A phase 1b/2a multicenter study of the safety and preliminary pharmacodynamic effects of selective muscarinic M1 receptor agonist HTL0018318 in patients with mild-to-moderate Alzheimer's disease.

INTRODUCTION: This study examined the safety and pharmacodynamic effects of selective muscarinic M1 receptor orthosteric agonist HTL0018318 in 60 patients with mild-to-moderate Alzheimer's disease (AD) on background donepezil 10 mg/day. METHODS: A randomized, double-blind, placebo-controlled 4-week safety study of HTL0018318 with up-titration and maintenance phases, observing exploratory effects on electrophysiological biomarkers and cognition. RESULTS: Treatment-emergent adverse events (TEAEs) were mild and less frequently reported during maintenance versus titration. Headache was most commonly reported (7-21%); 0 to 13% reported cholinergic TEAEs (abdominal pain, diarrhea, fatigue, nausea) and two patients discontinued due to TEAEs. At 1 to 2 hours post-dose, HTL0018318-related mean maximum elevations in systolic and diastolic blood pressure of 5 to 10 mmHg above placebo were observed during up-titration but not maintenance. Postive effects of HTL0018318 were found on specific attention and memory endpoints. DISCUSSION: HTL0018318 was well tolerated in mild-to-moderate AD patients and showed positive effects on attention and episodic memory on top of therapeutic doses of donepezil.

Effects of a topical treatment with spleen tyrosine kinase inhibitor in healthy subjects and patients with cold urticaria or chronic spontaneous urticaria: Results of a phase 1a/b randomised double-blind placebo-controlled study.

AIMS: To explore the safety, tolerability, pharmacokinetics and pharmacodynamics (PD) of GSK2646264 using skin challenge models. METHODS: Healthy volunteers (HV) with a positive allergen skin prick test received GSK2646264 (0.5% or 1% ww) and placebo creams on up to 10% body surface area (BSA). Cold (ColdU) or chronic spontaneous (CSU) urticaria patients received 1% GSK2646264 or placebo on up to 10% BSA. PD assessments included weal characteristics after skin allergen challenge, critical temperature threshold (CTT) in ColdU patients and defined area urticaria activity score in CSU patients. RESULTS: Thirty-four patients were randomised (17 HV, 12 ColdU, 5 CSU). Topical application of GSK2646264 and placebo was well tolerated. Systemic pharmacokinetics (AUC [0-24] h*ng/mL) was similar between HVs (Geomean 97.9 [%CV 37]) and ColdU patients (Geomean 68.2 [%CV 14; 3.5% BSA] or 167 [%CV 120; 10% BSA]). Whilst in HVs a similar reduction in skin allergen challenge weal area was observed following 3 applications of GSK2646264 and placebo, a trend towards a greater reduction was seen in ColdU with GSK2646264 compared to placebo. A clinically meaningful reduction in CTT, in ColdU patients treated with GSK2646264, was observed in 4 of 9 patients, who demonstrated either a complete inhibition of ColdU to ≤4°C (n = 2) or partial response (reduction by >4°C, n = 2). Due to the small number of CSU patients recruited, no meaningful conclusions could be drawn from the defined area urticaria activity score PD endpoint. CONCLUSION: This Phase 1/1b study confirms that GSK2646264 cream applied topically penetrates the skin and some reduction in CTT was observed. (NCT02424799).

The effects of GSK2981710, a medium-chain triglyceride, on cognitive function in healthy older participants: A randomised, placebo-controlled study.

OBJECTIVE: This double-blind, randomised, placebo-controlled, two-part study assessed the impact of GSK2981710, a medium-chain triglyceride (MCT) that liberates ketone bodies, on cognitive function, safety, and tolerability in healthy older adults. METHODS: Part 1 was a four-period dose-selection study (n = 8 complete). Part 2 was a two-period crossover study (n = 80 complete) assessing the acute (Day 1) and prolonged (Day 15) effects of GSK2981710 on cognition and memory-related neuronal activity. Safety and tolerability of MCT supplementation were monitored in both parts of the study. RESULTS: The most common adverse event was diarrhoea (100% and 75% of participants in Parts 1 and 2, respectively). Most adverse events were mild to moderate, and 11% participants were withdrawn due to one or more adverse events. Although GSK2981710 (30 g/day) resulted in increased peak plasma ß-hydroxybutyrate (BHB) concentrations, no significant improvements in cognitive function or memory-related neuronal activity were observed. CONCLUSION: Over a duration of 14 days, increasing plasma BHB levels with daily administration of GSK2981710 had no effects on neuronal activity or cognitive function. This result indicates that modulating plasma ketone levels with GSK2981710 may be ineffective in improving cognitive function in healthy older adults, or the lack of observed effect could be related to several factors including study population, plasma BHB concentrations, MCT composition, or treatment duration.

Pharmacokinetic and pharmacodynamic profiling of a P2X7 receptor allosteric modulator GSK1482160 in healthy human subjects.

AIMS: This paper describes findings from the first-in-human study for GSK1482160, an orally available allosteric P2X7 receptor modulator. The study aimed to assess the pharmacokinetics (PK), pharmacodynamics (PD), safety and tolerability of the compound in healthy subjects. METHODS: Escalating single doses of up to 1 g were administered to healthy subjects in a single-blind and placebo-controlled fashion. Safety, tolerability, blood drug concentrations and ex vivo Il-1ß production in blood were evaluated. RESULTS: Drug concentration peaked within 3.5 h of dosing under fasting conditions and declined thereafter with a relatively short half-life of less than 4.5 h. Exposure was proportional to dose with between subject variability of less than 60%. A PK/PD model quantified Il-1ß as a function of drug exposure. The model allowed simulation of in vivo pharmacology for various untested dose levels and regimens. Furthermore, the mechanistic model supported the hypothesis that the compound reduces the efficacy of ATP at the P2X7 receptor without affecting its affinity. No major safety or tolerability concerns were identified in this small study (n = 29), except for one case of asymptomatic accelerated idioventricular rhythm at the top dose. CONCLUSION: The model-based approach maximized analysis power by integrating all biomarker data and revealed mechanistic insight into the pharmacology of P2X7 modulation by GSK1482160. Simulations by this model ultimately led to the discontinuation of the development of this compound. The therapeutic relevance of the P2X7 receptor remains to be tested in patients. The mechanistic-model-based approach can be applied widely to drug development.

Effects of donepezil on cognitive performance after sleep deprivation.

OBJECTIVES: To identify tasks that were sensitive to a temporary decline in cognitive performance after sleep deprivation and to investigate the ability of the acetylcholinesterase inhibitor donepezil to reverse any sleep deprivation-induced impairment. METHODS: Thirty healthy volunteers were administered either a 5-mg daily dose of donepezil or placebo for 14-17 days, in a double-blind parallel group design, then underwent either 24 h sleep deprivation or a normal night of sleep in non-blinded crossover, and were subsequently tested on a battery of cognitive tasks designed to measure different components of memory and executive function. RESULTS: Sleep deprivation selectively impaired performance on several memory tasks whilst also impairing non-memory function on these tasks. Performance on other tasks was spared. Despite partially reversing the decline in subjective alertness associated with sleep deprivation, treatment with donepezil failed to significantly reverse the decline in cognitive performance on any of the tasks. CONCLUSIONS: The results demonstrate the sensitivity of certain tests, particularly those that measure memory function, to cognitive impairment after sleep deprivation. The inability of donepezil to reverse this performance decline suggests that the sleep deprivation model of cognitive impairment may not be suitable for detecting pro-cognitive effects of cholinergic augmentation.

A randomized, controlled study comparing the effects of vestipitant or vestipitant and paroxetine combination in subjects with tinnitus.

OBJECTIVE: Tinnitus is a common symptom that demonstrates a significant comorbidity with anxiety and depression. The novel neurokinin-1 receptor antagonist, vestipitant, has anxiolytic properties and a good safety profile. Vestipitant was investigated for potential effect against chronic tinnitus as a stand-alone treatment and in conjunction with a selective serotonin reuptake inhibitor, paroxetine. STUDY DESIGN: Randomized, double-blind, crossover study. SETTING: Tertiary neurotologic and audiologic center with additional referrals from a secondary university hospital center. PATIENTS: Twenty-four adult patients with tinnitus were randomized into the study. MAIN OUTCOME MEASURES: Visual analogue scale (VAS) measurements of tinnitus loudness (intensity), pitch and distress, VAS measurements of arousal/anxiety, Tinnitus Handicap Inventory, Quick Inventory of Depressive Symptomatology, and plasma concentrations of trial drugs. RESULTS: No statistically significant treatment benefit effect was detected for tinnitus (intensity, pitch, and distress) VAS scores, arousal-anxiety VAS scores, Tinnitus Handicap Inventory, or tinnitus aggravation scores assessed on Days 1 and 14. However, a statistically significant worsening of tinnitus intensity and distress scores was observed after vestipitant compared with placebo for the mean data collected over the treatment period. No relevant differences in vestipitant plasma concentrations were observed between the subjects given the combination with paroxetine and those receiving vestipitant alone. No specific relationships were observed between tinnitus intensity and vestipitant plasma concentrations. CONCLUSION: Although well-tolerated vestipitant, alone or in combination with paroxetine, was not effective in ameliorating tinnitus in this patient group.

Neurophysiological evaluation of convergent afferents innervating the human esophagus and area of referred pain on the anterior chest wall.

Noxious stimuli in the esophagus cause pain that is referred to the anterior chest wall because of convergence of visceral and somatic afferents within the spinal cord. We sought to characterize the neurophysiological responses of these convergent spinal pain pathways in humans by studying 12 healthy subjects over three visits (V1, V2, and V3). Esophageal pain thresholds (Eso-PT) were assessed by electrical stimulation and anterior chest wall pain thresholds (ACW-PT) by use of a contact heat thermode. Esophageal evoked potentials (EEP) were recorded from the vertex following 200 electrical stimuli, and anterior chest wall evoked potentials (ACWEP) were recorded following 40 heat pulses. The fear of pain questionnaire (FPQ) was administered on V1. Statistical data are shown as point estimates of difference +/- 95% confidence interval. Pain thresholds increased between V1 and V3 [Eso-PT: V1-V3 = -17.9 mA (-27.9, -7.9) P < 0.001; ACW-PT: V1-V3 = -3.38 degrees C (-5.33, -1.42) P = 0.001]. The morphology of cortical responses from both sites was consistent and equivalent [P1, N1, P2, N2 complex, where P1 and P2 are is the first and second positive (downward) components of the CEP waveform, respectively, and N1 and N2 are the first and second negative (upward) components, respectively], indicating activation of similar cortical networks. For EEP, N1 and P2 latencies decreased between V1 and V3 [N1: V1-V3 = 13.7 (1.8, 25.4) P = 0.02; P2: V1-V3 = 32.5 (11.7, 53.2) P = 0.003], whereas amplitudes did not differ. For ACWEP, P2 latency increased between V1 and V3 [-35.9 (-60, -11.8) P = 0.005] and amplitudes decreased [P1-N1: V1-V3 = 5.4 (2.4, 8.4) P = 0.01; P2-N2: 6.8 (3.4, 10.3) P < 0.001]. The mean P1 latency of EEP over three visits was 126.6 ms and that of ACWEP was 101.6 ms, reflecting afferent transmission via Adelta fibers. There was a significant negative correlation between FPQ scores and Eso-PT on V1 (r = -0.57, P = 0.05). These data provide the first neurophysiological evidence of convergent esophageal and somatic pain pathways in humans.

Patient and caregiver perspective on pediatric eosinophilic esophagitis and newly developed symptom questionnaires*.

OBJECTIVE: Eosinophilic esophagitis (EE), a rare chronic inflammatory condition of the esophagus, is predominantly observed in children and is primarily manifested with feeding difficulties. To our knowledge, no self- or caregiver-reported questionnaires are available to assess pediatric EE symptoms and their impact as reported directly by children or their parents/caregivers. The objectives of this study were to characterize the symptoms and impact of EE among children as reported by patients and parents/caregivers and to assess the content validity of two newly developed pediatric eosinophilic esophagitis symptom questionnaires, one parent/caregiver-reported questionnaire for ages 2-7 years and one child-reported questionnaire for ages 8-17 years. The questionnaires were developed based on a review of the literature and clinical expert consultation. RESEARCH DESIGN AND METHODS: This cross-sectional study involving one-on-one interviews with patients and caregivers was conducted at an American Partnership for Eosinophilic Disorders conference. Parents of patients aged 2-7 years (n = 12) and patients aged 8-17 years (n = 16) were first asked about symptoms and their impact on everyday life, using open-ended questions. Participants then completed the appropriate symptom questionnaire and were asked to provide feedback on the relevance, comprehensiveness, and clarity of each item and other questionnaire issues (time to complete, length, format, etc.). All reported symptoms were enumerated, and the feedback on the symptom questionnaires was analyzed qualitatively. RESULTS: The majority of study participants were white (82%) and male (86%). The most frequently reported symptoms of 2-7-year olds were vomiting (92%), "reflux" (50%), dysphagia (25%), abdominal pain (25%), and trouble sleeping (25%). The 8-17-year group reported abdominal pain (56%), vomiting (31%), throat pain (25%), diarrhea (25%), and food getting stuck (25%). Symptoms and treatment were reported to have a major impact on daily life, particularly on school, after-school activities and social events, feeling frustrated regarding symptoms and treatment, and feeling "different". Overall, participants thought that the questionnaires were clear, relevant, and appropriate for symptom assessment. LIMITATION: This study was based on a small and convenient sample of participants attending an EE conference and hence may not be representative of the general EE patient population. CONCLUSIONS: EE is associated with a range of symptoms that vary in terms of the type, frequency and severity across and within patients. The results provide adequate support for the content validity of the self- and caregiver-reported versions of the symptom-specific questionnaires. Minor modifications were made based on the feedback obtained. A psychometric evaluation of the revised questionnaires is needed next to assess the construct validity, reliability, and responsiveness of the measures.

Training in paediatric clinical pharmacology in the UK.

AIMS: To produce a training programme in paediatric clinical pharmacology. METHODS: A working group, consisting of clinical pharmacologists (paediatric and adult), general paediatricians and the pharmaceutical industry was established to produce the training programme. RESULTS: Following a two year training programme in general paediatrics, a three year training programme in clinical pharmacology has been established. This includes one year of research in clinical pharmacology (paediatric or adult). The other two years involve training in different aspects of paediatric clinical pharmacology and general paediatrics. CONCLUSION: The existence of a formal training programme should result in a significant increase in the number of paediatric clinical pharmacologists.

Changes in circulating concentrations of vitamins and trace elements after cessation of nocturnal enteral tube feeding.

BACKGROUND: This study aimed to examine whether circulating concentrations of a range of vitamins and trace elements in patients receiving long-term cyclic enteral tube feeding vary during the day, and whether standardised time points for blood sampling are required for assessment of nutrient status. METHODS: Circulating concentrations or activities of water-soluble vitamins (thiamine, riboflavin, and vitamins B6, B12, folate and C), fat-soluble vitamins (A, D, E) and trace elements (iron, zinc, copper and selenium (assessed by glutathione peroxidase activity), were measured at 0,3,6 and 9-12h after cessation of nocturnal feeding (fasting), in eight clinically stable patients receiving cyclic nocturnal enteral nutrition. RESULTS: The circulating concentrations of the nutrients did not change between the fed and fasted state (repeated-measures-ANOVA) except the following: plasma folate increased progressively from 10.9 (SD 4.6)nmol/l in the fed state to 14.0 (SD 4.4)nmol/l at 9-12 h after cessation of feeding (P<0.05); plasma zinc increased progressively throughout the fasting period by 33.5% (8.57, SD 0.68 vs. 11.44, SD 1.85 micromol/l, in fed state vs. 9-12h fast respectively, P<0.05); and total tocopherol/cholesterol ratio decreased by 9.6% during the study period (P<0.02), while gamma-tocopherol increased by 59.2% (P<0.05). For all analytes, the concentrations in blood samples taken at 3 and 6h after cessation of feeding were not significantly different from those at 9-12h. CONCLUSIONS: Although cessation of nocturnal tube feeding had no significant effect on the circulating concentrations of most micronutrients, it increased plasma folate and zinc concentrations, and decreased the tocopherol/cholesterol ratio. The timing for blood sampling should be standardised when the status of these nutrients is assessed in patients receiving cyclic tube feeding.