implantation-recording-wireless-electroretinogram-visual-evoked

Implantation and Recording of Wireless Electroretinogram and Visual Evoked Potential in Conscious Rats

The full-field electroretinogram (ERG) and visual evoked potential (VEP) are useful tools to assess retinal and visual pathway integrity in both ...

Pfizer Neusentis

This study provides feedback from research with staff and clients of a medium secure learning disability service in north-west England. Participants were asked about incidents which required the use of physical intervention, using unstructured interviews within a participatory research framework. The article explores clients' and staff accounts of aggressive incidents and the consequences of physical intervention. Clients cited other clients and the ward atmosphere as the main reasons for aggressive behaviour. Some clients said that the use of physical intervention made them more frustrated and brought back memories of frightening experiences. Staff reported that incidents of aggression and the use of physical intervention were upsetting and traumatic, causing feelings of guilt and self-reproach. Staff said that they always used physical intervention as a last resort, although clients often reported otherwise. Time out and post-incident discussions were valued by both groups, as were strong staff/client relationships.

The last resort? Staff and client perspectives on physical intervention.

Incorporation of fluorine at the 4-position of an existing series of sulfonyl piperidine 5-HT2A antagonists gave compounds with increased selectivity over the IKr potassium channel. This work led to the identification of 3b, a compound that gave no increase in QTc in the anesthetized dog up to plasma levels as high as 148 microM. Furthermore, 3b has been shown to increase slow-wave sleep bout duration and to decrease the number of awakenings in rats, indicating the potential utility of 5-HT2A antagonists in the treatment of insomnia.

4-Fluorosulfonylpiperidines: selective 5-HT2A ligands for the treatment of insomnia.

In the present study, the occupancy of flumazenil (Ro 15-1788; 1-30mg/kg p.o.) at the benzodiazepine site of rat brain GABA(A) receptors was compared using in vivo and ex vivo binding methodologies with [(3)H]flumazenil as the radioligand. Animals either received tracer quantities of [(3)H]flumazenil 3min before being killed for the in vivo binding, or were killed and brain homogenates incubated with 1.8nM [(3)H]flumazenil. The flumazenil dose required to inhibit in vivo binding of [(3)H]flumazenil by 50% (ID(50)) was 2.0mg/kg, which represents the most accurate measure of benzodiazepine site occupancy by flumazenil in vivo. Occupancy measured in crude brain homogenates using the ex vivo method was time dependent with a 3mg/kg dose giving occupancies of 77% and 12% using 0.5 or 60min ex vivo incubations times, respectively, presumably due to dissociation from the binding site during the ex vivo incubation. When incubation time was minimised (0.5min), and despite being under non-equilibrium conditions, the ex vivo method gave an ID(50) of 1.5mg/kg which was not too dissimilar from that observed using in vivo binding (2.0mg/kg). As expected, ex vivo binding can give an underestimation of receptor occupancy but this can be minimised by careful attention to the kinetics of unlabelled drug and radioligand.

Comparison of in vivo and ex vivo [3H]flumazenil binding assays to determine occupancy at the benzodiazepine binding site of rat brain GABAA receptors.

This report describes the effect of replacing the central basic amine present in many known 5-HT(2A) ligands with an aromatic residue. We targeted the isomeric phenethylpyridines 2 and 3 and these compounds proved to be excellent leads, possessing good 5-HT(2A) receptor binding affinity and selectivity over the 5-HT(2C) subtype. Optimization of one isomer led to the identification of 25, a compound with sub-nanomolar 5-HT(2A) affinity and selectivity over 5-HT(2C) of greater than 4600-fold.

2,5-Disubstituted pyridines: the discovery of a novel series of 5-HT2A ligands.

The present study describes the optimisation of an autoradiography assay that provides a means to measure the in vitro potency of melanin-concentrating hormone receptor 1 (MCH(1)) antagonists in native tissues and their ex vivo receptor occupancy. Initial localisation studies demonstrated that the MCH(1) receptor radioligand [(125)I]-S36057 bound to rat caudate putamen with specific binding of consistently >60%. In vitro, the MCH(1) receptor antagonists GW3430, SNAP-94847 and 4'-{[1-(cyclopropylmethyl)piperidin-4-ylidene] [5-fluoro-6-(trifluoromethyl)-1H-benzimidazol-2-yl]methyl}biphenyl-3-carbonitrile (referred to as Compound A) exhibited concentration dependent inhibition of the specific binding of [(125)I]-S36057, with a rank order of affinity of SNAP-94847>Compound A>GW3430. In an ex vivo occupancy assay, Compound A dosed orally to rats caused a concentration dependent inhibition of the specific binding of [(125)I]-S36057 to rat caudate putamen. The occupancy reached 87+/-11% at 30 mg/kg and the estimated ED(50) was 9.3 mg/kg, which was equivalent to a free plasma concentration of 40 nM. As MCH has been reported to play a role in the regulation of the sleep cycle, the effect of Compound A on sleep parameters was investigated. However Compound A, at exposures that achieved near maximal receptor occupancy, failed to demonstrate any effects on the sleep/wake pattern in telemetered rats. We conclude that our ex vivo receptor occupancy assay is suitable for selecting centrally penetrant MCH(1) receptor antagonists and that, despite high levels of receptor occupancy, the selective MCH(1) receptor antagonist Compound A failed to elicit any changes in sleep electroencephalogram (EEG) parameters.

Localisation of melanin-concentrating hormone receptor 1 in rat brain and evidence that sleep parameters are not altered despite high central receptor occupancy.

Scaffold hopping from a non-basic series of 5-HT(2A) receptor antagonists developed in-house that possessed reduced activity in vivo enabled the discovery of a novel series of diaryl sulfones that gave excellent occupancy on oral dosing. Not only does this work further demonstrate that oral bioavailability of a given series can be enhanced by improving physicochemical parameters such as log P, but it corroborates the growing evidence that a protonated amine is not essential for affinity at aminergic GPCRs.

Non-basic ligands for aminergic GPCRs: the discovery and development diaryl sulfones as selective, orally bioavailable 5-HT2A receptor antagonists for the treatment of sleep disorders.

A series of novel non-peptide corticotropin releasing factor type-1 receptor (CRF(1)) antagonists were found to display varying degrees of insurmountable and non-competitive behaviour in functional in vitro assays. We describe how we attempted to relate this behaviour to ligand receptor-binding kinetics in a quantitative manner and how this resulted in the development and implementation of an efficient pharmacological screening method based on principles described by Motulsky and Mahan.

Quantitative pharmacological analysis of antagonist binding kinetics at CRF1 receptors in vitro and in vivo.

GABA(A) receptors containing α2/3 subunits are current targets in the battle to develop new pain medications, as they are expressed in the spinal cord where increasing inhibitory drive should result in analgesia. However, this approach is prone to a range of side effects including sedation, cognitive impairment, and abuse as a consequence of the widespread influence of GABA. The ability to make subtype selective low-efficacy benzodiazepine compounds, which potentiate the action of GABA at specific α subunits, has the potential to reduce this side effect profile. In this study, we have investigated the effects of the medium-efficacy positive allosteric modulator (PAM) L-838,417 and the low-efficacy PAM TPA023 in a number of preclinical inflammatory and neuropathic pain models. We conclude that either the higher level of efficacy at α2/3 or efficacy at α5 is required for compounds to have a significant analgesic effect in a range of models, and, therefore, although the side-effect profile of compounds can be reduced compared to typical benzodiazepines, it is unlikely that it can be completely eliminated.

A Comparison of the α2/3/5 Selective Positive Allosteric Modulators L-838,417 and TPA023 in Preclinical Models of Inflammatory and Neuropathic Pain.

Low-grade appendiceal mucinous neoplasm (LAMN) is a precursor lesion of pseudomyxoma peritonei, which, if treated suboptimally, may later disseminate throughout the abdominal cavity. We previously demonstrated the role of cytoreductive surgery (CRS) and heated intraperitoneal chemotherapy (HIPEC) to reduce the dissemination risk. Here we describe the feasibility and safety of minimal access cytoreductive surgery (MACRS) and HIPEC as an alternative to the open approach.

Risk-reducing laparoscopic cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for low-grade appendiceal mucinous neoplasm: early outcomes and technique.

The electroretinogram (ERG, retina) and visual evoked potential (VEP, brain) are widely used in vivo tools assaying the integrity of the visual pathway. Current recordings in preclinical models are conducted under anesthesia, which alters neural physiology and contaminates responses. We describe a conscious wireless ERG and VEP recording platform in rats. Using a novel surgical technique to chronically implant electrodes subconjunctivally on the eye and epidurally over the visual cortex, we are able to record stable and repeatable conscious ERG and VEP signals over at least 1 month. We show that the use of anaesthetics, necessary for conventional ERG and VEP measurements, alters electrophysiology recordings. Conscious visual electrophysiology improves the viability of longitudinal studies by eliminating complications associated with repeated anaesthesia. It will also enable uncontaminated assessment of drug effects, allowing the eye to be used as an effective biomarker of the central nervous system.

Conscious wireless electroretinogram and visual evoked potentials in rats.

We describe a novel approach to analyze fluorescein angiography to investigate fluorescein flow dynamics in the rat posterior retina as well as identify abnormal areas following laser photocoagulation.

Quantitative spatial and temporal analysis of fluorescein angiography dynamics in the eye.

The National Adult Immunization Plan: Strengthening Adult Immunization Through Coordinated Action.

Objective. To examine whether retinal electrophysiology is a useful surrogate marker of drug penetrance into the central nervous system (CNS). Materials and Methods. Brain and retinal electrophysiology were assessed with full-field visually evoked potentials and electroretinograms in conscious and anaesthetised rats following systemic or local administrations of centrally penetrant (muscimol) or nonpenetrant (isoguvacine) compounds. Results. Local injections into the eye/brain bypassed the blood neural barriers and produced changes in retinal/brain responses for both drugs. In conscious animals, systemic administration of muscimol resulted in retinal and brain biopotential changes, whereas systemic delivery of isoguvacine did not. General anaesthesia confounded these outcomes. Conclusions. Retinal electrophysiology, when recorded in conscious animals, shows promise as a viable biomarker of drug penetration into the CNS. In contrast, when conducted under anaesthetised conditions confounds can be induced in both cortical and retinal electrophysiological recordings.

Article	Year
The last resort? Staff and client perspectives on physical intervention. Journal of intellectual disabilities : JOID\| PubMed ID: 15937049	2005
4-Fluorosulfonylpiperidines: selective 5-HT2A ligands for the treatment of insomnia. Bioorganic & medicinal chemistry letters\| PubMed ID: 15993598	2005
Comparison of in vivo and ex vivo [3H]flumazenil binding assays to determine occupancy at the benzodiazepine binding site of rat brain GABAA receptors. Neuropharmacology\| PubMed ID: 16697018	2006
2,5-Disubstituted pyridines: the discovery of a novel series of 5-HT2A ligands. Bioorganic & medicinal chemistry letters\| PubMed ID: 17314044	2007
Localisation of melanin-concentrating hormone receptor 1 in rat brain and evidence that sleep parameters are not altered despite high central receptor occupancy. European journal of pharmacology\| PubMed ID: 19540226	2009
Non-basic ligands for aminergic GPCRs: the discovery and development diaryl sulfones as selective, orally bioavailable 5-HT2A receptor antagonists for the treatment of sleep disorders. Bioorganic & medicinal chemistry letters\| PubMed ID: 20493697	2010
Quantitative pharmacological analysis of antagonist binding kinetics at CRF1 receptors in vitro and in vivo. British journal of pharmacology\| PubMed ID: 21449919	2011
A Comparison of the α2/3/5 Selective Positive Allosteric Modulators L-838,417 and TPA023 in Preclinical Models of Inflammatory and Neuropathic Pain. Advances in pharmacological sciences\| PubMed ID: 22162674	2011
Risk-reducing laparoscopic cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for low-grade appendiceal mucinous neoplasm: early outcomes and technique. Surgical endoscopy\| PubMed ID: 24061624	2014
Conscious wireless electroretinogram and visual evoked potentials in rats. PloS one\| PubMed ID: 24069276	2013
Quantitative spatial and temporal analysis of fluorescein angiography dynamics in the eye. PloS one\| PubMed ID: 25365578	2014
The National Adult Immunization Plan: Strengthening Adult Immunization Through Coordinated Action. American journal of preventive medicine\| PubMed ID: 27236479	2016
Retinal Electrophysiology Is a Viable Preclinical Biomarker for Drug Penetrance into the Central Nervous System. Journal of ophthalmology\| PubMed ID: 27239335	2016

Rebecca Fish

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