4-Oxypiperidine Ethers as Multiple Targeting Ligands at Histamine H3 Receptors and Cholinesterases.

This study examines the properties of a novel series of 4-oxypiperidines designed and synthesized as histamine H3R antagonists/inverse agonists based on the structural modification of two lead compounds, viz., ADS003 and ADS009. The products are intended to maintain a high affinity for H3R while simultaneously inhibiting AChE or/and BuChE enzymes. Selected compounds were subjected to hH3R radioligand displacement and gpH3R functional assays. Some of the compounds showed nanomolar affinity. The most promising compound in the naphthalene series was ADS031, which contained a benzyl moiety at position 1 of the piperidine ring and displayed 12.5 nM affinity at the hH3R and the highest inhibitory activity against AChE (IC50 = 1.537 µM). Eight compounds showed over 60% eqBuChE inhibition and hence were qualified for the determination of the IC50 value at eqBuChE; their values ranged from 0.559 to 2.655 µM. Therapy based on a multitarget-directed ligand combining H3R antagonism with additional AChE/BuChE inhibitory properties might improve cognitive functions in multifactorial Alzheimer's disease.

The introduction of mindfulness groups to a psychiatric rehabilitation in-patient setting: a feasibility study.

BACKGROUND: Patients within psychiatric rehabilitation services have multiple, complex and enduring difficulties, and are frequently described as 'treatment resistant'. This group have diagnoses of major mental health conditions, most commonly schizophrenia, often alongside a history of complex trauma, co-morbid alcohol/ substance misuse, and cognitive impairment. There is no known effective medical treatment other than Clozapine in this patient group, however, there is preliminary evidence that mindfulness can help individuals with psychosis by improving their ability to cope with stressful internal experiences. This study aimed to determine if mindfulness practice groups are an acceptable therapeutic intervention in an in-patient rehabilitation setting. The study also aimed to monitor the well-being of those who participated. METHODS: Mindfulness practice groups were offered three times weekly on a 15-bedded rehabilitation ward in a psychiatric hospital over 5 months, and weekly in a second ward over an 18 month period. The sessions were delivered by Clinical Psychologists in accordance with adaptations for a psychosis population. Attendance data were gathered on both wards and additional measures of well-being were collected on one ward. Qualitative interviews were conducted with a sample of patients, group facilitators, and staff, to provide supplementary information about the acceptability of the intervention. RESULTS: In both wards around two thirds (65, 67%) of in-patients attended at least one group and smaller proportion (around a third) went on to attend regularly. There was no discernible impact on well-being using the Warwick-Edinburgh well-being scale. Qualitative interviews suggested a number of benefits to individuals attending as well as the potential for groups to enhance the therapeutic culture within wards. CONCLUSIONS: Clinical guidelines suggest that all patients with a diagnosis of psychosis should have access to psychological therapies, but delivering psychological therapy within an in-patient rehabilitation setting can be challenging. This preliminary feasibility study suggests that mindfulness practice groups are an acceptable intervention, and that further research to look at the effectiveness of mindfulness for symptoms of treatment-resistant psychosis is both possible and merited.

Modulatory effect of insulin on T cell receptor mediated calcium signaling is blunted in long lasting type 1 diabetes mellitus.

Insulin significantly influences Ca(2+) signals evoked by various stimulants. In type 1 recent onset diabetes mellitus the proliferative response of T cells is significantly decreased. The number of clinical trials exploring the role of anti-CD3 monoclonal antibodies (mAb) as a therapeutic agent in recent onset diabetes mellitus type 1 is increasing last years. Therefore, a better understanding of the interplay between T cell receptor (TCR) dependent Ca(2+) increase, and insulin is of vital clinical significance. The aim of the study was to assess the effect of insulin on TCR evoked Ca(2+) responses in T lymphocytes obtained from healthy volunteers and patients suffering from long lasting diabetes mellitus type 1. Analysis was performed with use of the flow cytometer. We demonstrated that T cells ability to mobilize Ca(2+) was significantly reduced in long lasting diabetes mellitus type 1. Ca(2+) decrease achieved by the long term incubation with anti-CD3 mAb in T cells from healthy volunteers was restored by insulin. Strong interrelationship between baseline Ca(2+) level and plateau phase response to TCR stimulation was observed in the cytoplasm of cells pre-incubated with insulin from both healthy subjects and diabetic patients (r = 0.95, p < 0.0001 and r = 0.94, p < 0.0001, respectively). We postulate the existence of the interplay between TCR mediated activation and insulin. The TCR-insulin interplay is blunted in long lasting diabetes mellitus type 1. These observations may have an important implication for future therapeutic options in diabetes.

Effects of the Valsalva maneuver on pial artery pulsation and subarachnoid width in healthy adults.

AIM: The objective was to characterize the effects of Valsalva maneuver (VM) on the amplitude of cerebrovascular pulsation (CVP), and to explore the direct interactions between the cerebral vasculature and the cerebrospinal fluid compartment in VMIII. METHODS: Twenty-nine healthy volunteers between the ages of 25 and 40 (29.3 ± SE 4.0) were studied. Changes in the amplitude of CVP (cc-TQ) and width of subarachnoid space (SAS; sas-TQ) were recorded with NIR-T/BSS sensor. Changes in arterial blood pressure (ABP) and heart rate were measured using Finapres. Cerebral blood flow velocity (CBFV) in the left middle cerebral artery was recorded with transcranial doppler. RESULTS: sas-TQ remained unchanged, while cc-TQ increased in VMI (+40% vs. baseline). In VMIIa, sas-TQ increase (+3.4% vs. baseline) and deep decrease in cc-TQ (-81% vs. baseline) were observed. sas-TQ decrease started in VMIIb (-2.7% vs. baseline), with simultaneous slight increase in cc-TQ (-58% vs. baseline). In VMIII deep sas-TQ decrease (-6.2% vs. baseline) was associated with huge increase in cc-TQ (+110% vs. baseline; r=-0.56, p<0.01). During VMIV sas-TQ increased (-4.8% vs. baseline) while cc-TQ decreased (+38% vs. baseline). The drop of cc-TQ in VMIIa was significantly greater than corresponding changes in CBFV and ABP. Increase in cc-TQ in VMIII preceded CBFV and ABP changes in VMIV. CONCLUSION: The VM evokes significant changes in the amplitude of CVP. Changes in small vessel pulsation precede changes in CBFV. There are direct interactions between cc-TQ and sas-TQ in VMIII. NIR-T/BSS allows for continuous, non-invasive monitoring of the amplitude of CVP and width of the SAS.