Discovery of positive allosteric modulators for the metabotropic glutamate receptor subtype 5 from a series of N-(1,3-diphenyl-1H- pyrazol-5-yl)benzamides that potentiate receptor function in vivo

This report describes the discovery of the first centrally active allosteric modulators of the metabotropic glutamate receptor subtype 5 (mGluR5). Appropriately substituted N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamides (e.g., 8) have been identified as a novel class of potent positive allosteric modulators of mGluR5 that potentiate the response to glutamate. An iterative analogue library synthesis approach provided potentiators with excellent potency and selectivity for mGluR5 (vs mGluRs 1-4, 7, 8). Compound 8q demonstrated in vivo proof of concept in an animal behavior model where known antipsychotics are active, supporting the development of new antipsychotics based on the NMDA hypofunction model for schizophrenia.     

Methotrexate and misoprostol for early abortion: A multicenter trial. I. Safety and efficacy

A prospective trial was conducted including 300 pregant women seeking elective abortion to evaluate the safety and efficacy of methotrexate and misoprostol for abortion at ≤56 days gestation. Subjects received methotrexate 50 mg/m² intramuscularly followed 7 days later by misoprostol 800 μg vaginally. The misoprostol dose was repeated the next day if the abortion did not occur. Outcome measures included successful abortion (complete abortion without requiring a surgical procedure), duration of vaginal bleeding, and side effects. Complete abortion occurred in 263/300 (87.7%, 95% CI 83.4, 91.2%) patients. The complete abortion rate was higher for early gestations: 183/202 (90.6%, 95% CI 85.7, 94.2%) at ≤49 days gestation, and 80/98 (81.6%, 95% CI 72.5, 88.7%) from 50–56 days gestation (p=0.038). Abortion occurred in the 24 hours following the initial or repeat misoprostol dose (immediate success) in 65.0%; the remaining 22.7% of women who aborted did so after a delay of 23.6 ± 9.1 (mean ± standard deviation) days. Vaginal bleeding lasted 14 ± 7 days and 11 ± 9 days in immediate success and delayed success patients, respectively. Overall, 69.7%, 87.7%, and 91.7% of patients had passed the pregnancy by 14, 28, and 35 days, respectively, after receiving methotrexate. Methotrexate and misoprostol side effects were minimal. This treatment regimen offers an alternative to surgical abortion or the use of antiprogestins and prostaglandin for medical abortion.     

Effects of instruction by practice assistants on inhaler technique and respiratory symptoms of patients. A controlled randomized videotaped intervention study

BACKGROUND: Many patients with asthma or chronic obstructive pulmonary diseaseuse their medication inhalers incorrectly. General practitioners,pharmacists and other health care providers do not always havethe opportunity to instruct patients in correct inhaler technique. OBJECTIVE: To find out whether the inhaler technique and respiratory symptomsof patients can be improved after instruction by practice assistants. METHODS: Single blind, randomized intervention study in which 48 patientswho had been using a dry powder inhaler for at least one monthtook part. Their inhaler technique was videotaped on two visitswith a two-week interval between visits. The inhaler techniqueon the videos was subsequently scored by two experts on ninecriteria. At both visits the patients completed a questionnaireabout their respiratory symptoms. After the first video, 25patients were randomly chosen to receive instruction from oneof six practice assistants who had followed a one evening courseabout inhaler instruction, and who had been issued an instruction-set. RESULTS: The patients who received instruction had a significantly greaterreduction in number of mistakes at the second visit than thepatients who did not (P = 0.01). The instructed patients alsoreported less dyspnoea at the second visit (P = 0.03). No effectof instruction was found on wheezing, cough and sputum production. CONCLUSION: The inhaler technique of patients can be improved significantlyby the instruction of patients by trained practice assistants,possibly resulting in less dyspnoea. Keywords. Administration-inhalation, obstructive lung diseases, airways symptoms, patient-education, general practice.     

Who cares for the carer? Codesigning a carer health and wellbeing clinic for older care partners of older people in Australia

Introduction

Older carers or ‘care partners’ of older people experiencing care needs often provide essential support, at times while neglecting their own health and well-being. This is an increasingly frequent scenario due to both demographic changes and policy shifts towards ageing in place. Multiple community stakeholders within the care and support ecosystem hold valuable expertise about the needs of older care partners, and the programme and policy responses that may better support their health and well-being. The aim of this study was to identify the perspectives of stakeholders obtained through the codesign phase of a multicomponent research project investigating new models of care and support for older care partners suitable for the Australian context.

Methods

Principles of codesign were used to engage a purposeful sample of older care partners, health professionals, researchers, policy makers and health service administrators. Participants took part in a series of three codesign workshops conducted remotely via video conferencing. The workshops were supported with briefing material and generated consensus-based summaries, arriving at a preferred service model.

Findings

This paper reports the research design and structure of the codesign panels, the range of findings identified as important to support the health and well-being of older carers of older people, and the resulting service model principles. The codesigned and preferred model of care is currently being prepared for implementation and evaluation in Australia.

Public Contribution

This study was conducted using codesign methodology, whereby stakeholders including older care partners and others involved in supporting older carers, were integrally involved with design, development, results and conclusions.     

Association of childhood and adult socioeconomic indicators with cardiovascular risk factors and its modification by age: the CARLA Study 2002-2006

Background  

The influence of socioeconomic status (SES) on cardiovascular diseases and risk factors is widely known, although the role of different SES indicators is not fully understood. The aim of this study was to investigate the role of different SES indicators for cardiovascular disease risk factors in a middle and old aged East German population.     

Arsenic-induced toxicity: effect on protein composition in sciatic nerve

Exposure to arsenic compounds may lead to skin and lung cancer and various disorders such as vascular disease and peripheral neuropathy in humans. Peripheral arsenic neurotoxicity has been demonstrated clinically and in electrophysiological studies. Patients intoxicated with arsenic show neurological symptoms in their feet and hands. These patients show significantly lower nerve conduction velocities (NCVs) in their peripheral nerves in comparison with controls. The mechanism of arsenic peripheral nervous system (PNS) toxicity, however, has never been described before. This is the first study to investigate the toxicity of arsenic on the PNS. Male Wistar rats were exposed to arsenite given as a single dose i.v. After sacrifice, sciatic nerves were excised and the protein composition was analysed. Protein analysis of sciatic nerves showed disappearance of neurofilament and fibroblast proteins in rats treated with arsenite doses of 15 and 20 mg/kg in comparison with the control groups. Some fibroblast protein bands had disappeared in the 20-mg/kg dose group. The analysed neurofilament-M and -L proteins decreased dose dependency over time. arsenic affects the composition of proteins in the rat sciatic nerve, especially the neurofilaments. The reduction of signals in Western blot analysis reveals changes in cytoskeletal composition, which may well lead to neurotoxic effects in vivo.     

Effect of intersection spacing on MR image contrast and study time

The effects of section separation on image contrast and calculated T1 relaxation times were investigated in healthy volunteers and a phantom using an early commercial version magnetic resonance imaging system. The effects are explained qualitatively on the basis of side lobes of excitation occurring outside the selected section resulting in reduction of the time permitted for T1 relaxation. The options for dealing with imperfect section selection, including separation of the sections (i.e., leaving gaps) and nonsequential excitation, are illustrated and the trade-offs involved in each explained.     

Moclobemide pharmacokinetics in depressed patients: Lack of age effect

The pharmacokinetics of moclobemide were examined in 19 depressed patients following a single oral dose of 50 mg. Ten patients were aged >60 years and nine <59 years. Plasma concentrations were analysed by gas chromatography with nitrogen-specific detection. Pharmacokinetic parameters calculated were peak concentration, time to reach the peak, terminal disposition half-life, area under the curve, oral clearance and apparent volume of distribution. No clinically significant differences were found betwen the two patient groups for these parameters. Thus there is no requirement for dosage adjustment in the older patient for moclobemide. This contrasts with some tricyclic and tetracyclic antidepressants which show significant age effects. Further studies of moclobemide for the treatment of elderly depression are warranted.