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Biomedical subjects

Thomas Hunt

Publications and source records attributed to Thomas Hunt.

6 recordsLinked to original sources
PubMed2006

Evaluation of the abuse potential of pagoclone, a partial GABAA agonist.

This study assessed the abuse potential of pagoclone, a partial agonist at the gamma-aminobutyric acid type A (GABAA) benzodiazepine receptor site, in healthy recreational drug users. Twenty-three young adults, who reported past recreational use of sedative drugs or alcohol, participated in 4 sessions during which capsules containing pagoclone (doses: 1.2 mg, the higher end of the proposed therapeutic dose range, and 4.8 mg, a 4-fold higher dose), diazepam (dose, 30 mg), or placebo were randomly administered under double-blind conditions. Subjective ratings of mood, drug effects, and psychomotor tests were completed at regular intervals after ingesting the capsules. On most of the standardized measures of abuse potential, pagoclone (dose, 4.8 mg) was rated as being similar to diazepam. Both drugs increased the ratings of good effects and drug liking. However, pagoclone also produced some adverse mood effects that might limit its potential to be used recreationally, and it produced fewer sedativelike effects on some measures. In general, the results with these doses indicate that the abuse potential of pagoclone is similar to that of diazepam, although its profile as a partial agonist suggests that differences between the drugs may emerge at higher doses.

Adolescent↗
PubMed2004

Pharmacokinetics and steady-state bioequivalence of treprostinil sodium (Remodulin) administered by the intravenous and subcutaneous route to normal volunteers.

Treprostinil sodium is a chemically stable analogue of prostacyclin administered as a chronic, continuous subcutaneous infusion for the treatment of pulmonary arterial hypertension (PAH). There has been significant clinical interest in determining the feasibility of delivering treprostinil by intravenous infusion. Therefore, a bioequivalence and comparative pharmacokinetics study of the two routes of administration was conducted in normal volunteers. A randomized, two-period, crossover study design was employed. Each subject was dosed at 10 ng/kg/min for 72 hours by each route, with the infusions separated by a 4-day wash-out period. In the 51 subjects who received at least 24 hours of treprostinil administered subcutaneously and intravenously, the steady-state ratios of the geometric means (i.v./s.c.) and 90% confidence intervals for AUCss and Cmaxss were 92.9% (89.8-96.1%) and 106% (99.4-113%), respectively. Secondary pharmacokinetic assessments confirmed the comparability of the two routes of administration at steady state, and also demonstrated that the elimination half-life of treprostinil was 4.4 and 4.6 hours following intravenous and subcutaneous administration, respectively. Based on these findings it was concluded that intravenously and subcutaneously administered treprostinil are bioequivalent at steady state.

Adolescent↗
PubMed2004

Multiple-dose FTY720: tolerability, pharmacokinetics, and lymphocyte responses in healthy subjects.

FTY720 is a sphingosine-1-phosphate receptor agonist being developed as an immunomodulator for acute rejection prophylaxis after organ transplantation. This study was performed to characterize the pharmacokinetics of and lymphocyte response to multiple-dose FTY720. In this randomized, double-blind study, three groups of 20 healthy subjects each received either placebo, 1.25 mg/day FTY720, or 5 mg/day FTY720 for 7 consecutive days. FTY720 blood concentrations and lymphocyte counts were assessed over the weeklong treatment phase and over a month-long washout phase. The relationship between FTY720 blood concentrations and lymphocyte counts was explored by an inhibitory E(max) model. First-dose exposure was consistent with dose proportionality between the low- and high-dose groups. Blood levels accumulated fivefold over the treatment period. Exposure on day 7 was dose proportional for C(max) (5.0 +/- 1.0 vs. 18.2 +/- 4.1 ng/mL) and for AUC (109 +/- 24 vs. 399 +/- 85 ng.h/mL). Washout pharmacokinetics after the last dose indicated an elimination half-life averaging 8 days. Lymphocyte counts decreased by 80% in subjects receiving the lower dose to a nadir of 0.4 +/- 0.1 x 10(9)/L and by 88% in subjects receiving the upper dose to a nadir of 0.2 +/- 0.1 x 10(9)/L. Descriptive exposure-response modeling estimated that the lymphocyte response at 5 mg/day is near the maximal response achievable. By the end-of-study evaluation on day 35, lymphocyte counts had recovered to within 75% and 50% of baseline in the low- and high-dose groups, respectively. In summary, systemic exposure to FTY720 was consistent with dose-proportionality after both single- and multiple-dose administration. Total lymphocyte counts decreased from baseline by 80% and 88% at regimens of 1.25 and 5 mg/day, respectively. Exposure-response modeling provided evidence that 5 mg/day FTY720 resulted in a near-maximal dynamic effect of this drug on lymphocytes.

Administration, Oral↗
PubMed2003

Effect of food on pharmacokinetics of an inhaled drug: a case study with a VLA-4 antagonist, HMR1031.

HMR1031 is a potent and specific antagonist of the integrin VLA-4 (alpha4beta1) binding to vascular cell adhesion molecule-1 (VCAM-1) and fibronectin. HMR1031 is an inhaled drug being developed for the treatment of asthma using an Ultrahaler dry-powder inhalation device. A pharmacoscintigraphic study of HMR1031 suggests a lung deposition of approximately 25% and gastrointestinal tract deposition of approximately 75%. Since oral absorption may be contributing to systemic plasma concentrations, the effect of food on HMR1031 was assessed. This was a single-dose (3 mg), open-label, randomized, two-way crossover (fasted vs. fed) study in 8 healthy male subjects. Blood samples were collected at predose and up to 24 hours postdose. Plasma concentrations were determined by the LC/MS/MS method. HMR1031 was rapidly absorbed, with median tmax values of 1.0 and 0.75 hours under fasted and fed conditions, respectively. Under fasted conditions, mean AUCinfinity and Cmax values were 16.4 ng x h/mL and 4.56 ng/mL, respectively. Under fed conditions, mean AUCinfinity and Cmax values decreased to 11.7 ng x h/mL and 2.81 ng/mL, respectively. The mean terminal elimination half-life (t1/2) for both treatment groups was similar (2.7 h). HMR1031 population estimates of the apparent clearance, apparent volume of distribution, and absorption rate were 225 L/h (4.1% coefficient of variation [CV]), 44.5 L (26% CV), and 0.340 h-1 (7.0% CV), respectively. Food is a significant covariate on clearance. These data suggest that food unexpectedly decreases the systemic exposure of inhaled HMR1031 by approximately 30%, probably due to increased liver blood flow and increased biliary excretion. This decrease in systemic exposure is unlikely to affect the topical effect of the drug but may result in increased variability in plasma pharmacokinetics. The disposition and food effect of HMR1031 can be described using mixed-effect modeling.

Absorption↗
PubMed2002

Lack of clinically relevant interaction between desloratadine and erythromycin.

OBJECTIVE: To evaluate the bioavailability, cardiac safety and tolerability of desloratadine when given in combination with the CYP3A4 inhibitor erythromycin. DESIGN: A randomised, 2-way crossover, placebo-controlled, third party-blind, multiple dose study. PARTICIPANTS: 24 healthy volunteers (12 men, 12 women) aged 19 to 46 years. INTERVENTIONS: Oral desloratadine 7.5mg daily in combination with either placebo (n = 24) or erythromycin 500mg every 8 hours (n = 24) for 10 days. After a minimum 7-day washout period, participants crossed over to the alternative regimen. MAIN OUTCOME MEASURES: ECG parameters. RESULTS: Desloratadine/erythromycin did not induce clinically or statistically significant changes in any ECG parameter. The maximum corrected QT (QT(c)) interval was 445 msec for both treatments. The peak plasma concentration and area under the plasma concentration-time curve from 0 to 24 hours of desloratadine were slightly increased by 1.2- and 1.1-fold by concomitant administration of erythromycin compared with desloratadine/placebo. Gastrointestinal adverse events were more frequent after desloratadine/erythromycin than desloratadine/placebo (46 vs 4%), reflecting the poor gastrointestinal tolerability of erythromycin. There were no reports of syncope. CONCLUSION: Combined desloratadine/erythromycin therapy was well tolerated and had no clinically relevant electrocardiographic effects at a dose that was 50% higher than the recommended dose of 5mg. Although coadministration of erythromycin slightly increased plasma concentrations of desloratadine, this change did not correlate with any prolongation of the QT(c) interval, and no toxicity was observed clinically.

Adult↗