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The aim was to assess the central nervous system (CNS) effects, pharmacokinetics and safety of GPI 5693, an inhibitor of a novel CNS-drug target, NAALADase which is being evaluated for the treatment of neuropathic pain. This was a double-blind, placebo-controlled, exploratory study in healthy subjects receiving oral GPI 5693 single ascending doses of 100, 300, 750, 1125 mg with a placebo treatment randomly interspersed. An open-label, parallel extension examined the effects of food and sex on the pharmacokinetics of 750, 1125 and 1500 mg doses. Blood samples were collected for pharmacokinetic and biochemical/haematological safety analysis, vital signs, ECG and adverse event checks were performed regularly up to 48 h postdose. Postdose CNS effects were assessed using eye movements, adaptive tracking, electroencephalography (EEG), body sway and Visual Analogue Scales (VAS). CNS effects were mainly observed after the 1125 mg dose, showing a significant decrease of adaptive tracking performance, VAS alertness and VAS mood, and an increase of EEG occipital alpha and theta power. Gastro-intestinal (GI) adverse effects were frequent at higher doses. No clinically significant changes in vital signs or ECG were noted during any of the treatments. The therapeutically relevant concentration range (950–11 100 ng ml−1) as determined from animal experiments was already reached after the 300 mg dose. C max after the 300 mg and 750 mg dose was 2868 and 9266 ng ml−1 with a t1/2 of 2.54 and 4.78 h, respectively. Concomitant food intake (with the 750 mg and 1125 mg doses) reduced C max by approximately 66% and AUC by approximately 40%. With concomitant food intake, the dose-normalized C max also decreased significantly by −5.6 (CI: −2.6 to −8.7) ng ml−1 mg−1. The pharmacokinetic variability was largest after the 300 mg and 750 mg dose, resulting in a SD of approximately 50% of the C max. NAALADase inhibition with GPI 5693 was safe and tolerable in healthy subjects. Plasma concentrations that were effective in the reversal of hyperalgesia in the chronic constrictive injury animal model of neuropathic pain were obtained at doses of 300, 750 and 1125 mg in the fasted state. Comcomitant food intake reduced C max and AUC. CNS effects and GI AEs increased in incidence over placebo only at the 1125 mg dose. [ABSTRACT FROM AUTHOR]

Studies of novel centrally acting drugs in healthy volunteers are traditionally concerned with kinetics and tolerability, but useful information may also be obtained from biomarkers of clinical endpoints. This paper provides a systematic overview of CNS-tests used with SSRIs in healthy subjects. A useful biomarker should meet the following requirements: a consistent response across studies and drugs; a clear response of the biomarker to a therapeutic dose; a dose–response relationship; a plausible relationship between biomarker, pharmacology and pathogenesis.These criteria were applied to all individual tests found in studies of selective serotonin reuptake inhibitors (SSRIs), performed in healthy subjects since 1966, identified with a systematic MedLine search. Separate databases were created to evaluate the effects of single or multiple dose SSRI-studies, and for amitriptyline whenever the original report included this antidepressant as a positive control. Doses of the antidepressant were divided into high- and low-dose ranges, relative to a medium range of therapeutic doses. For each test, the drug effects were scored as statistically significant impairment/decrease (–), improvement/increase (+) or no change (=) relative to placebo.56 single dose studies and 22 multiple dose studies were identified, investigating the effects of 13 different SSRIs on 171 variants of neuropsychological tests, which could be clustered into seven neuropsychological domains. Low single doses of SSRIs generally stimulated tests of attention and memory. High doses tended to impair visual/auditory and visuomotor systems and subjective performance, while showing an acceleration in motor function. The most pronounced effects were observed using tests that measure flicker discrimination (improvement at low doses: 75%, medium doses: 40%, high doses: 43% of studies); REM sleep (inconsistent decrease after medium doses, decrease in 83% of studies after high doses); and EEG recordings, predominantly in alpha (decrease in 60% and 43% of studies after low and medium doses, respectively) and in theta activity (increase in 43% and 33% of studies after medium and high doses, respectively). Amitriptyline generally impaired central nervous system (CNS) functions, which increased with doses. Multiple doses caused less pronounced effects on the reported tests. The most responsive tests to amitriptyline appeared to be EEG alpha and theta, and REM sleep duration.SSRIs in healthy subjects appear to cause slight stimulating effects after low doses, which tend to diminish with dose. The most consistent effects were observed with flicker discrimination tests, EEG (alpha and beta bands), REM sleep duration, and subjective effects at higher doses. These effects are small compared with amitriptyline and other CNS-active drugs. Multiple dosing with SSRIs caused even fewer measurable differences from placebo, probably due to adaptive processes. SSRI-effects are best detected with a test battery that is sensitive to general CNS-stimulation, but such tests only comprise a very small portion of the close to 200 different methods that were found in current review. [ABSTRACT FROM AUTHOR]

Studies of novel centrally acting drugs in healthy volunteers are traditionally concerned with kinetics and tolerability, but useful information may also be obtained from biomarkers of clinical endpoints. A useful biomarker should meet the following requirements: a consistent response across studies and drugs; a clear response of the biomarker to a therapeutic dose; a dose–response relationship; a plausible relationship between biomarker, pharmacology and pathogenesis. In the current review, all individual tests found in studies of benzodiazepine agonists registered for anxiety in healthy volunteers since 1966 were progressively evaluated for compliance with these requirements. A MedLine search yielded 56 different studies, investigating the effects of 16 different benzodiazepines on 73 different (variants of ) neuropsychological tests, which could be clustered into seven neuropsychological domains. Subjective and objective measures of alertness were most sensitive to benzodiazepines. The most consistent effects were observed on saccadic peak velocity (SPV) and visual analogue scores ( VAS) of alertness, where 100% and 79% of all studies respectively showed statistically significant effects. A dose–response relationship could be constructed for temazepam and SPV, which was used to determine dose equivalencies relative to temazepam, for seven different benzodiazepines. These dose equivalencies correlated with the lowest recommended daily maintenance dose (r 2 = 0.737, P < 0.05). This relationship between SPV reduction and clinical efficacy could reflect the clinical practice of aiming for maximum tolerated levels, or it could represent a common basis behind SPV reduction and anxiolytic activity for benzodiazepines (probably sedation). The number of tests used in human psychopharmacology appears to be excessive and their sensitivity and reproducibility low. [ABSTRACT FROM AUTHOR]

Aims The aim of this study was to compare the effect profiles of i.v. administered rilmenidine aimed at the same target plasma concentration, but attained with different rates. Methods The study was placebo-controlled, randomized, double-blind, double-dummy, three-way, cross-over in nine healthy volunteers. All subjects randomly received either a fast infusion, a slow infusion or a placebo infusion. The target concentration was set at 8 ng ml-1 with a fivefold difference in the time to reach the maximum concentration. Saccadic eye movements, electroencephalography (EEG), blood pressure and heart rate were measured every half hour. Drug plasma concentrations, adverse events, salivary flow and visual analogue scales were obtained every hour. Results Changes in systolic/diastolic blood pressure at the end of the infusion were (mean ± s.d.) 13.3 ± 16.4/7.9 ± 7.5 mmHg with the fast infusion and 16.3 ± 12.7/10.2 ± 7.9 mmHg during the slow infusion, compared with 0.0 ± 13.2/1.3 ± 8.3 mmHg for the placebo occasion. Decrease of saccadic peak velocity (SPV) at the end of the infusion was 18.0 ± 5.2% during the fast infusion, 23.0 ± 7.0% with the slow infusion, and 6.1 ± 5.2% with placebo. PK/PD analysis showed similar concentration-dependent linear reduction in SPV and blood pressure up to the maximum observed rilmenidine plasma level for both the fast and the slow infusion. Conclusions The rate of infusion of rilmenidine in healthy volunteers does not influence the PK/PD relationship of saccadic eye movements and blood pressure up to the maximum observed rilmenidine plasma concentrations. Rilmenidine causes clear concentration-dependent blood pressure reductions in healthy volunteers. [ABSTRACT FROM AUTHOR]