Robert Lai

The effects of the TRPV1 antagonist SB-705498 on TRPV1 receptor-mediated activity and inflammatory hyperalgesia in humans.

Abstract TRPV1 is a cation channel activated by a range of noxious stimuli and highly expressed in nociceptive fibres. TRPV1 receptors are involved in pain and sensitisation associated with tissue injury and inflammation; hence, TRPV1 antagonists are potentially useful for the treatment of such pain states. SB‐705498 is a potent, selective and orally bioavailable TRPV1 antagonist with demonstrated efficacy in a number of preclinical pain models. In this first‐time‐into‐human study, we have investigated the pharmacodynamic and antihyperalgesic activity of SB‐705498. The compound was safe and well tolerated at single oral doses up to 400 mg. In a cohort of 19 healthy volunteers, we used a randomised placebo‐controlled single‐blind cross‐over design to assess the effects of SB‐705498 (400 mg) on heat‐evoked pain and skin sensitisation induced by capsaicin or UVB irradiation. Compared with placebo, SB‐705498 reduced the area of capsaicin‐evoked flare (P = 0.0047). The heat pain threshold on non‐sensitised skin was elevated following SB‐705498 (estimated difference from placebo [95% confidence intervals]: 1.3 °C [0.07, 2.53], P = 0.019). Following capsaicin sensitisation, the heat pain threshold and tolerance were similar between SB‐705498 and placebo. However, SB‐705498 increased heat pain tolerance at the site of UVB‐evoked inflammation (estimated difference from placebo: 0.93 °C [0.25, 1.6], P = 0.0054). The magnitude of the pharmacodynamic effects of SB‐705498 appeared to be related to plasma concentration. These results indicate that SB‐705498, at a clinically safe and well‐tolerated dose, has target‐specific pharmacodynamic activity in humans. These data provide the first clinical evidence that a TRPV1 antagonist may alleviate pain and hyperalgesia associated with inflammation and tissue injury.

Chronic oral gabapentin reduces elements of central sensitization in human experimental hyperalgesia

Background:In chronic pain, increased activity from intact or damaged peripheral nerve endings results in an enhanced response in central pain transmission systems, a mechanism known as central sensitization. Central sensitization can also be invoked in human experimental models. Therefore, these models may be useful to characterize novel analgesics in humans. The anticonvulsant gabapentin has demonstrated efficacy in patients with neuropathic pain, but its mode of action remains unclear. This study examined the effects of gabapentin on signs of central sensitization (brush and pinprick hyperalgesia) in a human model of capsaicin-evoked pain, using a gabapentin dosing regimen similar to that used in the clinic. The aims were to determine whether gabapentin, dosed in a manner similar to that used in the clinic, affected the various components of central sensitization and to assess the utility of this model for characterizing novel analgesics. Methods:Intradermal capsaicin (100 &mgr;g/20 &mgr;l) was administered in the volar forearm of 41 male human volunteers to induce pain and clinical signs of central sensitization. Gabapentin (titrated to 2,400 mg daily) or placebo was given orally for 15 days in a randomized, double-blind, parallel-group design. The capsaicin test was conducted at baseline and after gabapentin or placebo. Endpoints were the size of areas of brush-evoked allodynia (with cotton gauze) and pinprick hyperalgesia (with von Frey filament), and the intensity of ongoing brush- and pinprick-evoked pain. Results:Gabapentin significantly reduced the area of brush allodynia compared with placebo (P ≤ 0.05) and insignificantly attenuated the area of pinprick hyperalgesia. Gabapentin had no significant effect on spontaneous and evoked pain intensity. Conclusion:Oral gabapentin, administered to healthy volunteers in a regimen similar to that used in treating chronic neuropathic pain, reduces measures of central sensitization evoked by intradermal capsaicin. This suggests that the pain-relieving effect in chronic neuropathic pain condition is linked to the effect of gabapentin on central sensitization. The ability of the capsaicin model to detect the efficacy of this standard treatment of neuropathic pain suggests that it may have a predictive value for detection of efficacy in human subjects.

Clinical trial of the p38 MAP kinase inhibitor dilmapimod in neuropathic pain following nerve injury

Current treatments of neuropathic pain arising from conditions such as nerve injury/compression are only partially effective, and limited in their use by side‐effects. p38 mitogen‐activated protein kinase (MAPK) is involved in the regulation and synthesis of inflammatory mediators, and is the target for a novel class of cytokine‐suppressive anti‐inflammatory drugs. p38 inhibitors may reduce neuronal sensitisation in preclinical models of neuropathic pain, particularly where there is a substantial inflammatory component. An exploratory, multicentre, double‐blind, placebo‐controlled, two‐period, cross‐over trial was undertaken to evaluate the effect of dilmapimod (SB‐681323), a selective p38 MAPK inhibitor, on neuropathic pain symptoms and signs. Fifty patients with nerve trauma, radiculopathy or carpal tunnel syndrome were randomised; 43 patients completed the study. Eligible patients received oral dilmapimod and placebo twice daily for 2 weeks, with an intervening washout period of 2–4 weeks. Subjects attended weekly for efficacy and safety assessments, which included evaluation of daily and current pain intensity using an 11‐point numerical rating scale (NRS), quantitative sensory testing, allodynia and global impression of change. There was a statistically significant reduction in the primary endpoint of average daily pain score during the second week of treatment among patients treated with dilmapimod (15 mg/day) compared to placebo using NRS [0.80; 95% CI (0.28, 1.33); p = 0.0034]. A similar trend for effect was seen in some secondary endpoints. Dilmapimod was well tolerated, with no clinically relevant safety findings. p38 MAPK inhibitors merit further evaluation for neuropathic pain in larger clinical trials, particularly for clinically meaningful analgesic effect size.

Pittsburgh Compound B (11C-PIB) and Fluorodeoxyglucose (18 F-FDG) PET in Patients With Alzheimer Disease, Mild Cognitive Impairment, and Healthy Controls

Amyloid load in the brain using Pittsburgh compound B (11C-PIB) positron emission tomography (PET) and cerebral glucose metabolism using fluorodeoxyglucose (18F-FDG) PET were evaluated in patients with mild Alzheimer disease (AD, n = 18), mild cognitive impairment (MCI, n = 24), and controls (CTR, n = 18). 11C-PIB binding potential (BPND) was higher in prefrontal cortex, cingulate, parietal cortex, and precuneus in AD compared to CTR or MCI and in prefrontal cortex for MCI compared to CTR. For 18F-FDG, regional cerebral metabolic rate for glucose (rCMRGlu) was decreased in precuneus and parietal cortex in AD compared to CTR and MCI, with no MCI—CTR differences. For the AD—CTR comparison, precuneus BPND area under the receiver operating characteristic (ROC) curve (AUC) was 0.938 and parietal cortex rCMRGlu AUC was 0.915; for the combination, AUC was 0.989. 11C-PIB PET BPND clearly distinguished diagnostic groups and combined with 18F-FDG PET rCMRGlu, this effect was stronger. These PET techniques provide complementary information in strongly distinguishing diagnostic groups in cross-sectional comparisons that need testing in longitudinal studies.

A simultaneous ERP/fMRI investigation of the P300 aging effect

One of the most reliable psychophysiological markers of aging is a linear decrease in the amplitude of the P300 potential, accompanied by a more frontal topographical orientation, but the precise neural origins of these differences have yet to be explored. We acquired simultaneous electroencephalogram (EEG)/functional magnetic resonance imaging (fMRI) recordings from 14 older and 15 younger adults who performed a 3-stimulus visual oddball task designed to elicit P3a and P3b components. As in previous reports, older adults had significantly reduced P3a/P3b amplitudes over parietal electrodes but larger amplitudes over frontal scalp with no between-group differences in accuracy or reaction time. Electroencephalogram/functional magnetic resonance imaging fusion revealed that the P3a age effects were driven by increased activation of left inferior frontal and cingulate cortex and decreased activation of inferior parietal cortex in the older group. P3b differences were driven by increased activation of left temporal regions, right hippocampus, and right dorsolateral prefrontal cortex in the older group. Our results support the proposal that the age-related P300 anterior shift arises from an increased reliance on prefrontal structures to support target and distractor processing.

A Multi-Center Randomized Proof-of-Concept Clinical Trial Applying [18F]FDG-PET for Evaluation of Metabolic Therapy with Rosiglitazone XR in Mild to Moderate Alzheimer's Disease

Here we report the first multi-center clinical trial in Alzheimers disease (AD) using fluorodeoxyglucose positron emission tomography ([18F]FDG-PET) measures of brain glucose metabolism as the primary outcome. We contrasted effects of 12 months treatment with the PPARγ agonist Rosiglitazone XR versus placebo in 80 mild to moderate AD patients. Secondary objectives included testing for reduction in the progression of brain atrophy and improvement in cognition. Active treatment was associated with a sustained but not statistically significant trend from the first month for higher mean values in Kiindex and CMRgluindex, novel quantitative indices related to the combined forward rate constant for [18F]FDG uptake and to the rate of cerebral glucose utilization, respectively. However, neither these nor another analytical approach recently validated using data from the Alzheimers Disease Neuroimaging Initiative indicated that active treatment decreased the progression of decline in brain glucose metabolism. Rates of brain atrophy were similar between active and placebo groups and measures of cognition also did not suggest clear group differences. Our study demonstrates the feasibility of using [18F]FDG-PET as part of a multi-center therapeutics trial. It suggests that Rosiglitazone is associated with an early increase in whole brain glucose metabolism, but not with any biological or clinical evidence for slowing progression over a 1 year follow up in the symptomatic stages of AD.

Evaluation of 11C-GSK189254 as a Novel Radioligand for the H3 Receptor in Humans Using PET

The histamine H3 receptor is implicated in the pathophysiology of several central nervous system disorders. N-methyl-6-(3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)-nicotamide (GSK189254) is a highly potent, selective, and brain-penetrant H3 receptor antagonist. Previous studies in the pig using PET have shown that 11C-GSK189254 uptake in H3-rich regions of the brain can be blocked by the selective H3 antagonist ciproxifan. The purpose of the present study was to evaluate 11C-GSK189254 as a PET radioligand for human studies and to determine the dose–receptor occupancy relationship of GSK189254 in the human brain. Methods: Dynamic PET scans were obtained in healthy subjects over 90 min after intravenous administration of approximately 370 MBq of 11C-GSK189254. Blood samples were taken throughout the scans to derive the arterial plasma parent input function. Each subject was scanned twice, either with tracer alone (test–retest) or before and after a single oral dose of GSK189254 (10–100 μg). Data were analyzed by compartmental analysis, and regional receptor-occupancy estimates were obtained by graphical analysis of changes in the total volumes of distribution (VT) of the radioligand. Results: 11C-GSK189254 readily entered the brain; its regional brain distribution reflected the known distribution of H3 receptors, with high binding in the caudate and putamen, intermediate binding in cortical regions, and low binding in the cerebellum. GSK189254 displayed a high receptor affinity, and a marked reduction in VT was apparent at all the doses tested. The oral dose equaling 50% occupancy of the available receptor sites (ED50) was estimated as 4.33 μg. Additional data on plasma pharmacokinetics after oral dosing and the plasma free fraction gave a corresponding estimate of the free concentration of GSK189254 required to occupy 50% of the available receptor sites (EC50) (0.011 nM). The test–retest data showed reductions in regional VT on the second scan in all subjects. A nonlinear compartmental analysis of this effect demonstrated that this reduction was consistent with carryover of a tracer mass dose effect with an estimated in vivo apparent dissociation constant of 0.010 nM, close to the independent estimate of the plasma EC50. Conclusion: 11C-GSK189254 can be used to quantify H3 receptor availability in humans in vivo using PET but requires high specific activity; the possibility of tracer mass dose effects should be carefully analyzed.

The Safety, Tolerability, Pharmacokinetics and Cognitive Effects of GSK239512, a Selective Histamine H 3 Receptor Antagonist in Patients with Mild to Moderate Alzheimer’s Disease: A Preliminary Investigation

BACKGROUND The histamine H3 receptor plays a critical role in the negative neuromodulation of neurotransmitters involved in cognitive function. H3 receptor antagonists/inverse agonists have been shown to exert pro-cognitive effects in pre-clinical models. GSK239512 is a potent and selective H₃ receptor antagonist developed for the treatment of cognitive dysfunction in neurodegenerative disorders. In this study we examined the safety, tolerability, pharmacokinetics and pro-cognitive effects of GSK239512 (oral) in patients with mild to moderate Alzheimers disease using ascending dose titration regimens. METHODS The study was conducted in two parts. Part A was a single-blind, placebo run-in, flexible dose titration over 9 days in two cohorts, each consisting of two patients. Part B was a double-blind, randomised, placebo controlled, parallel group, which investigated 3 flexible dose titration regimens over 4 weeks in 3 cohorts, each consisting of eight patients. RESULTS Overall, the 5/10/20/40 μg and 10/20/40/80 μg regimens were well-tolerated. The regimen of 20/40/80/150 μg showed the poorest tolerability likely due to the higher starting dose. There were no clinically significant abnormalities in haematology, clinical chemistry, urinalysis parameters and cardiovascular parameters. GSK239512 had positive effects on tasks of attention and memory with effect sizes between 0.56 and 1.37. CONCLUSIONS GSK239512 displayed asatisfactory level of tolerability in patients with Alzheimers disease with evidence for positive effects on attention and memory. The findings suggest that a titration regimen with a starting dose of 5-10 μg and a maximum dose of 80 μg is likely to be a well-tolerated and potentially efficacious regimen for future clinical trials in patients with Alzheimers disease. These findings await replication in a larger study.

Voxel-Based Analysis of 11C-PIB Scans for Diagnosing Alzheimer's Disease

The positron emission tomography (PET) radioligand N-methyl-11C-2-(4-methylaminophenyl)-6-hydroxybenzothiazole (also known as 11C-6-OH-BTA-1 or 11C-PIB) binds to amyloid-β (Aβ), which accumulates pathologically in Alzheimers disease (AD). Although 11C-PIB accumulation is greater in patients with AD than in healthy controls at a group level, the optimal method for discriminating between these 2 groups has, to our knowledge, not been established. We assessed the use of data-determined standardized voxels of interest (VOIs) to improve the classification capability of 11C-PIB scans on patients with AD. Methods: A total of 16 controls and 14 AD age-matched patients were recruited. All subjects underwent a 11C-PIB scan and structural MRI. Binding potential (a measure of amyloid burden) was calculated for each voxel using the Logan graphical method with cerebellar gray matter as the reference region. Voxel maps were then partial-volume corrected and spatially normalized by MRI onto a standardized template. The subjects were divided into 2 cohorts. The first cohort (control, 12; AD, 9) was used for statistical parametric mapping analysis and delineation of data-based VOIs. These VOIs were tested in the second cohort (control, 4; AD, 5) of subjects. Results: Statistical parametric mapping analysis revealed significant differences between control and AD groups. The VOI map determined from the first cohort resulted in complete separation between the control and the AD subjects in the second cohort (P < 0.02). Binding potential values based on this VOI were in the same range as other reported individual and mean cortical VOI results. Conclusion: A standardized VOI template that is optimized for control or AD group discrimination provides excellent separation of control and AD subjects on the basis of 11C-PIB uptake. This VOI template can serve as a potential replacement for manual VOI delineation and can eventually be fully automated, facilitating potential use in a clinical setting. To facilitate independent analysis and validation with more and a broader variety of subjects, this VOI template and the software for processing will be made available through the Internet.

Donepezil impairs memory in healthy older subjects: behavioural, EEG and simultaneous EEG/fMRI biomarkers.

Rising life expectancies coupled with an increasing awareness of age-related cognitive decline have led to the unwarranted use of psychopharmaceuticals, including acetylcholinesterase inhibitors (AChEIs), by significant numbers of healthy older individuals. This trend has developed despite very limited data regarding the effectiveness of such drugs on non-clinical groups and recent work indicates that AChEIs can have negative cognitive effects in healthy populations. For the first time, we use a combination of EEG and simultaneous EEG/fMRI to examine the effects of a commonly prescribed AChEI (donepezil) on cognition in healthy older participants. The short- and long-term impact of donepezil was assessed using two double-blind, placebo-controlled trials. In both cases, we utilised cognitive (paired associates learning (CPAL)) and electrophysiological measures (resting EEG power) that have demonstrated high-sensitivity to age-related cognitive decline. Experiment 1 tested the effects of 5 mg/per day dosage on cognitive and EEG markers at 6-hour, 2-week and 4-week follow-ups. In experiment 2, the same markers were further scrutinised using simultaneous EEG/fMRI after a single 5 mg dose. Experiment 1 found significant negative effects of donepezil on CPAL and resting Alpha and Beta band power. Experiment 2 replicated these results and found additional drug-related increases in the Delta band. EEG/fMRI analyses revealed that these oscillatory differences were associated with activity differences in the left hippocampus (Delta), right frontal-parietal network (Alpha), and default-mode network (Beta). We demonstrate the utility of simple cognitive and EEG measures in evaluating drug responses after acute and chronic donepezil administration. The presentation of previously established markers of age-related cognitive decline indicates that AChEIs can impair cognitive function in healthy older individuals. To our knowledge this is the first study to identify the precise neuroanatomical origins of EEG drug markers using simultaneous EEG/fMRI. The results of this study may be useful for evaluating novel drugs for cognitive enhancement.