A randomized, placebo-controlled trial of the analgesic efficacy and safety of the p38 MAP kinase inhibitor, losmapimod, in patients with neuropathic pain from lumbosacral radiculopathy.

Objectives: Preclinical studies have demonstrated involvement of p38 mitogen-activated protein kinase signaling pathways in the development of persistent pain after peripheral nerve injury. A double-blind, randomized, placebo-controlled study was undertaken to evaluate the analgesic efficacy of losmapimod (GW856553), a novel p38α/β inhibitor, in patients with chronic neuropathic pain due to lumbosacral radiculopathy.

Materials And Methods: A total of 144 patients with at least moderate baseline pain intensity (average daily score of ≥4 on an 11-point pain intensity numeric rating scale) were randomized to receive losmapimod, 7.

Model-based approach and signal detection theory to evaluate the performance of recruitment centers in clinical trials with antidepressant drugs.

The objective of this study was to characterize the performance of each recruitment center in multicenter clinical trials and to provide criteria to discriminate between informative and noninformative centers using the signal detection approach. Data were derived from the GlaxoSmithKline Clinical Trial database on paroxetine and bupropion, totaling 4,016 subjects with major depressive disorders (MDDs) across nine trials. The probability of observing clinically relevant difference of active treatment from placebo was estimated in each center as a function of the placebo Hamilton Depression Rating Scale (HAMD-17) scores at baseline and at week 8.

Pharmacokinetics and time-course of D(2) receptor occupancy induced by atypical antipsychotics in stabilized schizophrenic patients.

The (123)I-IBZM SPECT measured D(2) receptor occupancy (D(2)RO) in chronically dosed, stabilized schizophrenic patients and its relationship with antipsychotic (AP) pharmacokinetics (PK) over time is still unclear. The aims of this study were: 1) To define the relationship between striatal D(2) receptor occupancy (D( 2)RO) and plasma concentration (C(P)) in stabilized schizophrenic patients on clinically relevant doses using (123)I-IBZM SPECT; 2) To investigate the time course of AP-induced D(2)RO and corresponding C(P). Forty-six schizophrenic patients on their clinically required doses of risperidone, olanzapine, clozapine or quetiapine were included.

Targets for regulating angiogenesis in the ageing endothelium.

Vascular dysfunction underlies the pathophysiology of a wide range of diseases, including atherosclerosis, diabetes and arthritis. Angiogenic function is progressively impaired with increasing age and, therefore, has been linked to the increased risk of many of these diseases among older people. Elucidating the cellular and molecular angiogenic pathways that become dysregulated with age will lead to the identification of novel targets for the restoration of vascular repair mechanisms in the older population.

Test-retest variability and reliability of 123I-IBZM SPECT measurement of striatal dopamine D2 receptor availability in healthy volunteers and influence of iterative reconstruction algorithms.

Objective: 123I-IBZM single photon emission computed tomography (SPECT) is a widely used method to measure D(2) receptor availability. However, test-retest variability and reliability have not been reported yet. This study aimed to further characterize 123I-IBZM SPECT in healthy volunteers (HVs), by assessing (1) pseudoequilibrium interval after bolus injection; (2) normal specific uptake ratio (SUR) values using filtered-backprojection (FBP); and the iterative reconstruction algorithm ordered-subsets expectation maximization (OSEM); (3) test-retest variability and reliability (intraclass correlation coefficient); and (4) influence of OSEM on test-retest variability and reliability.

Pharmacogenetics and paediatric drug development: issues and consequences to labelling and dosing recommendations.

The area of pharmacogenetics (PGt) is evolving rapidly. However, ongoing efforts in this field are not aligned with the requirements for the inclusion of clinically relevant findings into the label, especially with reference to paediatric indications. Clinical research in children poses unique issues from a practical and technical perspective, but many challenges can be overcome by applying advanced study design and data analysis methods.

Serotonin transporter occupancy induced by paroxetine in patients with major depression disorder: a 123I-ADAM SPECT study.

Rationale: To assess the paroxetine-induced serotonin transporter (SERT) occupancy (SERTocc) using in vivo (123)I-ADAM SPECT.

Objectives: (123)I-ADAM SPECT was used to investigate the SERTocc induced by paroxetine in major depression disorder (MDD) patients, to compare the SERT availability in drug-free MDD patients and healthy volunteers, and to study the relationship between paroxetine plasma concentrations (Cp) and SERTocc.

Materials And Methods: Measures of SERT availability by means of (123)I-ADAM SPECT were obtained in ten MDD patients before and after 4- to 6-week treatment with paroxetine 20 mg/day.

Characterization of the SPECT 5-HT2A receptor ligand 123I-R91150 in healthy volunteers: part 2--ketanserin displacement.

Unlabelled: As part of the radioiodinated 4-amino-N-1-[3-(4-fluorophenoxy)propyl]-4-methyl-4-piperidinyl]5-iodo-2-methoxybenzamide ((123)I-R91150) characterization study, ketanserin challenges were performed on healthy volunteers with the aim of assessing the specificity of (123)I-R91150 binding to subtype 2A of the 5-hydroxytryptamine receptor (5-HT(2A)), the sensitivity of (123)I-R91150 SPECT in measuring ligand displacement, the relationship between ketanserin plasma concentrations and (123)I-R91150 displacement, and the suitability of the cerebellum as a reference region for quantification.

Methods: Dynamic SPECT was performed on 6 healthy men (mean age +/- SD, 21 +/- 0.89 y) from the time of (123)I-R91150 injection until 470 min afterward.

Characterization of the SPECT 5-HT2A receptor ligand 123I-R91150 in healthy volunteers: Part 1--pseudoequilibrium interval and quantification methods.

Unlabelled: With the aim of characterizing radioiodinated 4-amino-N-1-[3-(4-fluorophenoxy)propyl]-4-methyl-4-piperidinyl]5-iodo-2-methoxybenzamide ((123)I-R91150) as a SPECT ligand for subtype 2A of the 5-hydroxytryptamine receptor (5-HT(2A)), tracer kinetic compartmental analyses were compared with the tissue ratio method (TR). The pseudoequilibrium interval after a single bolus injection was identified, and a reference database of specific uptake ratio (SUR) values was obtained. Within-scan and between-subject variability was also assessed.

Fosamprenavir : clinical pharmacokinetics and drug interactions of the amprenavir prodrug.

Fosamprenavir is one of the most recently approved HIV-1 protease inhibitors (PIs) and offers reductions in pill number and pill size, and omits the need for food and fluid requirements associated with the earlier-approved HIV-1 PIs. Three fosamprenavir dosage regimens are approved by the US FDA for the treatment of HIV-1 PI-naive patients, including fosamprenavir 1,400 mg twice daily, fosamprenavir 1,400 mg once daily plus ritonavir 200mg once daily, and fosamprenavir 700 mg twice daily plus ritonavir 100mg twice daily. Coadministration of fosamprenavir with ritonavir significantly increases plasma amprenavir exposure.