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Biomedical subjects

G Dunbar

Publications and source records attributed to G Dunbar.

9 recordsLinked to original sources
PubMed2007

Effects of TC-1734 (AZD3480), a selective neuronal nicotinic receptor agonist, on cognitive performance and the EEG of young healthy male volunteers.

OBJECTIVES: The aim of this study was to get insight into the central effects of TC-1734 (renamed AZD3480), a selective agonist at the neuronal nicotinic receptor of the alpha4beta2 subtype. MATERIALS AND METHODS: Electroencephalography (EEG) techniques and computerized cognitive tests were performed in young, healthy male volunteers during two double-blind and placebo-controlled studies: a rising single dose crossover study (from 2 to 320 mg) and a rising repeated dose study with a parallel group design (50, 100, and 200 mg). RESULTS: In contrast to acute administration, administration of AZD3480 over 10 days produced statistically significant enhancement of several cognitive measures (attention and episodic memory) compared to placebo. Regarding EEG data, AZD3480 showed acceleration of the alpha centroid and of the alpha peak in the single-dose study. This EEG profile of the acceleration type was confirmed in the repeated dose study on both day 1 and day 10, with the greatest effect observed with the highest dose. The EEG pattern shown for AZD3480 was consistent with that previously described with other drugs known to improve attention and vigilance (including nicotine). In addition, subjects dosed with AZD3480 showed a statistically significant increase in mismatch negativity (MMN) amplitude at 50 and 200 mg while reducing MMN latency (200 mg only), suggesting an improvement of pre-attentional mechanisms. CONCLUSION: These early data in healthy subjects provide encouragement to consider development of AZD3480 as a novel agent for the treatment of cognitive decline in the elderly, including age-associated memory impairment and/or dementia of the Alzheimer's type.

Administration, Oral↗
PubMed2006

Pharmacokinetics and safety profile of ispronicline (TC-1734), a new brain nicotinic receptor partial agonist, in young healthy male volunteers.

Recent research suggests that drugs activating nicotine acetylcholine receptors might be promising therapy in cognitive decline seen in the elderly, including Alzheimer's disease. Ispronicline (TC-1734), a brain-selective alpha4beta2 nicotine acetylcholine receptor partial agonist, has shown memory-enhancing properties in rodents and a good tolerability profile. The safety and the full pharmacokinetic profile of TC-1734 and its N-desalkylated metabolite, TC-1784, were investigated in 2 phase I studies, and results are reported in this article. Study A used a double-blind, placebo-controlled, crossover design with a rising single-dose scheme (2-320 mg). Study B used a double-blind, placebo-controlled, parallel-group design with a rising multiple-dose scheme (doses: 50, 100, and 200 mg, once daily, x 10 days). Cmax of TC-1734 was reached around 1 to 2 hours postdose, and mean terminal half-life (t1/2) ranged from 3 to 5.3 hours (single doses) and from 2.7 to 8.8 hours (repeated doses). No accumulation of TC-1734 was observed after 10 days. Renal clearance appeared to be a minor method of elimination of TC-1734 and TC-1784. A high interindividual variability was noted for all parameters. Across the dose ranges explored, TC-1734 was safe and well tolerated. No changes of clinical significance were seen on laboratory and cardiovascular parameters. Adverse events were generally of mild to moderate intensity, with dizziness and headache being reported most frequently.

Administration, Oral↗
PubMed2001

Children's attentional skills and road behavior.

Switching attention and concentration, 2 skills expected to be used by skillful pedestrians, were studied. A sample of 160 children (aged 4 years 3 months-10 years) played a computer game involving attention switching. To examine concentration, a subset of the children was distracted with a cartoon video while they attempted a difficult task that required matching familiar figures. The same subset was also observed crossing roads. Older children switched faster and were less distracted. Children who were better at switching were more likely to show awareness of traffic when about to cross a road. Children who maintained concentration when challenged by a distracting event crossed the road in a less reckless manner. Parents and educators designing safety programs should take into account the development of these skills.

Attention↗
PubMed1997

A comparison of paroxetine, clomipramine and placebo in the treatment of panic disorder. Collaborative Paroxetine Panic Study Investigators.

The aim of this 12-week, double-blind, parallel group, placebo-controlled study was to compare paroxetine with clomipramine in 367 patients with DSM-III-R defined panic disorder. Efficacy assessments included the daily panic attack diary, the Clinical Global Impression Scale, the Hamilton Anxiety Rating Scale, the Marks Sheehan Phobia Scale and the Sheehan Disability Scale. Paroxetine produced significant improvements compared with placebo in various measurements of panic attack frequency, and was as effective as clomipramine. However, paroxetine appeared to have a more rapid onset of action than clomipramine in reducing the number of panic attacks to zero. There was an equivalent improvement with both paroxetine and clomipramine in the supportive efficacy variables which assessed associated aspects of therapeutic improvement. Significantly more adverse effects were reported in the clomipramine group compared with the paroxetine group, while there was no difference between the paroxetine and placebo groups.

Adolescent↗
PubMed1993

Molecular studies of mitochondrial acetoacetyl-coenzyme A thiolase deficiency in the two original families.

We describe mutations identified in stored skin fibroblast cell lines from two original probands (JB and JM), first reported with 2-methylacetoacetic aciduria, and shown later to have a deficiency of the K(+)-activated enzyme, mitochondrial acetoacetyl-coenzyme A thiolase (T2). JB is homozygous for a 4-base insertion (GCAG) which is derived mutation. The primary mutation is an AG/gt to AG/gc transition at the 5'-splice-junction site in intron 11. An alternative splice site 4 bp downstream (Ggcag/gt) is used which causes a frame shift and replaces 39 C-terminal residues by 70 nonfunctional residues. JM is homozygous for a mutation in the translation-initiation codon (ATG to AAG). By expression analyses the JB mutation (IVS11nt2) causes an unstable T2 polypeptide and the JM mutation (M1K) severely impairs T2 mRNA translation. The JB allele associates with Dutch ancestry (no consanguinity) and the JM allele with Chilean ancestry (distant consanguinity).

Acetyl-CoA C-Acetyltransferase↗
PubMed1993

Paroxetine is better than placebo in relapse prevention and the prophylaxis of recurrent depression.

In an investigation of the efficacy of paroxetine in relapse prevention and prophylaxis of depression, patients who met DSM-III-R criteria for major depression with a history of two or more previous episodes in the preceding four years and who had responded to eight weeks treatment with paroxetine, were randomized double-blind to receive either paroxetine 20-30 mg or placebo for one year. One hundred and seventy-two patients entered open treatment of whom 141 completed eight weeks treatment. One hundred and thirty-five responders entered the double-blind placebo-controlled study. There was a significant advantage for paroxetine compared with placebo in the reappearance of depression (p < 0.01) and in the time to reappearance (p < 0.001) over the one-year study. A significant advantage was seen for paroxetine compared with placebo in the first four months in relapse prevention (p < 0.01) and in the time to relapse (p < 0.005), and in the later period of treatment in preventing recurrence in the time to recurrence (p < 0.05). Paroxetine was effective in preventing the reappearance of depression following an acute illness. These results confirm the benefit of long-term pharmacotherapy for treating depressive illness.

Adult↗