Pharmacokinetics and central nervous system effects of the novel dual NK1 /NK3 receptor antagonist GSK1144814 in alcohol-intoxicated volunteers.

AIMS: Antagonism of both NK1 and NK3 receptors may be an effective strategy in the pharmacotherapy of schizophrenia, drug addiction or depression. GSK1144814 is a novel selective dual NK1 /NK3 receptor antagonist. The potential influence of GSK1144814 on the effects of alcohol was investigated. METHODS: In a blinded, randomized, placebo-controlled, two period crossover study, the pharmacokinetics and central nervous system (CNS) effects of single oral doses of 200 mg GSK1144814 were evaluated in 20 healthy volunteers, using a controlled alcohol infusion paradigm to maintain stable alcohol concentrations with subsequent analysis of eye movements, adaptive tracking, body sway, visual analogue scales, Epworth sleepiness scale and the verbal visual learning test. RESULTS: Frequent adverse effects were mild somnolence, fatigue and headache. Plasma concentration of GSK1144814 in the presence of alcohol was maximal 1.5 h after dose administration. GSK1144814 did not affect alcohol pharmacokinetics. Co-administration of GSK1144814 and alcohol impaired saccadic reaction time and peak velocity, adaptive tracking, alertness, sleepiness, word recognition and recognition reaction time compared with administration of alcohol alone, but the size of the interaction was small. CONCLUSIONS: Administration of GSK1144814 in the presence of alcohol was generally well tolerated and not likely to produce clinically relevant additional impairments after alcohol consumption.

Enhancing Distorted Metal-Organic Framework-Derived ZnO as Anode Material for Lithium Storage by the Addition of Ag2S Quantum Dots.

The lithium storage properties of the distorted metal-organic framework-derived nanosized ZnO@C are significantly improved by the introduction of Ag2S quantum dots (QDs) during the processing of the material. In the thermal treatment, the Ag2S QDs react to produce Ag nanoparticles and ZnS. The metal nanoparticles act to shorten electron pathways and improve the connectivity of the matrix, and the partial sulfidation of the ZnO surface improves the cycling stability of the material. The electrochemical properties of ZnO@C, Ag2S QDs-treated ZnO@C, and the amorphous carbon in ZnO@C have been compared. The small weight ratio of Ag2S QDs to ZnO@C at 1:180 shows the best performance in lithium storage. The exhibited specific capacities are improved and retained remarkably in the cycling at high current rates. At low current densities (200 mA g-1), treatment of ZnO@C with Ag2S QDs results in a 38% increase in the specific capacity.

Characterising the plasma-target occupancy relationship of the neurokinin antagonist GSK1144814 with PET.

GSK1144814 is a potent, insurmountable antagonist at human NK1 and NK3 receptors. Understanding the relationship between plasma pharmacokinetics and receptor occupancy in the human brain, was crucial for dose selection in future clinical studies. GSK1144814 occupancy data were acquired in parallel with the first-time-in-human safety and tolerability study. [¹¹C]GR-205171 a selective NK1 receptor PET ligand was used to estimate NK1 occupancy at several time-points following single dose administration of GSK1144814. The time-plasma concentration-occupancy relationship post-single dose administration was assessed, and used to predict the plasma concentration-occupancy relationship following repeat dose administration. Repeat dose predictions were tested in a subsequent cohort of subjects examined following approximately 7 and 14 days dosing with GSK1144814. GSK1144814 was shown to demonstrate a dose-dependent occupancy of the NK1 receptor with an estimated in vivo EC50~0.9 ng/mL in the human brain. A direct relationship was seen between the GSK1144814 plasma concentration and its occupancy of the brain NK1 receptor, indicating that in future clinical trials the occupancy of brain receptors can be accurately inferred from the measured plasma concentration. Our data provided support for the further progression of this compound and have optimised the likely therapeutic dose range.

Contribution of SPECT measurements of D2 and 5-HT2A occupancy to the clinical development of the antipsychotic SB-773812.

UNLABELLED: The aim of this study was to assess human striatal dopamine receptor 2 (D(2)) and cortical 5-hydroxytryptamine receptor 2A (5-HT(2A)) occupancy of SB-773812 to demonstrate brain penetration and binding to the target receptors and assess the pharmacokinetics-receptor occupancy relationship over time to aid dose selection and dosage regimen, in preparation for the phase II trials. METHODS: D(2) and 5-HT(2A) occupancy were measured over time (both at the time of maximum [T(max); 6 ± 2 h] and at the time of minimum [T(trough); 24 ± 4 h] plasma concentration after dosing) by means of (123)I-iodobenzamide and (123)I-4-amino-N-[1-[3-(4-fluorophenoxy)propyl]-4-methyl-4-piperidinyl]5-iodo-2-methoxybenzamide ((123)I-R91150) SPECT in 3 studies. Study A consisted of SB-773812 single doses in healthy volunteers-D(2) occupancy measured at 48 (n = 9) and 56 mg (n = 9) and 5-HT(2A) occupancy at 56 mg (n = 9); study B consisted of D(2) and 5-HT(2A) occupancy measured in 12 stabilized-schizophrenia patients on stable doses (16-18 d of 56 mg/d) after washout of previous medication; and study C included D(2) occupancy measured in a double-blind study of patients with acutely exacerbated schizophrenia (n = 10) on stable doses (18-21 d) of SB-773812 (100 mg/d; n = 7) or risperidone (6 mg/d; n = 3). RESULTS: Study A showed less than 30% D(2) occupancy at T(max), maintained at T(trough). 5-HT(2A) occupancy was 74%-97% and also maintained over time. Study B revealed that 8 of the 12 schizophrenia patients showed more than 40% D(2) occupancy. 5-HT(2A) occupancy ranged from 91% to 100%. In study C, SB-773812-induced D(2) occupancy was 60.3% ± 13.3% at T(max) and 55.1% ± 4.9% at T(trough). The pharmacokinetics-receptor occupancy relationship was assessed in each study and strengthened, combining all data to yield a concentration associated with 50% occupancy (EC(50)) of 92.7 ± 13.5 ng/mL for D(2) and 2.11 ± 0.50 ng/mL for 5-HT(2A). CONCLUSION: In all subjects, SB-773812 showed penetration into the brain, reaching its target receptors. In patients with schizophrenia, D(2) occupancy levels induced by a single dose were maintained over time, indicating that once-daily dosing regimens are appropriate. Pharmacokinetics-receptor occupancy analysis provided guidance for the selection of a clinically effective dose, supporting progression in phase II.