Influence of CYP2C19 polymorphism on the pharmacokinetics of nelfinavir and its active metabolite.

Aims: This study reports the pharmacokinetics of nelfinavir, its active metabolite, M8, and active moiety (nelfinavir + M8) in volunteers genotyped for CYP2C19 as extensive metabolizer (*1*1; n = 38), heterozygous poor metabolizer (PM) (*1*2; n = 22) and homozygous PM (*2*2; n = 6).

Methods: Subjects received nelfinavir at normal dose (3.5 days of 1250 mg q12h) or high dose (1250 mg q12h for 3 days and single dose of 3125 mg on day 4).

Effects of standard and supratherapeutic doses of nelfinavir on cardiac repolarization: a thorough QT study.

This was a randomized, 4-way crossover, third-party-blinded study in 68 healthy subjects to assess the effect of nelfinavir on QTc interval. Treatments included (A) nelfinavir 1250 mg every 12 hours on days 1-4, (B) nelfinavir 1250 mg every 12 hours on days 1-3 plus 3125 mg on day 4, (C) placebo, and (D) moxifloxacin 400 mg every 24 hours on days 1-4. Pharmacokinetics and triplicate 12-lead electrocardiograms were performed over 12 hours on days 1 and 4.

Pharmacokinetics and pharmacodynamics of the vasopeptidase inhibitor, omapatrilat in healthy subjects.

Aims: To determine the pharmacokinetics, pharmacodynamics and tolerability of omapatrilat, a vasopeptidase inhibitor, in healthy subjects.

Methods: The effects of oral omapatrilat were evaluated in healthy men in two double-blind, placebo-controlled, dose-escalation trials. In a single-dose study, subjects received omapatrilat in doses of 2.

Pharmacokinetics and tolerability of buspirone during oral administration to children and adolescents with anxiety disorder and normal healthy adults.

A 21-day, open-label, multisite, dose escalation study comprising three demographic groups (children, adolescents, and adults) was performed to determine the pharmacokinetics and tolerability of orally administered buspirone. Thirteen children and 12 adolescents with anxiety disorder and 14 normal healthy adults were escalated from 5 to 30 mg buspirone bid over the 3-week study. Pharmacokinetic analysis revealed that buspirone was rapidly absorbed in all study groups, reaching peak levels at about 1 hour after administration.

Omapatrilat: neurohormonal and pharmacodynamic profile when administered with furosemide.

Pharmacodynamic effects of combination therapy with omapatrilat and furosemide were evaluated. Two groups of 13 healthy subjects each received furosemide 20 mg dailyfor 15 days coadministered with either placebo on days 6 to 15 or omapatrilat 10 mg on days 6 to 10 and 25 mg on days 11 to 15. In the omapatrilat group, urinary excretion of atrial natriuretic peptide increased, and greater blood pressure reductions were seen compared with placebo.

A dose-escalation study of the safety, tolerability, and pharmacokinetics of intravenous gatifloxacin in healthy adult men.

Study Objectives: To examine single- and multiple-dose safety, tolerability, and pharmacokinetics of gatifloxacin administered as daily 1-hour intravenous infusions for 14 days, and to determine the effect of gatifloxacin on glucose tolerance, pancreatic beta-cell function, and electrocardiogram (ECG).

Design: Randomized, double-blind, placebo-controlled, ascending-dose study.

Setting: Bristol-Myers Squibb, Clinical Pharmacology Unit, Princeton, New Jersey, USA.

Open-label, nonrandomized study of the effects of gatifloxacin on the pharmacokinetics of midazolam in healthy male volunteers.

Study Objective: To confirm findings from an in vitro study that showed gatifloxacin did not substantially inhibit cytochrome P450 (CYP) 3A4 model substrate metabolism.

Design: Open-label, nonrandomized trial.

Setting: Clinical pharmacology unit.

Effect of Nifedipine on the Steady-State Pharmacokinetics and Pharmacodynamics of Irbesartan in Healthy Subjects.

BACKGROUND: In clinical practice, nifedipine has the potential to alter the pharmacokinetics, and therefore possibly the pharmacodynamics and efficacy or safety, of irbesartan. The objectives of the current study were to determine the effects of concomitant administration of nifedipine on the steady-state pharmacokinetics and pharmacodynamics of irbesartan in 12 healthy subjects. METHODS AND RESULTS: This was an open-label, randomized, crossover study.

Pharmacokinetics and pharmacodynamics of avitriptan during intravenous administration in healthy subjects.

Avitriptan, a selective 5-HT1-like receptor agonist, is an effective compound for the treatment of migraine headaches with a prolonged duration of response. A double-blind, placebo-controlled, parallel-group, ascending-dose study in 24 healthy subjects was designed to assess the safety, tolerance, pharmacokinetics, and pharmacodynamics of avitriptan. This antimigraine drug was administered as two consecutive constant-rate IV infusions at three dose levels (12.

Fosinopril and hydrochlorothiazide combination versus individual components: lack of a pharmacokinetic interaction.

Objective: To evaluate the pharmacokinetic interaction and bioequivalence of a combination formulation of the angiotensin-converting enzyme inhibitor fosinopril and the diuretic hydrochlorothiazide (HCTZ).

Methods: In an open-label, balanced, randomized incomplete block, three-way crossover fashion, healthy men received single doses of three of four regimens in one of two independent studies. Regimens for study A (36 subjects): (1) fosinopril 10-mg tablet, (2) HCTZ 12.

Pharmacokinetics and pharmacodynamics of irbesartan in healthy subjects.

The safety, pharmacokinetics, and pharmacodynamics of single and multiple doses of the angiotensin II (AII) AT1 blocker irbesartan were assessed in healthy subjects. In this single-center, placebo-controlled, double-blind within dose group, sequential, dose-ascending study, 48 men were randomized to receive irbesartan at doses of 150 mg, 300 mg, 600 mg, or 900 mg daily. Subjects received a single dose of irbesartan (n = 9 per group) or placebo (n = 3 per group), followed by 3 days of placebo, and then multiple doses of irbesartan or placebo once daily for 7 days.

The effect of nefazodone on the single-dose pharmacokinetics of phenytoin in healthy male subjects.

The effect of nefazodone on the pharmacokinetics of a single dose of phenytoin was evaluated in 18 healthy male subjects. The subjects received a single oral dose of phenytoin, 300 mg, on day 1 of the study and the pharmacokinetic profile of the drug was determined. After a washout period followed by oral administration of nefazodone, 200 mg twice daily for 7 days, subjects received a single dose of phenytoin, 300 mg concomitantly with the morning dose of nefazodone on day 12, and the pharmacokinetic profile of phenytoin was determined again.

Pharmacokinetic and pharmacodynamic evaluation during coadministration of nefazodone and propranolol in healthy men.

Potential interactions between nefazodone (200 mg every 12 hours) and propranolol (40 mg every 12 hours) were assessed in 18 healthy male volunteers in an open-label, randomized, three-way crossover study. The nature, frequency, and severity of adverse events during coadministration of nefazodone and propranolol were similar to those observed with either treatment alone. There were no clinically significant effects on vital signs, electrocardiographic results, or laboratory parameters.

Pharmacokinetic and pharmacodynamic evaluation of warfarin and nefazodone coadministration in healthy subjects.

Nefazodone, an antidepressant with serotonin and norepinephrine receptor modulating activity, is highly protein bound and eliminated by oxidative metabolism. This study evaluated the potential for clinically significant drug interactions with warfarin and nefazodone coadministration. Eighteen subjects received warfarin daily for 14 days, achieving steady-state warfarin concentrations and a stable prothrombin ratio.

Effects of thromboxane synthase inhibitors on renal function.

In general the effects of thromboxane A2(TXA2) on renal function are opposite those produced by other prostanoids. TXA2 synthase inhibitors decrease the biosynthesis of TXA2 and may increase the production of other prostanoids by causing endoperoxide shunting. Therefore, in situations of increased kidney arachidonate mobilization, inhibition of renal TXA2 synthase might alter renal function by reducing TXA2 production and/or increasing prostaglandin (PG) biosynthesis.

A simplified method for the iodination of prostanoids for radioimmunoassay.

This paper presents a simplified method for iodination of prostanoids which combines conjugation and iodination into one brief step. The prostanoid is first coupled to histamine with EDC, and is thereafter iodinated directly without an intervening TLC step. The iodination mixture is purified on an LH-20 column, and the final iodinated product can be located unequivocally.

Effects of indomethacin on systemic and coronary hemodynamics in patients with coronary artery disease.

The effects and possible mechanisms of actions of indomethacin on systemic and coronary hemodynamics were studied in 17 patients with coronary artery disease. Group I patients (12) were given either indomethacin or placebo in the absence of prior cyclooxygenase inhibition and group II (five) were given indomethacin after prior treatment with 2600 mg of aspirin. In group I, systolic blood pressure rose from a baseline of 136 +/- 5 mm Hg to a peak level of 158 +/- 8 mm Hg 5 minutes after drug (p less than 0.

Clinical studies with synthetic ovine corticotropin-releasing factor.

Ovine corticotropin-releasing factor (oCRF) stimulates increased plasma immunoreactive adrenocorticotropin (IR-ACTH) and IR-cortisol at threshold, half-maximal, and maximal doses of 0.01-0.03, 0.

Thromboxane synthetase inhibitor UK38,485 lowers blood pressure in the adult spontaneously hypertensive rat.

Treatment of young spontaneously hypertensive rats (SHR) with a thromboxane synthetase inhibitor (TSI) attenuates their subsequent development of hypertension. In this study, treatment of adult SHR during the established phase of hypertension with the TSI UK38,485 (100 mg/kg daily) lowered systolic blood pressure from baseline after 4 days of treatment to a maximum depression of 25 mm Hg on day 10 of the study. Additional confirmation of the fact that this TSI does not lower blood pressure acutely was made via continuous intraarterial recordings in SHR administered their first dose of UK38,485.

Attenuation of noradrenergic neurotransmission by the thromboxane synthetase inhibitor, UK 38,485.

The purpose of this study was to determine the effects of chronic administration of the thromboxane synthetase inhibitor, UK 38,485, on noradrenergic neurotransmission. Male Sprague Dawley rats (n = 14) were treated once daily with either UK 38,485 (100 mg/kg; n = 7) or the vehicle of UK 38,485 (olive oil; n = 7) by gavage. The dose of UK 38,485 chosen was sufficient to inhibit ex vivo platelet TXB2 production by greater than 90% for 24 hours.

Metabolic clearance and plasma disappearance rates of human pancreatic tumor growth hormone releasing factor in man.

The metabolic clearance rate (MCR) and plasma disappearance rate (t1/2) of human pancreatic tumor growth hormone releasing factor [hpGRF(1-40)] was determined in normal adult male subjects by single injection and constant infusion techniques. Single injections of 1, 3.3, and 10 micrograms/kg hpGRF(1-40) were administered intravenously, plasma immunoreactive (IR) GRF levels were measured during the subsequent 180 min, and biexponential curve analysis was performed.

Gonadotropin and steroid secretory patterns during chronic treatment with a luteinizing hormone-releasing hormone agonist analog in men.

LHRH agonist analogs induce hypogonadism in man but the mechanism is uncertain. To evaluate this, we treated 13 normal men with 50 micrograms/day D-Trp6,Pro9-NEt LHRH (LHRHA) for periods up to 8 weeks and measured (1) patterns of endogenous gonadotropin and testosterone secretion, (2) gonadal response to exogenous human LH infusions, and (3) gonadotropin and testosterone responses to hourly bolus doses of LHRH. Seven men were evaluated with frequent sampling for 12-h periods every 4 week during treatment with LHRHA.

Effect of tyramine on myocardial catecholamine release in coronary heart disease.

The influence of tyramine on myocardial catecholamine release and on coronary blood flow has not previously been determined in man. Therefore, the effect of tyramine was measured on coronary and systemic hemodynamics and on norepinephrine (NE) and epinephrine levels in blood from the aorta and coronary sinus in 9 patients with coronary artery disease. Tyramine produced a striking increase in coronary sinus NE, from a baseline of 344 +/- 56 to a peak level of 1416 +/- 310 pg/ml (p less than 0.

Plasma distribution, disappearance half-time, metabolic clearance rate, and degradation of synthetic ovine corticotropin-releasing factor in man.

The plasma distribution, disappearance half-time, MCR, and degradation of corticotropin-releasing factor (CRF) were studied in normal men who received a pulse injection of synthetic ovine CRF (oCRF). Graded iv doses of oCRF produced a linear increase in plasma immunoreactive oCRF (IR-oCRF). The calculated total plasma content of IR-oCRF 2 min after injection represented 41.