Pharmacodynamics and pharmacokinetics of the novel thrombopoietin mimetic peptide RWJ-800088 in humans.

RWJ-800088 is a novel thrombopoietin mimetic peptide for the treatment of thrombocytopenia. The objectives of this study were to evaluate the pharmacokinetics, pharmacodynamics, and safety of ascending doses of RWJ-800088 administered as a single intravenous delivery in a double-blind, placebo-controlled study with five parallel groups of eight healthy human subjects each. Platelet counts and functionality, peripheral stem cells, drug concentrations, and routine laboratory parameters were measured frequently up to day 29, and antibody formation was measured up to days 56-72. At doses > or = 0.75 microg/kg of RWJ-800088, platelet levels showed dose-related elevation as compared to results with placebo. The pharmacokinetic profile was characterized for doses of 2.5 and 3.0 microg/kg, although the dose relationship could not be fully defined. The two highest doses of RWJ-800088 appeared to increase burst-forming units-erythroid and colony-forming unit counts, suggesting some effects on progenitor lineages. RWJ-800088 was well tolerated, with no evidence of antibody formation in this single-dose study. Additional patient studies are warranted to investigate the therapeutic use of this novel peptide.

The effects of a glycine reuptake inhibitor R231857 on the central nervous system and on scopolamine-induced impairments in cognitive and psychomotor function in healthy subjects.

The effects of the selective inhibitor of the glycine transporter 1, R231857, in development for schizophrenia, on the central nervous system (CNS) were investigated in healthy males in the absence and presence of scopolamine. This was a double-blind, placebo-controlled, four-period crossover ascending dose study. Pharmacokinetics, body sway, saccadic and smooth pursuit eye movements, pupillometry, pharmacoelectroencephalogram (EEG), Visual Analogue Scales (VAS) for alertness, mood, calmness and psychedelic effects, adaptive tracking, finger tapping, Stroop test, Visual and Verbal Learning Task (VVLT) and hormone levels were assessed. R231857 was administered alone and together with scopolamine to investigate the potential reversal of anticholinergic CNS impairment by the glycine reuptake inhibitor. Forty-two of the 45 included subjects completed the study. Scopolamine significantly affected almost every CNS parameter measured in this study. R231857 alone showed some pharmacodynamic changes compared with placebo. Although these effects might be an indication that R231857 penetrated the CNS, they were not consistent or dose-related. R231857 had some small effects on scopolamine-induced CNS-impairment, which were also not clearly dependent on dose. Scopolamine proved to be an accurate, reproducible and safe model to induce CNS impairment by an anticholinergic mechanism. R231857 lacked consistent dose-related effects in this study, probably because CNS concentrations were too low to produce significant/ reproducible CNS-effects or to affect the scopolamine challenge in healthy volunteers. The effects of higher doses in healthy volunteers and the clinical efficacy in patients remain to be established.

The effects of the glycine reuptake inhibitor R213129 on the central nervous system and on scopolamine-induced impairments in psychomotor and cognitive function in healthy subjects.

In this study the effects of R213129, a selective glycine transporter 1 inhibitor, on central nervous system function were investigated in healthy males in the absence and presence of scopolamine. This was a double-blind, placebo-controlled, 4-period crossover ascending dose study evaluating the following endpoints: body sway, saccadic and smooth pursuit eye movements, pupillometry, electroencephalography, visual analogue scales for alertness, mood, calmness and psychedelic effects, adaptive tracking, finger tapping, Visual and Verbal Learning Task, Stroop test, hormone levels and pharmacokinetics. R213129 dose levels were selected based on exposure levels that blocked the GlyT1 sites >50% in preclinical experiments. Forty-three of the 45 included subjects completed the study. Scopolamine significantly affected almost every central nervous system parameter measured in this study. R213129 alone compared with placebo did not elicit pharmacodynamic changes. R213129 had some small effects on scopolamine-induced central nervous system impairments. Scopolamine-induced finger tapping impairment was further enhanced by 3 mg R213129 with 2.0 taps/10 seconds (95% CI -4.0, -0.1), electroencephalography alpha power was increased by 10 mg R213129 with respectively 12.9% (0.7, 26.6%), scopolamine-induced impairment of the Stroop test was partly reversed by 10 mg R213129 with 59 milliseconds (-110, -7). Scopolamine produced robust and consistent effects in psychomotor and cognitive function in healthy volunteers. The most logical reason for the lack of R213129 effects seems to be that the central nervous system concentrations were too low. The effects of higher doses in healthy volunteers and the clinical efficacy in patients remain to be established.

Psychomotor and cognitive effects of a single oral dose of talnetant (SB223412) in healthy volunteers compared with placebo or haloperidol.

Central Nervous System (CNS) effects of talnetant, an NK-3 antagonist in development for schizophrenia, were compared to those of haloperidol and placebo. The study was randomised, double-blind, three-way crossover of talnetant 200 mg, haloperidol 3 mg or placebo. Twelve healthy males participated and EEG, saccadic and smooth pursuit eye movements, adaptive tracking, body sway, finger tapping, hormones, visual analogue scales (VAS) for alertness, mood and calmness and psychedelic effects, left/right distraction task, Tower of London and Visual and Verbal Learning Task were assessed. Haloperidol showed (difference to placebo; 95% CI; p-value) decreases in EEG alpha power (-0.87microV; -1.51/-0.22; p = 0.0110), saccadic inaccuracy (2.0%; 0.5/3.6; p = 0.0133), smooth pursuit eye movements (-7.5%; -12.0/-3.0; p = 0.0026), adaptive tracking (-3.5%; -5.4/-1.7; p = 0.0009), alertness (-6.8 mm; -11.1/-2.4; p = 0.0039), negative mood (-4.6 mm; -8.6/-0.6; p = 0.0266), the ability to control thoughts (1.2 mm; 0.2/2.3; p = 0.0214), and an increase of serum prolactin (ratio 4.1; 3.0/5.6; p < 0.0001). Talnetant showed decreased alpha power (-0.69 muV; -1.34/-0.04; p = 0.0390), improved adaptive tracking (1.9%; 0.1/3.7; p = 0.0370) and reduced calmness on VAS Bond and Lader (-4.5 mm; -8.0/-1.0; p = 0.0151). Haloperidol effects were predominantly CNS-depressant, while those of talnetant were slightly stimulatory. The results suggest that talnetant penetrates the brain, but it remains to be established whether this dose is sufficient and whether the observed effect profile is class-specific for NK3-antagonists.