A phase I first-in-human pharmacokinetic and pharmacodynamic study of serdemetan in patients with advanced solid tumors.

Purpose: Originally isolated on the basis of its ability to induce p53, serdemetan showed potent activity in various preclinical models, inducing S-phase arrest and apoptosis in TP53 wild-type and mutant tumors. This study evaluated the safety and tolerability of serdemetan, determined the pharmacokinetic and pharmacodynamic profiles, and identified a recommended phase II dose.

Patients And Methods: Patients (71) with refractory solid tumors were allocated to dose-escalating cohorts (3+3 patients each) and received oral serdemetan once daily in 21-day cycles to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLT).

Phase I and pharmacological study of the broad-spectrum tyrosine kinase inhibitor JNJ-26483327 in patients with advanced solid tumours.

Background: JNJ-26483327 is an oral, potent, multi-targeted tyrosine kinase inhibitor, inhibiting kinases of epidermal growth factor receptor (EGFR)-1, -2 and -4, rearranged during transfection (RET) receptor, vascular endothelial growth factor receptor (VEGFR)-3 and Src family (Lyn, Fyn, Yes) at low nanomolar concentrations. This phase I, accelerated titration study assessed maximum tolerated dose, safety, pharmacokinetics and pharmacodynamic effects of JNJ-26483327.

Methods: Nineteen patients with advanced cancers received JNJ-26483327 continuous twice daily (BID) in escalating dose cohorts ranging from 100 to 2100 mg.

Structural priming of adjective-noun structures in hearing and deaf children.

We examined priming of adjective-noun structures in Dutch hearing and deaf children. In three experiments, hearing 7- and 8-year-olds, hearing 11- and 12-year-olds, and deaf 11- and 12-year-olds read a prenominal structure (e.g.

Evaluative expression in deaf children's written narratives.

Background: Deaf children vary in the use of and proficiency in signed language. The majority of studies on writing skills of children who are deaf did not assess deaf children's proficiency in signed language and/or grouped together deaf children with varying sign language skills.

Aims: Adopting a bimodal bilingual perspective, we examined evaluative expression, an important narrative tool in both oral/written languages and signed languages, in narratives written in Dutch by deaf children who are proficient in Sign Language of the Netherlands (SLN) and deaf children who are low-proficient in SLN, and hearing monolingual and bilingual children.

Pharmacokinetic-pharmacodynamic modelling of fluvoxamine 5-HT transporter occupancy in rat frontal cortex.

Background And Purpose: The pharmacokinetic-pharmacodynamic (PK-PD) correlation of fluvoxamine 5-HT transporter (SERT) occupancy was determined in rat frontal cortex ex vivo.

Experimental Approach: Rats (n=47) with permanent arterial and venous cannulas received a 30 min intravenous infusion of fluvoxamine (1 or 7.3 mg kg(-1)).

Mechanistic model for the acute effect of fluvoxamine on 5-HT and 5-HIAA concentrations in rat frontal cortex.

A mechanistic model is proposed to predict the time course of the concentrations of 5-HT and its metabolite 5-hydroxyindolacetic acid (5-HIAA) in rat frontal cortex following acute administration of SSRIs. In the model, SSRIs increase synaptic 5-HT concentrations by reversible blockade of the SERT in a direct concentration-dependent manner, while the 5-HT response is attenuated by negative feedback via 5-HT autoreceptors. In principle, the model allows for the description of oscillatory patterns in the time course of 5-HT and 5-HIAA concentrations in brain extracellular fluid.

Pharmacokinetic-pharmacodynamic modeling of the effect of fluvoxamine on p-chloroamphetamine-induced behavior.

The pharmacokinetic-pharmacodynamic (PK-PD) correlation of the effect of fluvoxamine on para-chloroamphetamine (PCA)-induced behavior was determined in the rat. Rats (n=66) with permanent arterial and venous cannulas received a 30-min intravenous infusion of 1.0, 3.

Pharmacokinetic modeling of non-linear brain distribution of fluvoxamine in the rat.

Introduction: A pharmacokinetic (PK) model is proposed for estimation of total and free brain concentrations of fluvoxamine.

Materials And Methods: Rats with arterial and venous cannulas and a microdialysis probe in the frontal cortex received intravenous infusions of 1, 3.7 or 7.

Tissue distribution and depletion kinetics of bortezomib and bortezomib-related radioactivity in male rats after single and repeated intravenous injection of 14 C-bortezomib.

Purpose: The body distribution of total radioactivity (TR) and bortezomib was investigated in male Sprague-Dawley rats after single and repeated i.v. (bolus) administration with (14)C-labelled bortezomib (VELCADE) (0.

Population pharmacokinetic model of fluvoxamine in rats: utility for application in animal behavioral studies.

The limitations of blood sampling in pharmacokinetic (PK)/pharmacodynamic (PD) studies in behavioral animal models could in part be overcome by a mixed effects modeling approach. This analysis characterizes and evaluates the population PK of fluvoxamine in rat plasma using nonlinear mixed effects modeling. The model is assessed for its utility in animal behavioral PK/PD studies.

Intestinal uptake and biodistribution of novel polymeric micelles after oral administration.

To determine the fate of polymeric micelles after oral administration, we investigated the possible transport of polymeric micelles across Caco-2 monolayers and their biodistribution in rats after per os administration of [14C]-labelled mmePEG750P(CL-co-TMC) micelles containing risperidone (BCS Class II drug). mmePEG750P(CL-co-TMC) was able to cross Caco-2 monolayer via a saturable transport mechanism. The oral bioavailability of the polymer was 40%.

Synthesis, structure-activity relationship, and receptor pharmacology of a new series of quinoline derivatives acting as selective, noncompetitive mGlu1 antagonists.

We describe the discovery and the structure-activity relationship of a new series of quinoline derivatives acting as selective and highly potent noncompetitive mGlu1 antagonists. We first identified cis-10 as a fairly potent mGlu1 antagonist (IC(50) = 20 nM) in a cell-based signal transduction assay on the rat mGlu1 receptor expressed in CHO-K1 cells, and then we were able to design and synthesize highly potent compounds on both rat and human mGlu1 receptors as exemplified by compound cis-64a, which has an antagonist potency of 0.5 nM for the human mGlu1 receptor.

Pharmacokinetics and tissue distribution of galantamine and galantamine-related radioactivity after single intravenous and oral administration in the rat.

The plasma kinetics and tissue distribution of galantamine hydrobromide [4aS-(4a alpha,6beta,8aR*)]-4a,5,9,10,11,12-hexahydro-3-methoxy-11-methyl-6H-benzofuro-[3a,3,2-ef] [2benzazepin-6-ol hydrobromide, CAS-1953-04-4], a reversible acetylcholinesterase inhibitor, were studied in male and female non-pregnant and pregnant SPF Wistar rats and in male Fisher x Copenhagen pigmented rats. Most studies were performed using 3H-labelled galantamine hydrobromide, measuring unchanged drug (UD) and non-volatile radioactivity (NVR) in plasma and tissues by high-performance liquid chromatography (HPLC), liquid scintillation counting and quantitative whole-body autoradiography (QWBA). Plasma levels after single intravenous administration of UD (1.

Effect of efflux inhibition on brain uptake of itraconazole in mice infected with Cryptococcus neoformans.

Itraconazole is a fungistatic agent that, although highly lipophilic, shows poor transport through the blood brain barrier that may be due to efflux proteins. The combined administration of an efflux inhibitor with itraconazole should increase cerebral itraconazole concentrations and therefore, improve the treatment of Cryptococcus neoformans meningitis with this antifungal agent. To test this hypothesis, we have studied the influence of murine cerebral infection with C.

The metabolism and excretion of galantamine in rats, dogs, and humans.

Galantamine is a competitive acetylcholine esterase inhibitor with a beneficial therapeutic effect in patients with Alzheimer's disease. The metabolism and excretion of orally administered (3)H-labeled galantamine was investigated in rats and dogs at a dose of 2.5 mg base-Eq/kg body weight and in humans at a dose of 4 mg base-Eq.

Strategies for absorption screening in drug discovery and development.

This review gives an overview of the current approaches to evaluate drug absorption potential in the different phases of drug discovery and development. Methods discussed include in silico models, artificial membranes as absorption models, in vitro models such as the Ussing chamber and Caco-2 monolayers, in situ rat intestinal perfusion and in vivo absorption studies. In silico models such as iDEA can help optimizing chemical synthesis since the fraction absorbed (Fa) can be predicted based on structural characteristics only.

Gastrointestinal distribution of the prodrug loperamide oxide and its active drug loperamide in the dog.

Loperamide oxide is a prodrug of the effective antidiarrheal loperamide. Administration of this prodrug improves efficacy and tolerability. For better understanding of these effects, the absorption and gastrointestinal distribution of loperamide oxide and of its active drug loperamide were studied.

The pharmacokinetics of risperidone in humans: a summary.

Risperidone is rapidly and completely absorbed after oral administration; less than 1% is excreted unchanged in the feces. The principal metabolite was found to be 9-hydroxyrisperidone. Hydroxylation of risperidone is subject to the same genetic polymorphism as debrisoquine and dextromethorphan.

Regional brain distribution of risperidone and its active metabolite 9-hydroxy-risperidone in the rat.

Risperidone is a new benzisoxazole antipsychotic. 9-Hydroxy-risperidone is the major plasma metabolite of risperidone. The pharmacological properties of 9-hydroxy-risperidone were studied and appeared to be comparable to those of risperidone itself, both in respect of the profile of interactions with various neurotransmitters and its potency, activity, and onset and duration of action.

Detection of aspartic acid enantiomers by chiral capillary gas chromatography. Determination of in vivo racemization and reduction of metal-induced background.

Racemization of aspartyl residues in proteins is a post-translational process, related to ageing. A method is presented for the detection of aspartic acid enantiomers in protein hydrolysates, based on chiral capillary gas chromatography. It is fast, easy and preferable to the usual diastereomeric dipeptide technique.