Investigation of the predictive validity of laser-EPs in normal, UVB-inflamed and capsaicin-irritated skin with four analgesic compounds in healthy volunteers.

Aims: The aim of the present study was to assess the predictivity of laser-(radiant-heat)-evoked potentials (LEPs) from the vertex electroencephalogram, using an algesimetric procedure, testing the anti-nociceptive/anti-hyperalgesic effects of single oral doses of four marketed analgesics (of different compound classes) vs. placebo, in healthy volunteers with three skin types.

Methods: This was a randomized, placebo-controlled, single-blind, five-way-crossover trial.

Investigation of combined CYP3A4 inductive/inhibitory properties by studying statin interactions: a model study with the renin inhibitor ACT-178882.

Purpose: ACT-178882, a direct renin inhibitor, was used as a model compound in an elaborate drug-drug interaction study with atorvastatin and simvastatin to explore complex CYP3A4 inductive and inhibitory properties.

Methods: Thirty-two healthy male subjects received single doses of 20 mg atorvastatin and 20 mg simvastatin on days 1, 9, 31, and 41. On days 6 to 33, 500 mg ACT-178882 was administered once daily.

Relative bioavailability of a newly developed pediatric formulation of bosentan vs. the adult formulation.

What Is Known: Bosentan is a dual endothelin receptor antagonist approved for the treatment of pulmonary arterial hypertension (PAH). Since bosentan is frequently used to treat pediatric PAH patients, a pediatric formulation was developed.

Aim: To evaluate the pharmacokinetic properties of bosentan and its active metabolite, Ro 48-5033, of the quadrisected, dispersible pediatric vs.

Effect of Multiple-Dose Diltiazem on the Pharmacokinetics of the Renin Inhibitor ACT-077825.

This open-label, randomized study evaluated the effects of steady-state diltiazem on the pharmacokinetic, safety, and tolerability profile of a single dose of the novel renin inhibitor ACT-077825. Twelve healthy Caucasian male subjects (20-50 years) received in treatment sequence A, a single dose of 100 mg ACT-077825 (Days 1 and 17), and oral diltiazem 300 mg once daily (Days 14-26). In treatment sequence B, subjects received a single dose of 100 mg ACT-077825 (Days 4 and 22) and oral diltiazem 300 mg once daily (Days 1-13).

Comparative pharmacokinetic, pharmacodynamic, safety, and tolerability profiles of 3 different formulations of epoprostenol sodium for injection in healthy men.

Background: Epoprostenol sodium for injection is approved for the treatment of severe cases of primary pulmonary arterial hypertension. Currently, there are 3 approved formulations of this drug containing the same active ingredient (epoprostenol sodium) but differing with regard to excipients. When compared with epoprostenol sodium formulated with glycine-mannitol (epoprostenol GM), 2 new formulations of epoprostenol sodium, one formulated with arginine-mannitol (epoprostenol AM) and one formulated with arginine-sucrose (epoprostenol AS), have improved stability after reconstitution and dilution.

Pharmacokinetics, pharmacodynamics, and tolerability of ACT-077825, a new direct renin inhibitor after multiple-ascending doses in healthy subjects.

This study was conducted to characterize the multiple-dose tolerability, pharmacokinetics, and pharmacodynamics of ACT-077825, a new direct renin inhibitor, in healthy male subjects. In this single-center, double-blind, placebo-controlled, active-controlled (20 mg of enalapril), randomized multiple-ascending dose study, ACT-077825 was administered once a day. for 7 days in the 50-1000 mg dose range to sodium- and potassium-restricted subjects.

Determination of 6-keto prostaglandin F1α and its metabolites in human plasma by LC-MS/MS.

An HPLC-MS/MS method was developed and validated for the quantification of 6-keto prostaglandin F1α, the stable hydrolysis product of prostacyclin, and its metabolites 2,3-dinor-6-keto prostaglandin F1α and 6,15-diketo-13,14-dihydro prostaglandin F1α in human plasma. For sample preparation, a solid phase extraction step was combined with a column switching approach for analytes enrichment and further sample clean-up of the processed sample. The assay was validated in the concentration range 50.

Integrated pharmacokinetics and pharmacodynamics of epoprostenol in healthy subjects.

Aim: The aim of the study was to report the first thorough characterization of the pharmacokinetics (PK) and pharmacodynamics (PD) of epoprostenol in an integrated manner.

Method: Twenty healthy male subjects received two formulations of i.v.

Entry-into-humans study with a new direct renin inhibitor.

Purpose: To evaluate the pharmacokinetics, pharmacodynamics, safety, and tolerability of escalating single oral doses of ACT-077825, a novel orally active renin inhibitor, in healthy male subjects.

Methods: In this single-center, double-blind, placebo- and active-controlled (with enalapril) randomized study, 70 subjects received a single dose of ACT-077825 (1-1,000 mg), placebo, or enalapril 20 mg under fasted conditions. The main pharmacokinetic endpoints were area under the plasma ACT-077825 concentration-time curve from time zero to infinity and the terminal half-life (t(1/2)).

Imaging trait anxiety in high anxiety F344 rats: Focus on the dorsomedial prefrontal cortex.

Functional magnetic resonance imaging (fMRI) has become an important method in clinical psychiatry research whereas there are still only few comparable preclinical investigations. Herein, we report that fMRI in rats can provide key information regarding brain areas underlying anxiety behavior. Perfusion as surrogate for neuronal activity was measured by means of arterial spin labeling-based fMRI in various brain areas of high anxiety F344 rats and control Sprague-Dawley rats.

Examining face and construct validity of a noninvasive model of panic disorder in Lister-hooded rats.

Rationale: Increasing evidence suggests that defensive escape behavior in Lister-hooded (LH) rats induced by ultrasound application may be an animal model of panic disorder.

Objective: The objectives of this study were to further explore the face and construct validity of ultrasound-induced escape behavior by characterizing the autonomic and neuroendocrine response to ultrasound, and to examine the underlying neuronal structures by comparing the effects of the anxiolytic with panicolytic properties, diazepam, with a preclinical anxiolytic without panicolytic-like activity, the NOP agonist Ro 64-6198.

Materials And Methods: LH rats were implanted with telemetry transmitters to monitor heart rate and core body temperature before, during, and after ultrasound application.

The steroid sulfatase inhibitor COUMATE attenuates rather than enhances access of dehydroepiandrosterone sulfate to the brain in the mouse.

Intraperitoneal injection of adult male mice with the neuroactive steroid dehydroepiandrosterone sulfate (DHEAS) at 1 and 40 mg/kg caused dose-dependent increases in the concentration of both this compound and its corresponding free steroid DHEA in brain within 1 h of injection. Pretreatment of these animals for 24 h with the steroid sulfatase inhibitor COUMATE at a dose (10 mg/kg, p.o.

Defensive-like behaviors induced by ultrasound: further pharmacological characterization in Lister-hooded rats.

Rationale: In rats, dorsal periaqueductal gray (dPAG) stimulation elicits escape behavior that is thought to be related to fear and panic. A noninvasive technique--exposure to ultrasound-has been reported to stimulate the dPAG and induce escape followed by freezing in Lister-hooded (LH) rats.

Objective: Further characterize pharmacologically the ultrasound--induced defensive behaviors test with anxiolytics acting via different mechanisms.

A combined marble burying-locomotor activity test in mice: a practical screening test with sensitivity to different classes of anxiolytics and antidepressants.

Over the last decades, the inhibition of spontaneous burying of glass marbles by mice has been used as an index of anxiolytic drug action in the so-called marble burying test. Indeed, acute administration of rapid-onset (e.g.

The effects of serotonin reuptake inhibitors on locomotor activity in gerbils.

In the current study we examined the effects of serotonin reuptake inhibitors on the locomotor activity of gerbils, and undertook experiments to understand the mechanisms involved in their effects. The selective serotonin reuptake inhibitors (SSRIs) fluoxetine (1-30 mg/kg, i.p.

Social approach-avoidance behavior of a high-anxiety strain of rats: effects of benzodiazepine receptor ligands.

Rationale: To better understand anxiety disorders with social impairments as well as to identify new treatments, it is important to develop preclinical procedures involving social components of anxiety. Recently, a novel procedure was reported: the rat Social Approach-Avoidance (SAA) test. In this test, the time spent by a test rat in a large social compartment containing an unfamiliar stimulus rat reflects the anxiety state of the animal.