Experiments with cocaine and heroin addicts--are they predictive?

Treating cocaine addiction using dopamine replacement strategies, treats withdrawal but not relapse. Experiments with diverse pharmacological agents shows involvement of multiple pharmacologies and new approaches are emerging to treat the drug seeking behaviour and craving associated with relapse. Neuropathological studies are showing structural and connectivity changes in the brain of addicts which appear permanent, making control of learned behaviours associated with these changes extremely challenging.

Clinical pharmacology in neuroscience drug discovery: quo vadis?

Clinical Pharmacology in Neuroscience Drug Discovery in recent years has concentrated on First Time in Human safety and pharmacokinetics. The more traditional pharmacological research in humans has been reduced mainly as a response to the difficulty of developing human pharmacology models in neuroscience diseases. As a consequence, opportunities are being missed to aid in target selection and in target validation.

Why receptor reserve matters for neurokinin1 (NK1) receptor antagonists.

The difference in location between the receptor occupancy curve of an agonist and its functional response has been described as receptor reserve. This "reserve" for a specific receptor has been found to differ from tissue to tissue and between agonists acting on the same tissue. Recently, two structurally different neurokinin 1 (NK1) receptor antagonists were taken into human and both were tested as antidepressants and for insomnia.

Results from 2 randomized, double-blind, placebo-controlled studies of the novel NK1 receptor antagonist casopitant in patients with major depressive disorder.

Clinical study results for neurokinin (NK) receptor antagonists in the treatment of depression have been mixed, with Phase III studies failing to fulfill the early promise demonstrated in Phase II studies. Casopitant, a selective NK1 antagonist that achieves nearly complete receptor occupancy was studied in 2 randomized, placebo-controlled, double-blind, Phase II trials in depressed outpatients to test the hypothesis that nearly complete NK1 receptor occupancy is required to achieve antidepressant efficacy. Study 092 used an interactive voice response system to recruit depressed patients with baseline Hamilton Depression (17-item, HAMD17) total scores higher than 24 who were randomized to fixed-dose casopitant 30 mg/d, 80 mg/d, or placebo for 8 weeks (n = 356).

Effect of sustained-release (SR) bupropion on craving and withdrawal in smokers deprived of cigarettes for 72 h.

Rationale: Sustained-release (SR) bupropion enhances quit rates of smokers, generally decreases tobacco withdrawal, and in some studies, reduces craving.

Objective: Investigate the effects of SR bupropion on craving and withdrawal during cigarette abstinence.

Methods: Twenty three smokers participated in three 17-day periods composed of 14 out-patient days followed by 3 (72 h) in-patient days.

EEG power spectra and auditory P300 during free smoking and enforced smoking abstinence.

We investigated resting EEG and auditory P300 during free smoking and 36 h of enforced smoking abstinence in 12 healthy volunteers. Resting EEG was recorded on 19 scalp leads and auditory P300 was obtained by an oddball paradigm task. Spectral analysis of EEG (absolute and relative power, mean frequency), latency and amplitude of auditory P300 were considered for statistical analysis.

Smokers deprived of cigarettes for 72 h: effect of nicotine patches on craving and withdrawal.

Rationale: Research on the effects of nicotine abstinence and nicotine replacement has not provided consistent information about the impact of replacement therapies on tobacco withdrawal and craving.

Objective: . This study investigated craving and withdrawal symptoms over a 72-h period of abstinence from cigarettes.

Correlation and predictive performances of saliva and plasma nicotine concentration on tobacco withdrawal-induced craving.

Aims: To investigate whether saliva is a useful alternative to plasma for routine monitoring of nicotine and evaluate the predictive performances of saliva and plasma concentration on craving estimated by a Tiffany Questionnaire on Smoking Urge-Brief Form.

Methods: Thirteen healthy smokers were enrolled in a randomized, two period, crossover trial. Linear and power models were evaluated to predict the plasma nicotine concentrations from the saliva measurements, whereas a population PK/PD indirect response model was used to predict craving using either saliva or plasma nicotine concentration as the independent variable.

Absolute quantification of cerebral blood flow with magnetic resonance, reproducibility of the method, and comparison with H2(15)O positron emission tomography.

While H2(15)O positron emission tomography (PET) is still the gold standard in the quantitative assessment of cerebral perfusion (rCBF), its technical challenge, limited availability, and radiation exposure are disadvantages of the method. Recent work demonstrated the feasibility of magnetic resonance (MR) for quantitative cerebral perfusion imaging. There remain open questions, however, especially regarding reproducibility.

In silico prediction of optimal in vivo delivery properties using convolution-based model and clinical trial simulation.

Purpose: To develop a new strategy for the in silico evaluation of the optimal in vivo delivery properties of a drug, minimizing a cost function defined by the brain receptor occupancy obtained in positron-emission tomography experiments.

Methods: A convolution-based model was formulated to link in vivo delivery rate to plasma concentrations whereas a second-stage model was used to link plasma concentrations to the pharmacodynamic effect. A feedback control approach was applied to identify the optimal in vivo delivery rate given an appropriate optimality criterion.

Estimate the time varying brain receptor occupancy in PET imaging experiments using non-linear fixed and mixed effect modeling approach.

Positron-Emission Tomography (PET) is an imaging technology currently used in drug development as a non-invasive measure of drug distribution and interaction with biochemical target system. The level of receptor occupancy achieved by a compound can be estimated by comparing time-activity measurements in an experiment done using tracer alone with the activity measured when the tracer is given following administration of unlabelled compound. The effective use of this surrogate marker as an enabling tool for drug development requires the definition of a model linking the brain receptor occupancy with the fluctuation of plasma concentrations.