Long-Term Use of Proton Pump Inhibitors Disrupts Intestinal Tight Junction Barrier and Exaggerates Experimental Colitis.

BACKGROUND: Proton pump inhibitors [PPIs] are widely used to treat a number of gastro-oesophageal disorders. PPI-induced elevation in intragastric pH may alter gastrointestinal physiology. The tight junctions [TJs] residing at the apical intercellular contacts act as a paracellular barrier. TJ barrier dysfunction is an important pathogenic factor in inflammatory bowel disease [IBD]. Recent studies suggest that PPIs may promote disease flares in IBD patients. The role of PPIs in intestinal permeability is not clear. AIM: The aim of the present study was to study the effect of PPIs on the intestinal TJ barrier function. METHODS: Human intestinal epithelial cell culture and organoid models and mouse IBD models of dextran sodium sulphate [DSS] and spontaneous enterocolitis in IL-10-/- mice were used to study the role of PPIs in intestinal permeability. RESULTS: PPIs increased TJ barrier permeability via an increase in a principal TJ regulator, myosin light chain kinase [MLCK] activity and expression, in a p38 MAPK-dependent manner. The PPI-induced increase in extracellular pH caused MLCK activation via p38 MAPK. Long-term PPI administration in mice exaggerated the increase in intestinal TJ permeability and disease severity in two independent models of DSS colitis and IL-10-/- enterocolitis. The TJ barrier disruption by PPIs was prevented in MLCK-/- mice. Human database studies revealed increased hospitalizations associated with PPI use in IBD patients. CONCLUSIONS: Our results suggest that long-term use of PPIs increases intestinal TJ permeability and exaggerates experimental colitis via an increase in MLCK expression and activity.

Biomarkers for response in major depression: comparing paroxetine and venlafaxine from two randomised placebo-controlled clinical studies.

The identification of biomarkers of response might speed drug development and set the premises to assist clinical practice in psychiatry. In this work, we evaluated a panel of peripheral biomarkers (including IL-6, IL-10, TNF-α, TNFRII, BDNF, CRP, MMP9 and PAI1) in depressed patients receiving paroxetine, venlafaxine, or placebo. Samples were obtained from two randomised placebo-controlled studies evaluating the efficacy and tolerability of a novel drug candidate, using either paroxetine or venlafaxine as active comparators. In both studies, the biomarker candidates were analysed in plasma collected at randomization and after 10 weeks of treatment with either placebo or active comparator (for a total of 106 and 108 subjects in the paroxetine and venlafaxine study, respectively). Data were obtained by multiplexing sandwich-ELISA system. Data were subjected to statistical analysis to assess their correlation with baseline severity and with response outcome. Increases in biomarker levels were correlated with reduction in depression severity for TNF-α, IL-6 IL-10 and CRP. Response to paroxetine treatment correlated with baseline IL-10, IL-6 and TNF-α levels, with the strongest signal being observed in males. In the venlafaxine study, a correlation was observed only between CRP level at randomisation and response, suggesting differences between the two active treatments and the two studies. Our investigations suggest that a combination of pro- and anti-inflammatory cytokines may predict response outcome in patients treated with paroxetine. The potential for IL-10, IL-6 and TNF-α as response biomarkers for a wider range of antidepressants warrants further investigations in clinical trials with other monoamine reuptake inhibitors.

GABAA receptor occupancy by subtype selective GABAAα2,3 modulators: PET studies in humans.

RATIONALE: Sedation, dependence, and abuse liability limit the use of non-selective γ-aminobutyric acid (GABAA) receptor positive modulators for the treatment of anxiety. AZD7325 and AZD6280 are novel, subtype-selective GABAAα2,3 receptor positive modulators with limited sedative effects. OBJECTIVES: The current study aimed to confirm target engagement at GABAA receptors by AZD7325 and AZD6280 in humans and to determine the relationship between exposure, GABAA receptor occupancy, and tolerability. METHOD: Two PET studies, using high-resolution research tomography (HRRT) and the radioligand [11C]flumazenil, were performed in 12 subjects at baseline and after administration of single oral doses of AZD7325 (0.2 to 30 mg) and AZD6280 (5 to 40 mg). PET images were analyzed using a simplified reference tissue model, and regional binding potentials (BPND) were obtained. The relationship between plasma concentration of AZD7325 or AZD6280 and GABAA receptor occupancy was described by hyperbolic function, and K i,plasma (plasma concentration required for 50% receptor occupancy) was estimated. Assessments of safety and tolerability included recording of adverse events, vital signs, electrocardiogram, and laboratory tests. RESULTS: The [11C]flumazenil binding was reduced in a dose-dependent, saturable manner by both agents. Maximum receptor occupancy could be reached for both compounds without causing sedation or cognitive impairment. The K i,plasma estimates for AZD7325 and AZD6280 were 15 and 440 nmol/l, respectively. CONCLUSION: High GABAA receptor occupancy by AZD7325 and AZD6280 could be reached without clear sedative effects.

Comparing the actions of lanicemine and ketamine in depression: key role of the anterior cingulate.

Intravenous infusion of lanicemine (formerly AZD6765), a low trapping non-selective N-methyl-D-aspartate (NMDA) receptor antagonist, induces antidepressant effects with a similar time course to ketamine. We investigated whether a single dose lanicemine infusion would reproduce the previously reported decrease in subgenual anterior cingulate cortex (sgACC) activity evoked by ketamine, a potential mechanism of antidepressant efficacy. Sixty un-medicated adults meeting the criteria for major depressive disorder were randomly assigned to receive constant intravenous infusions of ketamine, lanicemine or saline during a 60min pharmacological magnetic resonance imaging (phMRI) scan. Both ketamine and lanicemine gradually increased the blood oxygen level dependent signal in sgACC and rostral ACC as the primary outcome measure. No decreases in signal were seen in any region. Interviewer-rated psychotic and dissociative symptoms were minimal following administration of lanicemine. There was no significant antidepressant effect of either infusion compared to saline. The previously reported deactivation of sgACC after ketamine probably reflects the rapid and pronounced subjective effects evoked by the bolus-infusion method used in the previous study. Activation of the ACC was observed following two different NMDA compounds in both Manchester and Oxford using different 3T MRI scanners, and this effect predicted improvement in mood 1 and 7 days post-infusion. These findings suggest that the initial site of antidepressant action for NMDA antagonists may be the ACC (NCT01046630. A Phase I, Multi-centre, Double-blind, Placebo-controlled Parallel Group Study to Assess the pharmacoMRI Effects of AZD6765 in Male and Female Subjects Fulfilling the Criteria for Major Depressive Disorder; http://clinicaltrials.gov/show/NCT01046630).

Radiochemical synthesis and in vivo evaluation of [18F]AZ11637326: an agonist probe for the α7 nicotinic acetylcholine receptor.

INTRODUCTION: The alpha-7 nicotinic acetylcholine receptor (α7 nAChR) is key in brain communication and has been implicated in the pathophysiology of diseases of the central nervous system. A positron-emitting radioligand targeting the α7 nAChR would enable better understanding of a variety of neuropsychiatric illnesses, including schizophrenia and Alzheimer's disease, and could enhance the development of new drugs for these and other conditions. We describe our attempt to synthesize an α7 nAChR-selective radiotracer for positron emission tomography (PET). METHODS: We prepared the high-affinity (K(d) = 0.2 nM) α7 nAChR agonist, 5'-(2-[(18)F]fluorophenyl)spiro[1-azabicyclo-[2.2.2]octane]-3,2'-(3'H)furo[2,3-b]pyridine, [(18)F]AZ11637326, in two steps, a nucleophilic fluorination followed by decarbonylation. We studied [(18)F]AZ11637326 in rodents, including mice lacking α7 nAChR, and in non-human primates. RESULTS: [(18)F]AZ11637326 was synthesized in a non-decay-corrected radiochemical yield of 3% from the end of synthesis (90 min) with a radiochemical purity >90% and average specific radioactivity of 140GBq/µmol (3,781 mCi/µmol). Modest rodent brain uptake was observed (2-5% injected dose per gram of tissue, depending on specific activity), with studies comparing CD-1 and α7 nAChR null mice indicating an element of target-specific binding. Blocking studies in non-human primates did not reveal specific binding within the brain. CONCLUSION: Despite the high affinity and target selectivity of AZ11637326 for α7 nAChR in vitro and encouraging rodent studies, receptor-mediated binding could not be demonstrated in non-human primates. Further structural optimization of compounds of this class will be required for them to serve as suitable radiotracers for PET.

A PET study with [11C]AZ10419369 to determine brain 5-HT1B receptor occupancy of zolmitriptan in healthy male volunteers.

AIM: To investigate the occupancy at brain 5-hydroxytryptamine (5-HT) 1B receptors in human subjects after administration of the antimigraine drug zolmitriptan. METHODS: Positron emission tomography (PET) studies were undertaken using the radioligand [(11)C]AZ10419369 in eight control subjects at baseline and after administration of zolmitriptan orodispersible tablets. The subjects were examined after two consecutive administrations of 10 mg zolmitriptan, approximately 1 week apart. Two of the subjects were subsequently examined after administration of 5 mg zolmitriptan. One week after the last administration of zolmitriptan five of the subjects underwent additional PET measurements without drug pretreatment. RESULTS: After administration of 10 mg zolmitriptan, mean receptor occupancy was 4-5%. No consistent changes in 5-HT1B receptor binding were observed for subjects who received 5 mg zolmitriptan. There was a statistically significant negative relationship between binding potential ( BP ND) and plasma concentration of zolmitriptan and the active metabolite 183C91, respectively. All of the five subjects who were examined 1 week after dosing with zolmitriptan showed higher BP ND post drug administration compared with baseline. CONCLUSION: This is the first demonstration of CNS 5-HT1B receptor occupancy of a triptan. The findings are consistent with the low receptor occupancy previously reported in PET studies with agonists at other G protein coupled receptors.

Glutamate-based depression GBD.

We describe a new term: glutamate-based depression (GBD). GBD is defined as a chronic depressive illness associated with environmental stress and diseases associated with altered glutamate neurotransmission. We hypothesize that glutamate-induced over-activation of extrasynaptic NMDA receptors in the subgenual cingulate area called Brodmann's 25 plays an important role in the etiology of depression and may be responsible for the high incidence of co-morbid depression associated in diseases with glutamate etiology. While depression is a syndrome with multiple possible etiologies, we propose that a disruption in glutamatergic neurotransmission may underline a substantial proportion of clinically observed depression. The high rates of depressive symptoms associated with various disorders in which altered glutamatergic functions have been identified, may suggest a common pathophysiological mechanism is underlying the diverse clinical presentations.

2,6-Disubstituted pyrazines and related analogs as NR2B site antagonists of the NMDA receptor with anti-depressant activity.

Herein we describe the discovery of compounds that are competitive antagonists of the CP101-606 binding site within the NR2B subtype of the NMDA receptor. The compounds identified do not possess phenolic functional groups such as those in ifenprodil and related analogs. Initial identification of hits in this series focused on a basic, secondary amine side chain which led to good potency, but also presented a hERG liability. Further modifications led to examples of non-basic replacements which demonstrated much less liability in this regard. Finally, one compound in the series, 6a, was tested in the mouse forced swim depression assay and found to show activity (s.c. 60 mg/kg).

Dose-dependent binding of AZD3783 to brain 5-HT1B receptors in non-human primates and human subjects: a positron emission tomography study with [11C]AZ10419369.

RATIONALE: The serotonin 5-HT(1B) receptor is a potential target for the pharmacologic treatment of depression. Positron emission tomography (PET) determination of 5-HT(1B) receptor occupancy with drug candidates targeting this receptor in non-human primate and human subjects may facilitate translation of research from animal models and guide dose selection for clinical studies. AZD3783 is a recently developed, orally bioavailable 5-HT(1B) receptor antagonist with potential antidepressant properties. OBJECTIVES: To determine the relationship between plasma concentration of AZD3783 and occupancy at primate brain 5-HT(1B) receptors using PET and the radioligand [(11)C]AZ10419369. METHODS: PET studies with [(11)C]AZ10419369 were performed in three non-human primates at baseline and after intravenous injection of AZD3783. Subsequently, PET measurements were undertaken in six human subjects at baseline and after administration of different single oral doses of AZD3783 (1-40 mg). RESULTS: After administration in non-human primates and human subjects, AZD3783 reduced regional [(11)C]AZ10419369 binding in a dose-dependent and saturable manner. The AZD3783 plasma concentration required for 50% receptor occupancy (K (i,plasma)) for monkeys was 25 and 27 nmol/L in occipital cortex and striatum, respectively. Corresponding estimates for human occipital cortex and ventral striatum were 24 and 18 nmol/L, respectively. CONCLUSIONS: The potential antidepressant AZD3783 binds in a saturable manner to brain 5-HT(1B) receptors with a similar in vivo affinity for human and monkey receptors. [(11)C]AZ10419369 can be successfully used to determine occupancy at brain 5-HT(1B) receptors in vivo and constitutes a useful tool for dose selection in clinical studies with 5-HT(1B) receptor compounds.

Quantitative analysis of [11C]AZ10419369 binding to 5-HT1B receptors in human brain.

A novel radioligand for positron emission tomography (PET) imaging of serotonin 5-HT(1B) receptors, [(11)C]AZ10419369, has been recently described. In this study, the potential for quantitative analysis of [(11)C]AZ10419369 binding to central 5-HT(1B) receptors was evaluated in human subjects. PET measurements were performed after injection of [(11)C]AZ10419369 in 10 subjects. Data were analyzed with kinetic modeling and linear graphical analysis using the arterial plasma as input function, and with reference tissue models using cerebellar cortex as the reference region. Binding of [(11)C]AZ10419369 was highest in pallidum, ventral striatum, and occipital cortex and lowest in cerebellum. The percentage of unchanged radioligand in plasma was 97% to 99%, indicating that no significant amounts of radioactive metabolites were formed during the time of analysis. Time-activity curves of [(11)C]AZ10419369 could be described with both one-tissue compartment (1-TC) and two-tissue compartment (2-TC) models in the majority of subjects. The 2-TC model failed to deliver reasonable estimates of the kinetic parameters. However, stable estimates of binding potential (BP(ND)) were obtained by constraining K(1)/k(2) to the distribution volume obtained with the 1-TC model in the cerebellar cortex. BP(ND) values estimated with reference tissue models were correlated with the corresponding values obtained with kinetic modeling. The findings support the use of reference tissue models in applied clinical studies with [(11)C]AZ10419369.

Experimental solubility profiling of marketed CNS drugs, exploring solubility limit of CNS discovery candidate.

We determined the experimental solubility of CNS marketed drugs. Of the 98 drugs measured, greater than 90% had solubility >10 µM in pH 7.4 buffer. Only seven drugs had solubility <10 µM. Using these data, we established a solubility criterion to support CNS discovery. The implication of poor solubility with potential safety concerns and undesirable side effects are discussed.

Traumatic brain injury and driving assessment: an evidence-based literature review.

OBJECTIVE: We conducted a literature review of assessment tools predicting driving performance for people with traumatic brain injury (TBI). METHOD: Data sources were Web of Science, EBSCOhost, PubMed, and recently published literature from experts and team members not yet catalogued in the databases. We used the American Academy of Neurology's classification criteria to extract data from 13 studies, and we assigned a class (I-IV, with I being the highest level of evidence) to each study. We grouped primary studies into categories of driving assessment (neuropsychological; simulator; off-road; self-report, other report, and postinjury disability status; and comprehensive driving evaluation) and synthesized the predictability of these tools as it relates to driving performance for people with TBI. CONCLUSIONS: To assist clinicians and researchers in making decisions regarding testing the driving performance of people with TBI, we provide recommendations for neuropsychological tests; off-road tests; self-report, other report, and postinjury disability status; and comprehensive driving evaluation.

In defence of the 'low-mileage bias'.

There has been a long-recognised association between extent of driving and crash involvement: the lower the annual mileage driven, the higher the per-distance crash rate. Because older drivers generally drive less distance per year than others, this association has been used to explain much of their apparent over-involvement in crashes. Several studies from different countries around the world have demonstrated this 'low-mileage bias' and the relative safety of older drivers. However all studies have relied upon self-reported crash involvement and driving activity. Staplin et al. [Staplin, L., Gish, K., Joyce, J., 2008. 'Low mileage bias' and related policy implications-a cautionary note. Accident Analysis and Prevention 40, 1249-1252] have drawn attention to the discrepancy between self-reported and odometer-based driving distances and have argued against the credibility of the low-mileage bias. This paper has re-worked initial data from an early study which supported low-mileage bias, this time using odometer-based readings rather than self-reported mileage. Accepting the odometer readings at face value, the low-mileage bias remains evident, albeit at a reduced level.

[11C]AZ10419369: a selective 5-HT1B receptor radioligand suitable for positron emission tomography (PET). Characterization in the primate brain.

The 5-HT1B receptor has been implicated in several psychiatric disorders and is a potential pharmacological target in the treatment of depression. Here we report the synthesis of a novel PET radioligand, [11C]AZ10419369 (5-methyl-8-(4-methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic acid (4-morpholin-4-yl-phenyl)-amide), for in vivo visualization of 5-HT1B receptors in the brains of macaques and humans subjects. [11C]AZ10419369 was prepared by N-methylation of (8-(1-piperazinyl)-5-methylchrom-2-en-4-one-2-(4-morpholinophenyl) carboxamide, using carbon-11 methyl triflate. Regional brain uptake patterns of [11C]AZ10419369 were characterized by PET measurements in two macaques and a preliminary study in two human subjects. In addition, AZ10419369 was prepared in tritium labeled form for in vitro autoradiography studies in macaque brain tissue sections. The radiochemical purity of [11C]AZ10419369 was >99% and specific radioactivity was >3600 Ci/mmol. After iv injection of [11C]AZ10419369, 3-4% was in brain after 7.5 min. The regional brain distribution of radioactivity was similar in humans and macaques showing the highest uptake of radioactivity in the occipital cortex and the basal ganglia, in accord with autoradiographic studies performed using [3H]AZ10419369. Uptake was moderate in the temporal and frontal cortical regions, lower in the thalamus and lowest in the cerebellum. In macaques pre-treated with the selective 5-HT1B receptor antagonist, AR-A000002, binding was reduced in a dose-dependent manner, consistent with specific binding to 5-HT1B receptors. These data support [11C]AZ10419369 as a suitable radioligand for labeling 5-HT1B receptors in the primate brain. This radioligand may be useful in future studies evaluating drug-induced receptor occupancy and measurement of brain 5-HT1B receptor levels in patients with psychiatric disorders.

Predictability of clinical assessments for driving performance.

PROBLEM: As the number of older drivers grows, it is increasingly important to accurately identify at-risk drivers. This study tested clinical assessments predictive of real-time driving performance. METHOD: Selected assessment tools considered important in the identification of at-risk older drivers represented the domains of vision, cognition, motor performance, and driving knowledge. Participants were administered the battery of assessments followed by an on-road test. A univariate analysis was conducted to identify significant factors (<.05) to be included in a multivariate regression model. RESULTS: Assessments identified as independently associated with driving performance in the regression model included: FACTTM Contrast sensitivity slide-B, Rapid Pace Walk, UFOV rating, and MMSE total score. DISCUSSION: The domains of vision, cognitive, and motor performance were represented in the predictive model. SUMMARY: Due to the dynamic nature of the driving task, it is not likely that a single assessment tool will identify at risk drivers. IMPACT ON INDUSTRY: By standardizing the selection of clinical assessments used in driving evaluations, practitioners should be able to provide services more efficiently, more objectively, and more accurately to identify at-risk drivers.

The impact of roadway intersection design on driving performance of young and senior adults.

OBJECTIVE: To test the effectiveness of the FHWA guidelines for intersection design. METHODS: In an experimental design we used kinematics measures from an instrumented vehicle and behavioral (error) data collected during on-road evaluations to quantify the effects of improved versus unimproved intersections (turn phase) and to determine if these intersections were safer (vehicular stability and driver confidence) for both older (65-85 years) and younger (25 -45) drivers. We analyzed kinematics data with a 2 x 2 repeated measures ANOVA and behavioral data (driving errors yes, no) with Wilcoxon sign rank test (within subject variable: intersection improved vs. unimproved) and Wilcoxon rank sum test (between subject variable: age, younger vs. older driver). RESULTS: Kinematics measures (turn phase), showed three maneuvers had statistically significantly lesser side forces (measured by lateral acceleration and combined acceleration) for the improved conditions, and four maneuvers had statistically significantly greater, yet appropriate, speeds for the improved conditions. Lesser side forces indicated improved lateral stability and increased speed indicated greater confidence. Drivers made fewer errors on two of the improved intersections; but across all maneuvers, older drivers appeared to make fewer errors on the improved intersections. CONCLUSIONS: This study brings empirical intersection design and safety information for engineers and city planners to consider as they plan and develop intersections. Future researchers may want to use the conceptual and analytical framework of this study to determine the effectiveness of other FHWA guidelines. Given that these intersection design guidelines benefit younger and older drivers alike, plausible policy-making opportunities are opened in the design of safe roadway systems, to benefit the broad spectrum of adult drivers.

The impact of intersection design on simulated driving performance of young and senior adults.

PURPOSE: The Federal Highway Administration (FHWA) proposed guidelines for highway design to increase the safe driving ability of older drivers; however, little empirical evidence exists to support the effectiveness of these guidelines. The purpose of this study was to investigate the effects of implementing these guidelines (in 4 pairs of intersections) on safe driving performance of older and younger drivers using a high-fidelity driving simulator. DESIGN AND METHODS: We replicated four intersection pairs (improved versus unimproved) in a high-fidelity, virtual reality driving simulator. Simulator scenarios were created from actual road locations, replicating road geometrics and traffic control devices. The simulator's controls were integrated with an actual vehicle to make the driving experience as realistic as possible. Kinematic measures were obtained from the simulator in conjunction with driving errors recorded by trained driving evaluators sitting in the cab of the car. Thirty-nine subjects, 19 younger and 20 older adults, participated in the study. RESULTS: For the kinematic data we found greater lateral control, as indicated by significantly smaller maximum yaw during the turn phase, at all of the improved intersections when compared to the unimproved intersections. We found some significant age differences, but mostly in only one of the intersection-pairs. For the behavioral data, there were significant differences in driving errors between improved and unimproved intersections in two intersection-pairs; however, there were no significant differences in driving errors between the older and younger drivers. IMPLICATIONS: The findings suggest that both young and older drivers may benefit from roadways with safety features recommended by the FHWA guidelines as indicated by the increased lateral control of the vehicle when negotiating these intersections. These findings generate critical information for those involved in the design of roadway systems.

Synthesis and biodistribution of radiolabeled alpha 7 nicotinic acetylcholine receptor ligands.

UNLABELLED: Our objective was to develop an array of alpha(7)-selective nicotinic cholinergic receptor (nAChR)-based imaging agents for PET and SPECT. METHODS: (2'R)-N-(11)C-Methyl-N-(phenylmethyl)-spiro[1-azabicyclo[2.2.2]octane-3,2'(3'H)-furo[2,3-b]pyridin]-5'-amine 1 was synthesized by reaction of the corresponding desmethyl precursor with (11)C-CO(2) and reduction. N-(R)-1-Aza-bicyclo[2.2.2]oct-3-yl-4-(11)C-methylsulfanyl-benzamide 2 was synthesized by reduction of the corresponding disulfide precursor and reaction with (11)C-iodomethane. N-(R)-1-Aza-bicyclo[2.2.2]oct-3-yl-4-(125)I-iodo-benzamide 3 was synthesized by halogen exchange of the corresponding bromide. (2'R)-5'-(2-(125)I-iodo-3-furanyl)spiro[1-azabicyclo[2.2.2]octane]-3,2'(3'H)-furo[2,3-b]pyridine 4 was synthesized by the chloramine-T method. Kinetic biodistribution studies were done in male CD-1 mice by tail vein injection of 3.7 MBq (100 microCi) of the (11)C-labeled radiotracer or 0.67 MBq (2 microCi) of the (125)I-labeled radiotracer followed by brain dissection and tissue counting. Receptor blockade was determined by pretreatment of the mice with an excess of either unlabeled precursor or nicotine. RESULTS: We synthesized 4 radiolabeled, moderate- to high-affinity, alpha(7)-nAChR-based ligands. The compounds were a series of quinuclidine derivatives with an inhibition constant (K(i)) < 6 nmol/L (33 pmol/L for 4) for alpha(7)-nAChR and selectivities of alpha(7)/alpha(4)beta(2) subtypes of > or =14,000. All of the compounds were produced in adequate radiochemical yield and specific radioactivity (>74 GBq/micromol [2,000 Ci/mmol]). No site selectivity or receptor blockade was shown for 1 and 2 (0.91 +/- 0.05 and 0.14 +/- 0.03 %ID/g [percentage injected dose per gram] in the hippocampus [target tissue], respectively). Compound 3 showed low hippocampal uptake (0.25 +/- 0.05 %ID/g) but prolonged retention within that structure. Pretreatment with nicotine decreased its uptake by up to 50% in the hippocampus. Similar reductions were also observed within the cerebellum (nontarget tissue). Compound 4 showed hippocampal uptake of 2.41 +/- 0.03 %ID/g and target-to-nontarget uptake ratios of up to 2. Pretreatment of animals with unlabeled 4 resulted in a decrease of hippocampal uptake to 60% of its preblockade value without a corresponding decrease in cerebellar uptake. CONCLUSION: With further structural optimization, selective imaging of alpha(7)-nAChR may be possible.

International Older Driver Consensus Conference on Assessment, Remediation and Counseling for Transportation Alternatives: Summary and Recommendations.

On December 1 and 2, 2003, 63 international experts on older driver issues met to examine three critical issues related to the safe mobility of older drivers. Conference participants addressed standards and protocols for screening and evaluating the skills of older drivers. For drivers judged to lack the necessary skills to drive safely, participants addressed methods of remediation that could enable older persons with limited cognitive or physical abilities to continue to drive. For those persons whose skills are judged inadequate for safe driving, conference participants addressed the question as to how best to counsel individuals and their caregivers on practical alternatives to driving.Consensus was achieved as to the current methods for best assessing and screening drivers, remediation techniques, and providing advice and counsel for those persons and the caregivers as to appropriate actions for those no longer able to drive safely.