Diclofenac residues in carcasses of domestic ungulates available to vultures in India

Gyps vulture populations across the Indian subcontinent are declining rapidly and evidence indicates that veterinary use of the non-steroidal anti-inflammatory drug (NSAID) diclofenac is the major cause. Exposure of vultures to diclofenac is likely to arise from the consumption of livestock carcasses that have been treated shortly before death, however, detailed information regarding the prevalence and residual levels of diclofenac in carcasses available to vultures in India remains unreported. Here, we present data on diclofenac residues in 1848 liver samples taken from carcasses of dead livestock sampled at 67 sites in 12 states within India, between May 2004 and July 2005. Diclofenac residues were detected in carcasses in all states except Orisa, where only one site was sampled. The overall prevalence of detectable diclofenac (>10 microg kg(-1)) across all states was 10.1% and varied significantly among states, with up to 22.3% prevalence determined in Bihar. The geometric mean concentration of diclofenac found in samples in which the drug was detected was 352 microg kg(-1). The prevalence of carcasses containing diclofenac is similar to that previously proposed to be required to have caused the observed Gyps vulture declines in India. On the 11th of May 2006, the Drug Controller General (India) ordered the withdrawal of all licenses granted for the manufacture of diclofenac for veterinary use within India. However, if Gyps vultures are to be protected, potentially substantial existing stocks now need to be quickly and effectively removed from the Indian veterinary market.

The potential for kelp manufacture to lead to arsenic pollution of remote Scottish islands

Burning seaweed to produce kelp, valued for its high potash and soda content, was formerly a significant industry in remote coastal areas of Scotland and elsewhere. Given the high concentrations of arsenic in seaweeds, up to 100 mg kg(-1), this study investigates the possibility that the kelp industry caused arsenic contamination of these pristine environments. A series of laboratory-scale seaweed burning experiments was conducted, and analysis of the products using HPLC ICP-MS shows that at least 40% of the arsenic originally in the seaweed could have been released into the fumes. The hypothesis that the burning process transforms arsenic from low toxicity arsenosugars in the original seaweeds (Fucus vesiculosus and Laminaria digitata) to highly toxic inorganic forms, predominantly arsenate, is consistent with As speciation analysis results. A field study conducted on Westray, Orkney, once a major centre for kelp production, shows that elevated arsenic levels (10.7+/-3.0 mg kg(-1), compared to background levels of 1.7+/-0.2 mg kg(-1)) persist in soils in the immediate vicinity of the kelp burning pits. A model combining results from the burning experiments with data from historical records demonstrates the potential for arsenic deposition of 47 g ha(-1) year(-1) on land adjacent to the main kelp burning location on Westray, and for arsenic concentrations exceeding current UK soil guideline values during the 50 year period of peak kelp production.

Old drug, New target:Ellipticines selectively inhibit RNA Polymerase I transcription

Transcription byRNApolymerase I (Pol-I) is the main driving force behind ribosome biogenesis, a fundamental cellular process that requires the coordinated transcription of all three nuclear polymerases. Increased Pol-I transcription and the concurrent increase in ribosome biogenesis has been linked to the high rates of proliferation in cancers. The ellipticine family contains a number of potent anticancer therapeutic agents, some having progressed to stage I and II clinical trials; however, the mechanism by which many of the compounds work remains unclear. It has long been thought that inhibition of Top2 is the main reason behind the drugs antiproliferative effects. Here we report that a number of the ellipticines, including 9-hydroxyellipticine, are potent and specific inhibitors of Pol-I transcription, with IC50 in vitro and in cells in the nanomolar range. Essentially, the drugs did not affect Pol-II and Pol-III transcription, demonstrating a high selectivity.Wehave shown that Pol-I inhibition occurs by a p53-, ATM/ATR-, and Top2-independent mechanism. We discovered that the drug influences the assembly and stability of preinitiation complexes by targeting the interaction between promoter recognition factor SL1 and the rRNA promoter. Our findings will have an impact on the design and development of novel therapeutic agents specifically targeting ribosome biogenesis.

Influence of skin model on in vitro performance of drug-loaded soluble microneedle arrays

A plethora of studies have described the in vitro assessment of dissolving microneedle (MN) arrays for enhanced transdermal drug delivery, utilising a wide variety of model membranes as a representation of the skin barrier. However, to date, no discussion has taken place with regard to the choice of model skin membrane and the impact this may have on the evaluation of MN performance. In this study, we have, for the first time, critically assessed the most common types of in vitro skin permeation models - a synthetic hydrophobic membrane (Silescol(®) of 75 µm) and neonatal porcine skin of definable thickness (300-350 µm and 700-750 µm) - for evaluating the performance of drug loaded dissolving poly (methyl vinyl ether co maleic acid) (PMVE/MA) MN arrays. It was found that the choice of in vitro skin model had a significant effect on the permeation of a wide range of small hydrophilic molecules released from dissolving MNs. For example, when Silescol(®) was used as the model membrane, the cumulative percentage permeation of methylene blue 24h after the application of dissolvable MNs was found to be only approximately 3.7% of the total methylene blue loaded into the MN device. In comparison, when dermatomed and full thickness neonatal porcine skin were used as a skin model, approximately 67.4% and 47.5% of methylene blue loaded into the MN device was delivered across the skin 24h after the application of MN arrays, respectively. The application of methylene blue loaded MN arrays in a rat model in vivo revealed that the extent of MN-mediated percutaneous delivery achieved was most similar to that predicted from the in vitro investigations employing dermatomed neonatal porcine skin (300-350 µm) as the model skin membrane. On the basis of these results, a wider discussion within the MN community will be necessary to standardise the experimental protocols used for the evaluation and comparison of MN devices.

Drug and light delivery strategies for photodynamic antimicrobial chemotherapy (PACT) of pulmonary pathogens:a pilot study

Pulmonary disease is the main cause of morbidity and mortality in cystic fibrosis (CF) suffers, with multidrug-resistant Pseudomonas aeruginosa and Burkholderia cepacia complex as problematic pathogens in terms of recurrent and unremitting infections. Novel treatment of pulmonary infection is required to improve the prognosis and quality of life for chronically infected patients. Photodynamic antimicrobial chemotherapy (PACT) is a treatment combining exposure to a light reactive drug, with light of a wavelength specific for activation of the drug, in order to induce cell death of bacteria. Previous studies have demonstrated the susceptibility of CF pathogens to PACT in vitro. However, for the treatment to be of clinical use, light and photosensitizer must be able to be delivered successfully to the target tissue. This preliminary study assessed the potential for delivery of 635 nm light and methylene blue to the lung using an ex vivo and in vitro lung model. Using a fibre-optic light delivery device coupled to a helium-neon laser, up to 11% of the total light dose penetrated through full thickness pulmonary parenchymal tissue, which indicates potential for multiple lobe irradiation in vivo. The mass median aerodynamic diameter (MMAD) of particles generated via methylene blue solution nebulisation was 4.40 µm, which is suitable for targeting the site of infection within the CF lung. The results of this study demonstrate the ability of light and methylene blue to be delivered to the site of infection in the CF lung. PACT remains a viable option for selective killing of CF lung pathogens.

A comparison of the application of STOPP/START to patients' drug lists with and without clinical information

Background A European screening tool (STOPP/START) has been formulated to identify the prescribing of potentially inappropriate medicines (PIMs) and potential prescribing omissions (PPOs). Pharmacists working in community pharmacies could use STOPP/START as a guide to conducting medication use reviews; however, community pharmacists do not routinely have access to patients' clinical records. Objective To compare the PIM and PPO detection rates from application of the STOPP/START criteria to patients' medication details alone with the detection rates from application of STOPP/START to information on patients' medications combined with clinical information. Setting Community Pharmacy. Method Three pharmacists applied STOPP/START to 250 patient medication lists, containing information regarding dose, frequency and duration of treatment. The PIMs and PPOs identified by each pharmacist were compared with those identified by consensus agreement of two other pharmacists, who applied STOPP/START criteria using patients' full clinical records. Main outcome measure The main outcome measures were: (1) PIM and PPO detection rates among pharmacists with access to patients' clinical information compared to PIM and PPO detection rates among pharmacists using patients' medication information only, and (2) the levels of agreement (calculated using Cohen's kappa statistic (k)) for the three most commonly identified PIMs and PPOs. Results Pharmacists with access to patients' clinical records identified significantly fewer PIMs than pharmacists without (p = 0.002). The three most commonly identified PIMs were benzodiazepines, proton pump inhibitors and duplicate drug classes, with kappa (k) statistic agreement ranges of 0.87-0.97, 0.60-0.68 and 0.39-0.85 respectively. PPOs were identified more often (p 

TEENAGERS AND ILLICIT DRUG-USE - EXPANDING THE USER VS NONUSER DICHOTOMY

The present study examines proximal and distal factors associated with the use and non-use of illegal substances within a sample of 860 teenagers in North Wales. Arguing that there is predictive utility in expanding the traditional 'users vs non-users' design dichotomy, four groups are identified-resistant and vulnerable non-users and experimental and repeated users. 'Person' variables (life satisfaction, deviance, hopelessness and drug-related attributions) appeared to primarily differentiate the vulnerable group from their resistant counterparts and identify this, as yet non-using group, with user samples. It is suggested that these variables might represent 'risk' factors for illicit substance use and that the group design employed suggests they precede, rather than follow as a consequence of, illicit drug use. Like their resistant counterparts however, the vulnerable group are differentiated from user samples on some lifestyle and context indices. It is argued that these represent 'protective' influences in an otherwise at-risk group of non-users. Variables associated with an escalation of illicit drug use are discussed in considering the differences between the experimental and repeated user groups. Apart from the more proximal factor of drug-related attributions, 'person' variables appeared less involved here. Repeated users did however, tend to use a greater number of drugs, have a greater proportion of friends who also used illegal substances and significantly fewer had a Welsh cultural identity.