Utility of unbound plasma drug levels and P-glycoprotein transport data in prediction of central nervous system exposure.

1. Drug concentrations in cerebrospinal fluid have been assumed to be a natural surrogate for total drug exposures in the central nervous system. The present communication reports a data set from a study of 30 compounds in mice. An attempt was made to correlate cerebrospinal fluid and unbound plasma drug concentrations via incorporation of in vitro P-glycoprotein (Pgp)-mediated transport data. 2. Pgp-deficient (Pgp -/-) and wild-type mice were dosed with compounds of interest by oral gavage (orally) at 5 mg kg(-1). Plasma and cerebrospinal fluid samples were collected at 1 h post-dosing, and analysed by liquid chromatography-tandem mass spectrometry (LC-MS/MS) for drug concentrations. Mouse and human Pgp-mediated transport were evaluated in vitro by a bi-directional (B to A and A to B) transport assay using LLC-PK1 cells expressing mouse (mdr1a) and human (MDR1) forms of Pgp, respectively. 3. Compounds with B to A/A to B transport ratios < 2 were defined as non-substrates of Pgp, whereas those exhibiting B to A/A to B transport ratios > or =2 were considered Pgp substrates. Plasma protein binding was also determined in vitro via equilibrium dialysis. Of the 30 compounds, 13 were identified to be mouse Pgp substrates, all of which were also human Pgp substrates, demonstrating a good agreement between mouse and human data. 4. In Pgp wild-type mice, the unbound plasma and cerebrospinal fluid concentrations of the non-Pgp substrates correlated well, with a regression slope of approximately 1.0. A similar relationship existed for Pgp substrates in Pgp -/- mice. On the other hand, an improved correlation of cerebrospinal fluid and systemic exposures of the Pgp substrates in Pgp wild-type mice was observed when the unbound plasma concentrations were normalized to the corresponding B to A/A to B transport ratios. 5. These results reinforce the premise that a combined use of unbound plasma drug concentrations and in vitro Pgp transport data may be of value for the estimation of central nervous system exposures.

Orally bioavailable, indole-based nonpeptide GnRH receptor antagonists with high potency and functional activity.

Stereospecific introduction of a methyl group to the indole-3-side chain enhanced activity in our tryptamine-derived series of GnRH receptor antagonists. Further improvements were achieved by variation of the bicyclic amino moiety of the tertiary amide and by adjustment of the tether length to a pyridine or pyridone terminus. These modifications culminated in analogue 24, which had oral activity in a rat model and acceptable oral bioavailability and half-life in dogs and monkeys.

Intracatheter nitroglycerin infusion fails to prevent catheter-related venous thrombosis: a randomized, controlled trial.

OBJECTIVE: Catheter-related thrombosis is a common problem in the pediatric intensive care unit. Strategies that reduce the incidence of thrombosis may have significant clinical advantage. Nitroglycerin (NTG) infusions release nitric oxide (NO). NO is responsible for much of the vasodilating and antithrombotic properties of the vasculature. We hypothesized that an intracatheter NTG infusion would reduce the incidence of catheter-related thrombosis. DESIGN: Prospective, randomized, controlled trial. SETTING: Pediatric intensive care unit. PATIENTS AND PARTICIPANTS: Children of 6 years or less with femoral venous catheters who were not on antithrombotic therapy. INTERVENTIONS: Subjects were randomly assigned to NTG or control groups. NTG group patients received NTG at 0.1 mcg x kg x min in 5 % dextrose; control group patients received only 5 % dextrose. Infusions were delivered continuously through the catheter until the catheter was removed. Demographic data, physical and laboratory findings, catheter insertion attempts and infusate composition were recorded. Clinical evidence of vascular thrombosis or catheter malfunction was noted. Ultrasound examinations were performed within 2 days of catheter insertion and within 2 days after removal. MEASUREMENTS AND RESULTS: Forty-four patients (age 12.0 +/- 2.6 months) completed the study, 21 in the NTG group and 23 in the control group. Duration of catheter placement was 7.5 +/- 0.7 days. Twelve of 44 patients (27 %) had thrombi: 7/21 in the NTG group; 5/23 in the control group (p = NS). There were no significant differences between children with and without thrombi in age, gender, number of insertion attempts, duration of catheter placement, clinical signs of thrombosis or infections. CONCLUSIONS: Catheter-related thrombosis is common after placement of femoral venous catheters in children. Low dose intracatheter NTG infusion does not protect against catheter-related venous thrombosis in children.