Search

International audience; In case of a nuclear reactor accident affecting a large population the internal contamination of the workers and the public can be assessed through in vivo measurements. Since iodine-131 is one of the most important releases and since it is of health concern, thyroid monitoring of this radionuclide is of special interest. Intercomparisons of thyroid in vivo measurements usually focus on the adult case. Here we report about a European intercomparison exercise for spectroscopic devices. Three sets of thyroid phantoms of unknown activity were circulated, representing the following ages 5 years-old, 10 years-old and the adult. Nineteen institutions from twelve countries in Europe took part in an intercomparison exercise. Twenty-nine measurement devices have been tested. In the adult case, 5 results were outside the acceptance criteria and 10 in the 10-years old case. In the 5 years-old case, the result was not reported for one measurement device and 11 results were outside the acceptance criteria. Devices that have been tested during this intercomparison now dispose of calibration coefficients for the three age groups. © 2019

By reducing the basicity of the core heterocycle in a series of HCV NS5B inhibitors, the hERG liability was reduced. The SAR was then systematically explored in order to increase solubility and enable dose escalation while retaining potency. During this exploration, a facile decarboxylation was noted and was exploited as a novel prodrug mechanism. The synthesis and characterization of these prodrugs and their utilization in chronic toxicity studies are presented.

A new series of non-nucleoside reverse transcriptase inhibitors based on an imidazole-amide biarylether scaffold has been identified and shown to possess potent antiviral activity against HIV-1, including the NNRTI-resistant Y188L mutated virus. X-ray crystallography of inhibitors bound to reverse transcriptase, including a structure of the Y188L RT protein, was used extensively to help identify and optimize the key hydrogen-bonding motif. This led directly to the design of compound 43 that exhibits remarkable antiviral activity (EC501 nM) against a wide range of NNRTI-resistant viruses and a favorable pharmacokinetic profile across multiple species.

Several series of CCR5 antagonists have been discovered by derivatization at the N-terminal of the piperidine ring of the core template 2. Some derivatives exhibited potent inhibition against HIV-1infection. The pharmacokinetic properties of the lead compounds 11a, 14a, 15b, and 16b have been evaluated in vivo.

We describe robust chemical approaches toward putative CCR5 scaffolds designed in our laboratories. Evaluation of analogues in the (125)I-[MIP-1beta] binding and Ba-L-HOS antiviral assays resulted in the discovery of 64 and 68 in the 4,4-disubstitited piperidine class H, both potent CCR5 ligands (pIC 50 = 8.30 and 9.00, respectively) and HIV-1 inhibitors (pIC 50 = 7.80 and 7.84, respectively, in Ba-L-HOS assay). In addition, 64 and 68 were bioavailable in rodents, establishing them as lead molecules for further optimization toward CCR5 clinical candidates.

In the event of a radiation emergency, people close to the site of the incident may be exposed to radiation by external exposure, or as a result of intakes of radioactive material. For these incidents it may be necessary to monitor members of the public both for external and internal contamination. This work reviews currently available equipment for the assessment of internal exposure following an emergency. It concentrates on incidents involving the spread of radioactive material and on contamination by radionuclides which emit penetrating radiation. It is essential that this monitoring is carried out as soon as possible so that people who have been exposed at a level which could have an effect on health can be identified and receive prompt medical assessment. Proposed action levels to identify people who need medical attention are reviewed to determine the required sensitivity of monitoring equipment. For releases containing gamma-ray emitting radionuclides the best means of measuring internal contamination is to use detectors placed close to the body (whole body or partial body monitoring). Laboratory based whole body monitors could be used but these may well be inconveniently located and so equipment which can be deployed to the site of an incident has been developed and these are described. The need for rapid selection and prioritisation of people for monitoring, methods to deal with potentially high numbers of contaminated people and the requirement for a means of rapidly interpreting monitoring information are also discussed.It has been found that for many types of incidents and scenarios, systems based on unshielded high-resolution detectors and hand-held instruments do have the required sensitivity to identify people who require medical assessment.

The characterisation of an intertidal sediment, containing enhanced levels of radioactivity, collected from the Cumbrian coast of the U.K. by the Laboratory of the Government Chemist for the Department of the Environment is described. A wide variety of radiochemical and instrumental techniques were used including α-spectrometry, β-counting, liquid scintillation counting, γ-spectrometry, X-ray spectrometry and mass spectrometry. To derive mean values of the activity concentrations of radionuclides in the material, use was made of the technique developed by Woods and Munster. This technique first critically evaluates data for technical suitability. Then, to avoid excessive manipulation of data, calculation of the weighted (the statistical weighting is the inverse of the squared uncertainties, limited so that no one result contributes more than 50%) and unweighted means is performed, along with a χ2 test. If the value of χ2/(n−1) 2 determinations, 3 with 2 determinations and 2 with single determinations. Emphasis is placed where data appeared to be discrepant (e.g. 40K and 137Cs), where widely different measurement techniques were employed (e.g. the actinides), where there were analytical “difficulties” (e.g. uranium) or where the radionuclide is not commonly measured (e.g. 155Eu, 237Np and 241Pu). The material is now available to laboratories as a reference material and it is anticipated that it will be used to validate existing procedures and to research new methods of analysis.

We describe the preclinical development and in vivo efficacy of a novel chemical series that inhibits hepatitis C virus replication via direct interaction with the viral nonstructural protein 4B (NS4B). Significant potency improvements were realized through isosteric modifications to our initial lead 1a. The temptation to improve antiviral activity while compromising physicochemical properties was tempered by the judicial use of ligand efficiency indices during lead optimization. In this manner, compound 1a was transformed into (+)-28a which possessed an improved antiviral profile with no increase in molecular weight and only a modest elevation in lipophilicity. Additionally, we employed a chimeric "humanized" mouse model of HCV infection to demonstrate for the first time that a small molecule with high in vitro affinity for NS4B can inhibit viral replication in vivo. This successful proof-of-concept study suggests that drugs targeting NS4B may represent a viable treatment option for curing HCV infection.

Contract researchers comprise a substantial element in all areas of academic research, but numerous reports have exposed major concerns over status, security and conditions. As part of a larger review of its research activities, the ESRC in 1991 commissioned a quick survey of contract researchers on ESRC projects. This report summarizes that survey. The sample of 44 researchers consisted of 80 per cent of the eligible personnel. Its constitution was comparable to the one surveyed by Varlaam (1988) for the Institute of Management Studies covering all disciplines, except for the preponderance of females (59 per cent) in the present study. This seems to indicate acceptable representativeness, although the small size inevitably restricts the range and reliability of statistical analyses possible. For that reason, equal emphasis is given in this report to the open comments supplied by over half the respondents. The four‐page questionnaire addressed issues identified from other surveys extending back t...

We recently described ( J. Med. Chem. 2008 , 51 , 6538 - 6546 ) a novel class of CCR5 antagonists with strong anti-HIV potency. Herein, we detail SAR converting leads 1 and 2 to druglike molecules. The pivotal structural motif enabling this transition was the secondary sulfonamide substituent. Further fine-tuning of the substituent pattern in the sulfonamide paved the way to enhancing potency and bioavailability and minimizing hERG inhibition, resulting in discovery of clinical compound 122 (GSK163929).