Pharmacokinetics of sugammadex in subjects with moderate and severe renal impairment
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AIMS: Sugammadex rapidly reverses moderate and deep rocuronium- or vecuronium-induced neuromuscular blockade at doses of 4 mg/kg and 2 mg/kg, respectively. Sugammadex is renally eliminated. This study evaluated the pharmacokinetics of sugammadex in subjects with renal impairment versus those with normal renal function. METHODS: This open-label, two-part, phase 1 study included adults with moderate (creatinine clearance (CLcr) 30 - < 50 mL/min) and severe (CLcr < 30 mL/min) renal impairment and healthy controls (CLcr ≥ 80 mL/min). A single intravenous (IV) bolus injection of sugammadex 4 mg/kg was administered into a peripheral vein over 10 seconds directly by straight needle in part 1 (n = 24; 8/group), and via an IV catheter followed by a saline flush in part 2 (n = 18; 6/group). Plasma concentrations of sugammadex were collected after drug administration. Due to dosing issues in part 1, pharmacokinetic parameters were determined for part 2 only. Safety was assessed throughout the study. RESULTS: Pharmacokinetic data were obtained from 18 subjects. Mean sugammadex exposure (AUC0-∞) in subjects with moderate and severe renal impairment was 2.42- and 5.42-times, respectively, that of healthy controls. Clearance decreased and apparent terminal half-life was prolonged with increasing renal dysfunction. Similar Cmax values were observed in subjects with renal impairment and healthy controls. There were no serious adverse events. CONCLUSIONS: Sugammadex exposure is increased in subjects with moderate and severe renal insufficiency due to progressively decreased clearance as a function of worsening renal function. Sugammadex 4 mg/kg was well tolerated in subjects with renal impairment, with a safety profile similar to that of healthy subjects. These results indicate that dose adjustment of sugammadex is not required in patients with moderate renal impairment; however, current safety experience is insufficient to support the use of sugammadex in patients with CLcr < 30 mL/min.
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A randomised trial of the effect of the glycine reuptake inhibitor Org 25935 on cognitive performance in healthy male volunteers.

OBJECTIVE: Cognitive impairment is integral to many neurological illnesses. Specific enhancement of glutamatergic transmission may improve memory and learning. Org 25935 increases the synaptic availability of glycine, an obligate co-agonist with glutamate at N-methyl-D-aspartate receptors. We hypothesised that Org 25935 would acutely improve the learning and memory of healthy volunteers. METHODS: A randomised, double-blind, parallel-group, single-dose study of Org 25935 and placebo was carried out. Thirty-two healthy male volunteers took either 12-mg Org 25935 or matching placebo and were later assessed with the manikin task, digit span and verbal memory tests. Systematic assessments of cardiovascular and adverse events were also taken. RESULTS: There was no effect of Org 25935 on reaction time, number of correct responses or learning (greater or slower improvement over successive tasks) compared with placebo. Org 25935 caused significantly more dizziness and drowsiness compared with placebo; these side effects were mainly mild. CONCLUSIONS: A single dose of Org 25935 does not improve learning or memory in healthy male individuals. However, the drug was well tolerated, and it remains to be seen whether it would have a positive effect on cognition in patient groups with pre-existing cognitive deficits.

Early stage development of the glycine-1 re-uptake inhibitor SCH 900435: central nervous system effects compared with placebo in healthy men.

AIMS: To report the first three studies with SCH 900435, a selective glycine-1 re-uptake inhibitor in development for treating schizophrenia, using systematic evaluations of pharmacodynamics to understand the observed effects. METHODS: Three double-blind, placebo-controlled studies (single, visual effect and multiple dose) were performed. In the single and multiple dose study SCH 900435 (0.5-30 mg) was given to healthy males and frequent pharmacokinetic and pharmacodynamic measurements were performed. The visual effects study incorporated visual electrophysiological measures of macular, retinal and intracranial visual pathway function. RESULTS: In the single dose study (highest difference, 95% CI, P) increases in smooth pursuit eye movements (8, 12 mg (-6.09, 10.14, -2.04, 0.013), 30 mg), pupil : iris ratio (20 and 30 mg (-0.065, 0.09, -0.04, <0.0001)), VAS colour perception (30 mg (-9.48, 13.05, -5.91, <0.0001)) and changes in spontaneous reports of visual disturbance were found, while FSH (8 mg (0.42, 0.18, 0.66, 0.0015), 12, 20 mg), LH (8-30 mg (1.35, 0.65, 2.05, 0.0003)) and EEG alpha2 activity decreased (12, 20, 30 mg (0.27, 0.14, 0.41, 0.0002)). A subsequent dedicated visual effects study demonstrated that visual effects were transient without underlying electrophysiological changes. This provided enough safety information for starting a multiple ascending dose study, showing less visual symptoms after twice daily dosing and titration, possibly due to tolerance. CONCLUSIONS: Several central nervous system (CNS) effects and gonadotropic changes resulted from administration of 8 mg and higher, providing evidence for CNS penetration and pharmacological activity of SCH 900435. Antipsychotic activity in patients, specificity of the reported effects for this drug class and possible tolerance to visual symptoms remain to be established.

Design, synthesis and structure-activity relationships of (indo-3-yl) heterocyclic derivatives as agonists of the CB1 receptor. Discovery of a clinical candidate.

We report an expansion of the structure-activity relationship (SAR) of a novel series of indole-3-heterocyclic CB1 receptor agonists. Starting from the potent but poorly soluble lead, 1, a rational approach was taken in order to balance solubility, hERG activity and potency while retaining the desired long duration of action within the mouse tail flick test. This led to the discovery of compound 38 which successfully progressed into clinical development.

Effect of increased serotonin levels on [18F]MPPF binding in rat brain: fenfluramine vs the combination of citalopram and ketanserin.

[18F]MPPF is a selective serotonin-1A (5-HT1A) receptor antagonist and may be used to measure changes in the functional levels of serotonin (5-HT). The technique is based on the assumption that the injected radiolabeled ligand competes for the same receptor as the endogenous transmitter. Results from studies using serotonergic ligands are not always consistent. The aim of the present study was to investigate if [18F]MPPF binding is decreased after an increase in 5-HT levels. [18F]MPPF binding was assessed in conscious rats using ex vivo autoradiography. We studied the effect of the 5-HT-releasing agent and reuptake inhibitor fenfluramine (10 mg/kg i.p.) and of a combination of the selective serotonin reuptake inhibitor (SSRI) citalopram (10 micromol/kg, s.c.) with the 5-HT2C antagonist ketanserin (100 nmol/kg, s.c). The effect of both treatments on extracellular 5-HT levels was determined using microdialysis. Fenfluramine treatment resulted in a 30-fold increase in extracellular 5-HT levels in the ventral hippocampus and induced a significant reduction of [18F]MPPF binding in the frontal cortex, hypothalamus, amygdala, and hippocampus. The microdialysis results showed a 10-fold 5-HT increase in the ventral hippocampus after combined administration of ketanserin and citalopram. The combination, however, did not affect [18F]MPPF binding. Our data show that [18F]MPPF binding in conscious rats is only reduced after substantial and therefore nonphysiological increases in 5-HT levels. These results may imply that the majority of 5-HT1A receptors is in the low-affinity state, in vivo.

Glycine transporter inhibitor attenuates the psychotomimetic effects of ketamine in healthy males: preliminary evidence.

Enhancing glutamate function by stimulating the glycine site of the NMDA receptor with glycine, D-serine, or with drugs that inhibit glycine reuptake may have therapeutic potential in schizophrenia. The effects of a single oral dose of cis-N-methyl-N-(6-methoxy-1-phenyl-1,2,3,4-tetrahydronaphthalen-2-ylmethyl) amino-methylcarboxylic acid hydrochloride (Org 25935), a glycine transporter-1 (GlyT1) inhibitor, and placebo pretreatment on ketamine-induced schizophrenia-like psychotic symptoms, perceptual alterations, and subjective effects were evaluated in 12 healthy male subjects in a randomized, counter-balanced, within-subjects, crossover design. At 2.5 h after administration of the Org 25935 or placebo, subjects received a ketamine bolus and constant infusion lasting 100 min. Psychotic symptoms, perceptual, and a number of subjective effects were assessed repeatedly before, several times during, and after completion of ketamine administration. A cognitive battery was administered once per test day. Ketamine produced behavioral, subjective, and cognitive effects consistent with its known effects. Org 25935 reduced the ketamine-induced increases in measures of psychosis (Positive and Negative Syndrome Scale (PANSS)) and perceptual alterations (Clinician Administered Dissociative Symptoms Scale (CADSS)). The magnitude of the effect of Org 25935 on ketamine-induced increases in Total PANSS and CADSS Clinician-rated scores was 0.71 and 0.98 (SD units), respectively. None of the behavioral effects of ketamine were increased by Org 25935 pretreatment. Org 25935 worsened some aspects of learning and delayed recall, and trended to improve choice reaction time. This study demonstrates for the first time in humans that a GlyT1 inhibitor reduces the effects induced by NMDA receptor antagonism. These findings provide preliminary support for further study of the antipsychotic potential of GlyT1 inhibitors.

Methylphenidate-induced activation of the anterior cingulate but not the striatum: a [15O]H2O PET study in healthy volunteers.

The dopaminergic system has been implicated in the pathogenesis and treatment of a variety of neuropsychiatric disorders, such as schizophrenia, depression, and addiction. (Dys)function of the dopaminergic system may be studied by combining [15O]H2O PET with a dopaminergic drug challenge. In this pilot study we investigated the suitability of the dopamine reuptake blocker methylphenidate (MP) as a dopaminergic probe. Measurements of regional cerebral blood flow (rCBF) were made at 10 and 30 min after placebo and MP (0.25 mg/kg) injection to seven healthy volunteers. During scanning the behavioral condition of the subjects was standardized using a continuous performance task. Growth hormone levels were assessed and subjective ratings were obtained. MP significantly elevated growth hormone levels. After receiving MP, the subjective experience varied from neutral to highly pleasurable. Ten minutes after MP administration, significant relative increases in rCBF were found in the rostral anterior cingulate (AC), temporal poles, and the supplementary motor area. Significant reductions were seen in the superior temporal gyri, right medial frontal gyrus, and right inferior parietal cortex. At 30 min after MP administration, increases were seen in the AC, temporal pole, and right cerebellum. No changes were observed in the striatum. The activation in the right rostral AC was significantly higher in the subjects with the highest euphoria scores compared to the subjects with minimal MP-induced changes in euphoria. We suggest that the combined MP challenge with functional imaging, as described in our study, may be a useful tool to study the functional integrity of the dopaminergic system in psychiatric disorders.

Effect of fenfluramine-induced increases in serotonin release on [18F]MPPF binding: a continuous infusion PET study in conscious monkeys.

[(18)F]MPPF is a selective and reversible antagonist to the serotonin-1A (5-HT(1A)) receptor. The aim of the present study was to investigate whether the binding of [(18)F]MPPF is sensitive to increases in 5-HT levels. We used the 5-HT releasing agent and reuptake inhibitor fenfluramine (FEN) to increase the concentration of 5-HT. [(18)F]MPPF binding was assessed using positron emission tomography (PET) in conscious monkeys. Possible effects of blood flow on ligand binding were excluded by using a bolus-infusion paradigm. Control scans were obtained to assess the state of ligand equilibrium. FEN (5 or 10 mg/kg, i.v.) was administered between 90 and 130 min after the start of the [(18)F]MPPF infusion. The binding potential (BP) was calculated for an early interval (30 min preceding FEN administration) and late interval (20-50 min after administration of FEN). Microdialyses results showed a 20- and 35-fold increase in extracellular 5-HT levels in the prefrontal cortex after injection of FEN at a dose of 5 mg/kg and 10 mg/kg respectively. However, despite these large increases in 5-HT levels, no differences in BP were found between the control and FEN scans. These results may imply that the majority of 5-HT(1A) receptors is in the low affinity state in the living brain.

5-Hydroxytryptamine1A receptor occupancy by novel full antagonist 2-[4-[4-(7-chloro-2,3-dihydro-1,4-benzdioxyn-5-yl)-1-piperazinyl]butyl]-1,2-benzisothiazol-3-(2H)-one-1,1-dioxide: a[11C][O-methyl-3H]-N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide trihydrochloride (WAY-100635) positron emission tomography study in humans.

5-Hydroxytryptamine(1A) (5-HT(1A)) receptors have been implicated in the pathophysiology and treatment of anxiety and depression, and are a target for novel drug development. This is the first study examining the human brain in vivo occupancy by a novel, selective, silent 5-HT(1A) antagonist. 2-[4-[4-(7-Chloro-2,3-dihydro-1,4-benzdioxyn-5-yl)-1-piperazinyl]butyl]-1,2-benzisothiazol-3-(2H)-one-1,1-dioxide (DU 125530), a compound in clinical development, has potential applications in the treatment of anxiety and mood disorders. Positron emission tomography (PET) and [(11)C][O-methyl-3H]-N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide trihydrochloride (WAY-100635), were used to assess 5-HT(1A) autoreceptor and postsynaptic receptor occupancy in 12 healthy male volunteers. Over a 10- to 40-mg daily dose range, DU 125530 was well tolerated, and exhibited a dose-dependent occupancy from 0 to 72% at 2 h post the last dose. Occupancy correlated significantly with plasma levels of DU 125530, and a fitting of the data to a standard single-site binding model gave a maximum occupancy of approximately 80%, and a half-saturation concentration (ED(50)) of approximately 7 ng/ml. At 24 h after the last dose 5-HT(1A) occupancy was approximately 50% of that achieved at 2 h. This study demonstrates that high occupancy of the human brain 5-HT(1A) receptor can be achieved at doses producing minimal acute side effects.

5-HT(1A) receptor imaging in the human brain: effect of tryptophan depletion and infusion on [(18)F]MPPF binding.

The 5-HT(1A) receptor has been implicated in a variety of physiological processes, psychiatric disorders, and neurodegenerative disorders. [(18)F]MPPF is a useful radioligand for quantitative imaging of 5-HT(1A) receptors in human subjects. Previous studies have shown that the binding of some radioligands is sensitive to changes in neurotransmitter concentration, whereas in other cases, binding is not affected. In the present study we investigated if [(18)F]MPPF binding to the 5-HT(1A) receptor is sensitive to changes in 5-HT. Changes in 5-HT levels were achieved by influencing its synthesis through tryptophan depletion, including a tryptophan-free amino acid drink 4.5 h prior to the PET scan and tryptophan infusion (10 mg/ml, 50 mg/kg, 30 min, starting 60 min prior to the PET scan). Binding of [(18)F]MPPF in the brain of six healthy, male volunteers was compared in these two conditions. Mean binding potentials in the medial temporal cortex, cortical regions, and raphe nucleus did not significantly differ between the two conditions. The results of the study show that, under the experimental conditions used, [(18)F]MPPF binding was not affected. It is hypothesized that the increases in 5-HT levels needed to produce a measurable effect on [(18)F]MPPF binding would be significantly greater than that possible with tryptophan manipulation. Therefore, in pathological conditions, where such large increases in 5-HT levels are not expected, [(18)F]MPPF seems a useful ligand to measure 5-HT(1A) receptor distribution without the interference of endogenous 5-HT.