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Michael J Allen

Publications and source records attributed to Michael J Allen.

23 records · Page 2Linked to original sources
PubMed2002

Identification of potent and selective oxytocin antagonists. Part 1: indole and benzofuran derivatives.

Studies to discover novel, potent and selective oxytocin antagonists are reported. Combinatorial libraries designed to find novel replacements of fragments of oxytocin antagonist L-371,257, identified pyrimidine, thiazole, indole and benzofuran as potential alternatives to the benzoic acid moiety of L-371,257. Additional investigations identified indole and benzofuran derivatives with potent oxytocin antagonist activity.

Animals↗
PubMed2002

Combining constitutive materials modeling with atomic force microscopy to understand the mechanical properties of living cells.

The goal of this work is to study the properties of living cells and cell membranes by using atomic force microscopy. During atomic force microscopy (AFM) measurement, there is a strong mechanical coupling between the AFM tip and the cell. The purpose of this paper is to present a model of the overall mechanical response of the cell that allows us to separate out the mechanical response of the cell from the local surface interactions we wish to quantify. These local interactions include recognition (or binding) events between molecules bound to an AFM tip (e.g., an antibody) and molecules or receptors on the cell surface (e.g., the respective antigen). The computational model differs from traditional Hertzian contact models by explicitly taking into account the mechanics of the biomembrane and cytoskeleton. The model also accounts for the mechanical response of the living cell during arbitrary deformation. The indentation of a bovine sperm cell is used to test the validity of this model, and further experiments are proposed to fully parameterize the model.

Animals↗
PubMed2002

Pharmacodynamic effect of continuous vs intermittent dosing of dofetilide on QT interval.

AIMS: To investigate the pharmacokinetics and pharmacodynamics of dofetilide 1 mg twice daily continuously for 24 days compared with intermittent single dose treatments. METHODS: A randomized, single-blinded, placebo-controlled, parallel-group, multiple-dose study design was utilized. Healthy male volunteer subjects were randomized into three groups. Group 1 received dofetilide 1.0 mg twice daily for 23 days and once on day 24. Group 2 received matching placebo capsules under the same regimen as group 1. Group 3 received a single dose of dofetilide 1.0 mg on days 1, 5, 10, 17, and 24 with identical placebo capsules administered at all other times to match the dosing pattern of the other groups. RESULTS: Continuous administration of dofetilide resulted in the achievement of steady-state concentrations by day 5. Pharmacokinetic parameters following intermittent treatment showed no accumulation. Maximum daily QTc interval (mean +/- s.e. mean) increased in response to continuous twice-daily dofetilide from baseline (373 +/- 5) to day 2 (453 +/- 9) but thereafter decreased slightly, but not beyond day 5, by which time the mean maximum QTc was 440 +/- 7 ms. In contrast, single doses of dofetilide in the intermittently treated group led to reproducible increases in QTc. Thus mean (+/- s.e. mean) maximum QTc increased from a baseline of 387 +/- 7-467 +/- 14, 467 +/- 18, 469 +/- 14 and 458 +/- 10 ms on days 5, 10, 17 and 24, respectively. In view of the pharmacokinetic accumulation on continuous dosing, the attenuation of responsiveness is best represented by the slope of the QTc vs plasma concentration relationship. In the continuously treated group, an initial decrease in the value of the mean slope between day 1 (14.2 +/- 1.7 ms/ng ml(-1)) and day 5 (9.1 +/- 0.8 ms/ng ml(-1)) did not progress beyond day 5. The mean difference in slopes (95% CI) between the intermittent and continuously treated groups were 4.4 (1.3, 7.4) on day 5, 4.9 (1.6, 8.2) on day 10, 5.2 (1.1, 9.2) on day 17 and 4.4 (0.4, 8.4) on day 24. CONCLUSIONS: With continuous twice-daily administration the QT interval responsiveness to dofetilide is greater after the first dose than it is at steady state. After day 5 the relationship between dofetilide plasma concentration and its QT interval effect is predictable and stable over time.

Adolescent↗
PubMed2002

Pharmacokinetics, pharmacodynamics, and safety of the 5-HT(1B/1D) agonist eletriptan following intravenous and oral administration.

Four separate studies were conducted to examine the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of eletriptan, a 5-HT(1B/1D) receptor agonist being developed for the treatment of migraines, after oral and intravenous administration. Fifty-five males received oral (1.5-30 mg or 30-120 mg) or intravenous (1.67-50 microg/kg or 50-102 microg/kg) eletriptan in four double- and single-blind, placebo-controlled, ascending-dose crossover studies. The maximum plasma concentration (Cmax) and area under the concentration curve (AUC) appeared linear over all dose ranges, with an apparent terminal half-life of 4 to 5 hours. Clearance and volume of distribution remained constant with dose. The time to first occurrence of Cmax (tmax) for oral eletriptan was approximately 1 hour and was unaffected by dose. Comparison of AUC values suggested an absolute bioavailability of approximately 50%. A linear PK/PD model, fitted to the data, predicted small, transient elevations in diastolic blood pressure following eletriptan doses > or = 60 mg. These effects were considered unlikely to be clinically significant. Eletriptan was well tolerated, and treatment-related adverse events were mild to moderate and transient. These PK properties should result in eletriptan having a rapid onset and sustained duration of action in terms of migraine efficacy.

Administration, Oral↗