CNS Adverse Effects: From Functional Observation Battery/Irwin Tests to Electrophysiology.

This chapter describes various approaches for the preclinical assessment of drug-induced central nervous system (CNS) adverse effects. Traditionally, methods to evaluate CNS effects have consisted of observing and scoring behavioral responses of animals after drug is administered. Among several behavioral testing paradigms, the Irwin and the functional observational battery (FOB) are the most commonly used assays for the assessment of CNS effects. The Irwin and FOB are considered good first-tier assays to satisfy the ICH S7A guidance for the preclinical evaluation of new chemical entities (NCE) intended for humans. However, experts have expressed concern about the subjectivity and lack of quantitation that is derived from behavioral testing. More importantly, it is difficult to gain insight into potential mechanisms of toxicity by assessing behavioral outcomes. As a complement to behavioral testing, we propose using electrophysiology-based assays, both in vivo and in vitro, such as electroencephalograms and brain slice field-potential recordings. To better illustrate these approaches, we discuss the implementation of electrophysiology-based techniques in drug-induced assessment of seizure risk, sleep disruption, and cognitive impairment.

Transitioning between systems of care: missed opportunities for engaging adults with serious mental illness and criminal justice involvement.

Individuals with serious mental illness are overrepresented in the criminal justice system and face difficulties accessing mental health services both during incarceration and upon re-entry into the community. This study examines how such individuals describe their experiences receiving care both during and after their time in custody and explores the perspectives of mental health service providers who treat this population upon re-entry. Semi-structured interviews were conducted with 43 individuals identified as having a history of serious mental illness and criminal justice involvement, as well as with 25 providers who have worked with this population. Clients noted the stress of transitioning to criminal justice settings, the uneven availability of services within jail and prison, and the significant challenges faced upon re-entry. Providers reported barriers to working with this population, including minimal coordination with the criminal justice system and challenging behaviors and attitudes on the part of both clients and providers. Findings identify potential target areas for improved care coordination as well as for additional provider education regarding the unique needs of this population.

Incidence of spontaneous arrhythmias in freely moving healthy untreated Sprague-Dawley rats.

Spontaneous arrhythmia characterization in healthy rats can support interpretation when studying novel therapies. Male (n = 55) and female (n = 40) Sprague-Dawley rats with telemetry transmitters for a derivation II ECG. Arrhythmias were assessed from continuous ECG monitoring over a period of 24-48 h, and data analyzed using an automated detection algorithm with 100% manual over-read. While a total of 1825 spontaneous ventricular premature beats (VPB) were identified, only 7 rats (or 7.4%) did not present with any over the recording period. Spontaneous episode(s) of ventricular tachycardia (VT) were noted in males (27%) and females (3%). The incidence of VPB was significantly higher (p < 0.01) during the night time (7 pm-7 am) compared to daytime, while males presented with significantly (p < 0.001) more VPB than females. Most VPB were observed as single ectopic beats, followed by salvos (2 or 3 consecutive VPBs), and VT (i.e. 4 consecutive VPBs). Most VPBs were single premature ventricular contractions (PVCs) (57%), while the remaining were escape complexes (43%). Spontaneous premature junctional complexes (PJC) were also observed and were significantly more frequent during the night, and in males. Lastly, 596 episodes of spontaneous 2nd-degree atrioventricular (AV) block were identified and were significantly more frequent during the day time in males. Most 2nd-degree AV block episodes were Mobitz type I (57%), with a significantly (p < 0.05) higher incidence in males. This work emphasizes the importance of obtaining sufficient baseline data when undertaking arrhythmia analysis in safety study and provides a better understanding of both sex- and time- dependent effects of spontaneous arrhythmias in rats.

Perspectives of Treatment Providers and Clients with Serious Mental Illness Regarding Effective Therapeutic Relationships.

This study explores the nature of clinical therapeutic relationships between mental health treatment providers and high-need clients with serious mental illness who had recently discontinued treatment. Semi-structured qualitative interviews of 56 clients with serious mental illness who had recently discontinued care and 25 mental health treatment providers were completed. Both clients with serious mental illness and treatment providers emphasized the importance of client-focused goal setting, time and availability of treatment providers, a caring approach, and trust and honesty in the relationship. However, clients with serious mental illness placed greater emphasis on goals involving tangible services, a notable area of discord between the two groups. Individuals with serious mental illness and treatment providers agreed regarding several key elements to a positive clinical relationship. Further attention to client goals related to tangible services may serve to improve relationships between treatment providers and high-need clients with serious mental illness.

In silico prediction of hERG inhibition.

The voltage-gated potassium channel encoded by hERG carries a delayed rectifying potassium current (IKr) underlying repolarization of the cardiac action potential. Pharmacological blockade of the hERG channel results in slowed repolarization and therefore prolongation of action potential duration and an increase in the QT interval as measured on an electrocardiogram. Those are possible to cause sudden death, leading to the withdrawals of many drugs, which is the reason for hERG screening. Computational in silico prediction models provide a rapid, economic way to screen compounds during early drug discovery. In this review, hERG prediction models are classified as 2D and 3D quantitative structure-activity relationship models, pharmacophore models, classification models, and structure based models (using homology models of hERG).

Recombinant GABA(B) receptors formed from GABA(B1) and GABA(B2) subunits selectively inhibit N-type Ca(2+) channels in NG108-15 cells.

Efficient transfection of NG108-15 cells with GABA(B) receptor subunits was achieved using polyethylenimine. Baclofen modulated high voltage-activated Ca(2+) current in differentiated cells transfected with GABA(B1) and GABA(B2) receptor subunits or with the GABA(B2) subunit alone, but not with the GABA(B1) subunit alone. Characteristics of the current modulation were very similar for cells transfected with GABA(B1/2) and GABA(B2) subunits. Using antisense oligonucleotides against GABA(B1) subunits and also western immunoblotting, we are able to show that NG108-15 cells contain endogenous GABA(B1) subunits. Therefore, functional receptors can be formed by the combination of native GABA(B1) subunits with transfected GABA(B2) subunits, in agreement with the proposed heteromeric structure of GABA(B) receptors. Finally, we used selective channel blockers to identify the subtypes of Ca(2+) channels that are modulated by GABA(B) receptors. In fact, in differentiated NG108-15 cells, the recombinant GABA(B) receptors couple only to N-type Ca(2+) channels.

Circumventing seizure activity in a series of G protein coupled receptor 119 (GPR119) agonists.

Agonism of GPR119 is viewed as a potential therapeutic approach for the treatment of type II diabetes and other elements of metabolic syndrome. During progression of a previously disclosed candidate 1 through mice toxicity studies, we observed tonic-clonic convulsions in several mice at high doses. An in vitro hippocampal brain slice assay was used to assess the seizure liability of subsequent compounds, leading to the identification of an aryl sulfone as a replacement for the 3-cyano pyridyl group. Subsequent optimization to improve the overall profile, specifically with regard to hERG activity, led to alkyl sulfone 16. This compound did not cause tonic-clonic convulsions in mice, had a good pharmacokinetic profile, and displayed in vivo efficacy in murine models. Importantly, it was shown to be effective in wild-type (WT) but not GPR119 knockout (KO) animals, consistent with the pharmacology observed being due to agonism of GPR119.

Disengagement from care: perspectives of individuals with serious mental illness and of service providers.

OBJECTIVE: This study sought to describe reasons for disengagement from services and practical guidelines to enhance engagement among individuals with serious mental illness and high need for treatment. METHODS: Qualitative interviews were conducted with 56 individuals with serious mental illness and 25 providers recruited from a larger project that used administrative data to identify individuals with serious mental illness who had disengaged from care. Individuals with serious mental illness and providers described reasons for disengagement and effective provider engagement strategies. RESULTS: Individuals with serious mental illness and providers differed in reported reasons for disengagement. Reasons reported by individuals with serious mental illness included services that were not relevant to their needs, inability to trust providers, and a belief that they were not ill. Providers cited lack of insight, stigma, and language and cultural barriers as common reasons for disengagement. Strategies for increasing engagement were grouped into a framework of acceptable, accessible, and available services. Acceptable services reflect a partnership model that fosters support and instills hope; accessible services minimize barriers related to transportation and intake procedures; and available services address recovery needs in addition to treatment of general medical and psychiatric problems. CONCLUSIONS: Individuals with serious mental illness and providers often do not agree on reasons for seeking care. The framework of acceptable, accessible, and available services identifies opportunities for providers to adjust practices and maximize engagement in services among individuals with serious mental illness who are in high need of treatment.

It's good to know: how treatment knowledge and belief affect the outcome of distant healing intentionality for arthritis sufferers.

OBJECTIVE: This small-scale study explores the role of expectancy in response to distant healing by testing two hypotheses: 1) Participants aware of placement in the healing condition will report greater relief than those aware they are not receiving distant healing; 2) Participants who express belief in distant healing will report greater relief than those expressing disbelief. METHODS: Sixty patients were recruited from a rheumatology outpatient clinic, and through online support networks and blogs. Participants were randomly allocated to one of four conditions, those in the healing condition received distant healing from self-reported healers, while participants in the control condition received no intervention. Half of the participants knew their treatment allocation and half were blinded. The primary outcome measures were the General Health Questionnaire (GHQ-12) and the Short-form McGill Pain Questionnaire. The Paranormal Belief Scale and a measure designed to assess belief in distant healing were given to determine if belief was correlated with healing outcomes. RESULTS: Awareness of being a recipient of distant healing appeared to be associated with improved outcomes for those in the healing group. Medium to large improvements in GHQ scores (d=.76) and McGill Pain scores (d=.45) were calculated for the groups aware of their condition. Participants unaware that they were receiving healing showed no evidence of improved outcomes. Belief in healing did not have an effect on self-reported outcomes. CONCLUSIONS: Improvements in reported pain and well-being appear to have been caused by knowledge of allocation in the distant healing condition rather than distant healing alone.

Approaches to seizure risk assessment in preclinical drug discovery.

Assessment of seizure risk traditionally occurs late in the drug discovery process using low-throughput, resource intensive in vivo assays. Such approaches do not allow sufficient time to mitigate risk by influencing chemical design. Early identification using cheaper, higher throughput assays with lower animal and compound requirements would be preferable. Here we review the current techniques available to assess this issue and describe how they may be combined in a rational step-wise cascade allowing more effective assessment of seizure risk.