug metabolism in aquatic species as well as government and private organizations involved in the drug approval process for aquatic species.     

Discovery of a novel inhibitor of NAD（P）＋-dependent malic enzyme （ME2） by high-throughput screening

Aim： Malic enzymes are oxidative decarboxylases with NAD or NAD（P） as cofactor that catalyze the conversion of L-malate to pyruvate and CO2. The aim of this study was to discover and characterize a potent inhibitor of human NAD（P）＋-dependent malic enzyme 2 （ME2）. Methods： Recombinant human ME2-His-Tag fusion protein was overexpressed in E coil and purified with Ni-NTA resin. A high- throughput screening （HTS） assay was developed to find ME2 inhibitors. Detergent Brij-35 was used to exclude false positives. The characteristics of the inhibitor were analyzed with enzyme kinetics analysis. A thermal shift assay for ME2 was carried out to verify the binding of the inhibitor with the enzyme. Results： An HTS system for discovering ME2 inhibitors was established with a Z＇ factor value of 0.775 and a signal-to-noise ratio （S/N） of 9.80. A library containing 12 683 natural products was screened. From 47 hits, NPD387 was identified as an inhibitor of ME2. The primary structure-activity relationship study on NPD387 derivatives showed that one derivative NPD389 was more potent than the parent compound NPD387 （the ICso of NPD389 was 4.63±0.36 pmoVL or 5.59±0.38 pmoVL, respectively, in the absence or presence of 0.01% Brij-35 in the assay system）. The enzyme kinetics analysis showed that NPD389 was a fast-binding uncompetitive inhibitor with respect to the substrate NAD~ and a mixed-type inhibitor with respect to the substrate L-malate. Conclusion： NPD389 is a potent ME2 inhibitor that binds to the enzyme in a fast-binding mode, acting as an uncompetitive inhibitor with respect to the substrate NAD~ and a mixed-type inhibitor with respect to the substrate L-malate.     

Analysing drying unit performance in a continuous pharmaceutical manufacturing line by means of mass – Energy balances

The current trend in the pharmaceutical industry to move from batch-wise to continuous production processes strengthens the need for monitoring and controlling the process in-line. The ConsiGma™ continuous tableting line collects data of the different subunits in real-time, but these are not really used. In this paper the data of the six-segmented fluidized bed dryer in the line are used for the development and evaluation of a mass and energy balance. The objectives are multiple: (1) prediction of the moisture content of the granules leaving the dryer solely based on the currently logged data and (2) prediction of the gas outlet temperature to check the mass balances. Once a validated system is established the gas temperature in different horizontal sections of the drying unit can be predicted. Calculations are also used to identify errors in the system and to propose alternative sensor locations. A calibration is performed in order to predict the evaporation rate. The balances were able to predict both the moisture content of the granules at the end of the drying process and the gas outlet temperature quite accurately. Combining the gathered information with the height of the bed in the fluidized bed can be used to predict the gas temperature in different horizontal sections of the dryer. An extra sensor measuring the gas temperature and the humidity at the wet transfer line would increase the accuracy of the calculations. An extra gas velocity sensor at the outlet would be useful to incorporate an extra supervision of the calculations.     

Can Lemna minor mitigate the effects of cadmium and nickel exposure in a Neotropical fish?

We aimed to evaluate if Lemna minor can mitigate the observed effects of cadmium (Cd) and nickel (Ni) exposure in Prochilodus lineatus. Fish were exposed for 96 h to 20 µg L^-1 of Cd, 1.5 mg L^-1 of Ni, or to a mixture of these two metals. In all tests, one group was exposed to the metals with duckweed on the water surface, and other group was exposed only to the metals, without plants. After each exposure, samples of P. lineatus tissues were collected to evaluate multiple biomarkers. Duckweed prevented bioaccumulation in some fish tissues and attenuated changes in acetylcholinesterase activity, increases in erythrocytic nuclear abnormality frequency, and hyperglycemia. However, the changes in plasma ion concentrations, reduction in activity of ion transport enzymes, and histological damage were not mitigated. Therefore, we concluded that L. minor partially attenuates the effects caused by Cd and Ni exposure.     

Is heart rate in fish a sensitive indicator to evaluate acute effects of β-blockers in surface water?

We have investigated if propranolol, a non-selective β-blocker present in sewage effluents, affects heart rate in rainbow trout. During a 48 h exposure to a very high concentration of propranolol (70.9 μg/L) no effects on heart rate were found. After a subsequent intravenous injection of propranolol, heart rate remained unaffected in pre-exposed fish but was significantly lowered in naïve fish. Other studies have reported effects on the reproduction of fish by propranolol dissolved in water at much lower concentrations. The present study suggests that physiological systems under homeostatic control, like heart rate, may not be particularly sensitive despite being direct targets.     

Is heart rate in fish a sensitive indicator to evaluate acute effects of β-blockers in surface water?

We have investigated if propranolol, a non-selective β-blocker present in sewage effluents, affects heart rate in rainbow trout. During a 48 h exposure to a very high concentration of propranolol (70.9 μg/L) no effects on heart rate were found. After a subsequent intravenous injection of propranolol, heart rate remained unaffected in pre-exposed fish but was significantly lowered in naïve fish. Other studies have reported effects on the reproduction of fish by propranolol dissolved in water at much lower concentrations. The present study suggests that physiological systems under homeostatic control, like heart rate, may not be particularly sensitive despite being direct targets.     

Quantification of hordenine in a complex plant matrix by direct analysis in real time–high-resolution mass spectrometry: Application to the “plant of concern” Sceletium tortuosum

Recently, there has been an increase in the recreational abuse of several psychoactive plants, resulting in the United Nations Office on Drugs and Crime creating a list of “plants of concern.” One such material is Sceletium tortuosum and products derived from it. Regulation of these materials is challenging because of their innocuous appearance, the cumbersome sample preparation steps required to render the material into a form amenable to analysis by conventional techniques, the requirement for nuanced sample analysis protocols, and lengthy analysis times. It is demonstrated here that direct analysis in real time–high-resolution mass spectrometry (DART-HRMS) can be used to not only identify S. tortuosum material based on the detection of characteristic biomarkers including hordenine and several mesembrine alkaloids, but also quantify the amount of hordenine present. Using hordenine-d₆ as an internal standard, a protocol, validated according to US Food and Drug Administration (FDA) Guidelines for the Development and Validation of Bioanalytical Methods, was devised for the quantification of the psychoactive component hordenine. The method was then applied to the quantification of hordenine in six commercially available products derived from the foliage and stems of S. tortuosum. By this method, the lower limit of quantification (LLOQ) was found to be 1 μg/ml. Observed hordenine concentrations ranged from 0.02738 to 1.071 mg of hordenine per gram of plant material. The developed technique provides an effective and quick means for the detection and quantification of hordenine in S. tortuosum, which can be extended to analysis of other hordenine-containing products.     

Prevalence of hypothyroidism in Finland—a nationwide prescription study

Purpose  

The aim of this study was to estimate the 1-year prevalence of levothyroxine-treated hypothyroidism in Finland.     

Discovery of a highly potent and orally available importin-β1 inhibitor that overcomes enzalutamide-resistance in advanced prostate cancer

Nuclear transporter importin-β1 is emerging as an attractive target by virtue of its prevalence in many cancers. However, the lack of druggable inhibitors restricts its therapeutic proof of concept. In the present work, we optimized a natural importin-β1 inhibitor DD1 to afford an improved analog DD1-Br with better tolerability(>25 folds) and oral bioavailability. DD1-Br inhibited the survival of castration-resistant prostate cancer(CRPC) cells with sub-nanomolar potency and completely preven...     

Phytotoxicity and biotransformation of La₂O₃ nanoparticles in a terrestrial plant cucumber (Cucumis sativus)

With the increasing applications of metal-based nanoparticles in various commercial products, it is necessary to address their environmental fate and potential toxicity. In this work, we assessed the phytotoxicity of lanthanum oxide (La?O?) NPs to cucumber plants and determined its distribution and biotransformation in roots by TEM and EDS, as well as STXM and NEXAFS. LaCl? was also studied as a reference toxicant. La?O? NPs and LaCl? were both transformed to needle-like LaPO? nanoclusters in the intercellular regions of the cucumber roots. In vitro experiments demonstrated that the dissolution of La?O? NPs was significantly enhanced by acetic acid. Accordingly, we proposed that the dissolution of NPs at the root surface induced by the organic acids extruded from root cells played an important role in the phytotoxicity of La?O? NPs. The reactions of active NPs at the nano-bio interface should be taken into account when studying the toxicity of dissolvable metal-based nanoparticles.     

Efficacy of preoperative embolization in management of carotid body tumours — a pilot study

Henoch The aim of the study was to evaluate the efficacy of preoperative embolization in the management of carotid body tumours. Of the 15 patients admitted to the Department of Vascular Surgery (General Surgery Unit II), Christian Medical College, Vellore, from January 1^st 2002 to December 31^st 2006 for management of carotid body tumours, 4 patients underwent preoperative embolization and were grouped together. Of the remaining 9 patients who underwent surgical excision, there were 5 with comparable tumour size and these were grouped together into the control group. Surgical outcome of both the groups were compared in terms of operating time, intraoperative blood loss, nerve injury, postoperative morbidity and mortality. There was statistically significant reduction in blood loss and duration of surgery in patients who underwent preoperative embolization. In conclusion, the preoperative embolization is effective in the management of Shamblin type III carotid body tumours.     

Altered distribution of digoxin in renal failure—a cause of digoxin toxicity?

1 Three cases are described in which renal failure was accompanied by a lowered apparent volume of distribution of digoxin. In two cases this resulted in frank digoxin toxicity and in one equivocal toxicity. In all three cases digoxin plasma levels were greater than 2 ng/ml.

2 The possible causes of the abnormal distribution of digoxin in renal failure are discussed.

3 Recommendations are outlined for the use of digoxin in patients with renal failure aimed at circumventing the problem raised by a lowered apparent volume of distribution of the drug.

     

Tracking pan-continental trends in environmental contamination using sentinel raptors—what types of samples should we use?

Biomonitoring using birds of prey as sentinel species has been mooted as a way to evaluate the success of European Union directives that are designed to protect people and the environment across Europe from industrial contaminants and pesticides. No such pan-European evaluation currently exists. Coordination of such large scale monitoring would require harmonisation across multiple countries of the types of samples collected and analysed-matrices vary in the ease with which they can be collected and the information they provide. We report the first ever pan-European assessment of which raptor samples are collected across Europe and review their suitability for biomonitoring. Currently, some 182 monitoring programmes across 33 European countries collect a variety of raptor samples, and we discuss the relative merits of each for monitoring current priority and emerging compounds. Of the matrices collected, blood and liver are used most extensively for quantifying trends in recent and longer-term contaminant exposure, respectively. These matrices are potentially the most effective for pan-European biomonitoring but are not so widely and frequently collected as others. We found that failed eggs and feathers are the most widely collected samples. Because of this ubiquity, they may provide the best opportunities for widescale biomonitoring, although neither is suitable for all compounds. We advocate piloting pan-European monitoring of selected priority compounds using these matrices and developing read-across approaches to accommodate any effects that trophic pathway and species differences in accumulation may have on our ability to track environmental trends in contaminants.