Age-related changes in pharmacokinetics and pharmacodynamics of lerisetron in the rat: a population pharmacokinetic model.

Background: The importance of studying the effects of age on the pharmacokinetics and pharmacodynamics of lerisetron - a new 5-hydroxytryptamine-3 (serotonin) receptor antagonist - comes from the facts that lerisetron will be administered to patients that are being treated with cytotoxic drugs and that the elderly frequently suffer from neoplastic diseases.

Objective: The present study was designed to explore the effects of age on the pharmacokinetics and pharmacodynamics of lerisetron by using an aged rat model. A mixed-effects population study was carried out in order to analyze the sparse data and to create covariate models which could be used to derive dosage recommendations.

Design and function of a dendrimer-based therapeutic nanodevice targeted to tumor cells through the folate receptor.

Purpose: We sought to develop nanoscale drug delivery material that would allow targeted intracellular delivery while having an imaging capability for tracking uptake of the material. A complex nanodevice was designed and synthesized that targets tumor cell through the folate receptor.

Methods: The device is based on an ethylenediamine core polyamidoamine dendrimer of generation 5.

Pharmacokinetics and pharmacological effect of lerisetron, a new 5-HT3 antagonist, in rats.

The pharmacokinetics of lerisetron, a novel 5HT(3) antagonist, are studied together with its efficacy in inhibiting the serotonin (5-HT)-evoked transient bradycardia reflex (von Bezold-Jarisch reflex) in Sprague Dawley rats. [(14)C]Lerisetron (50, 100, and 200 microg/kg) was given to rats by intravenous (iv) injection and plasma levels of unchanged (UL) and total (unchanged + changed, TL) drug were measured by liquid chromatography with radioactivity monitoring and scintillation counting, respectively. Linearity of UL and TL pharmacokinetics over the dose range was established by noncompartmental analysis.

Altered disposition and effect of lerisetron in rats with elevated alpha 1-acid glycoprotein levels.

Purpose: To examine the effect of changes in plasma alpha1-acid glycoprotein (AAG) levels on the pharmacokinetics (PK) and pharmacodynamics (PD) of lerisetron, a novel serotonin 5-HT3 receptor antagonist, in the rat.

Methods: After subcutaneous administration of turpentine oil, AAG was significantly elevated compared with controls. The PK of unchanged lerisetron (UL; high-performance liquid chromatography with radioactivity monitoring) and total lerisetron (TL; unchanged + changed, scintillation counting) was characterized post intravenous (i.

Intravascular and endobronchial DNA delivery to murine lung tissue using a novel, nonviral vector.

Gene transfer to the lung can be achieved via either the airway or the pulmonary vasculature. We evaluated gene transfer and expression by intravascular and endobronchial routes, using DNA complexed with G9 PAMAM dendrimer or naked plasmid DNA. Intravascular tail vein delivery of dendrimer-complexed pCF1CAT plasmid resulted in high levels of transgene expression in the lung at 12 and 24 hr, followed by a second peak of expression 3 to 5 days after administration.

Effects of intravenous administration of prostacyclin on regional blood circulation in awake rats.

1. The effects of intravenous infusion of prostacyclin (PGI2, 0.1, 0.

The effect of synthetic surfactant Exosurf on gene transfer in mouse lung in vivo.

Gene transfer in the lung holds promise for the treatment of diseases such as pulmonary fibrosis, cystic fibrosis and asthma. Pulmonary surfactant has been reported to enhance expression from endobronchial, adenovirus-mediated gene transfer in experimental animals. This study examines the effect of exogenous synthetic surfactant (Exosurf) on gene expression from naked plasmid DNA administered endobronchially to adult mice.

Serum protein binding of lerisetron, a novel specific 5HT3 antagonist, in patients with cancer.

The aim of this study was, (1) to characterize the serum protein binding of lerisetron, a new 5-hydroxytryptamine (5-HT3) receptor antagonist under investigation as an antiemetic agent, and (2) to measure the percentage of unbound lerisetron in cancer patients. The binding parameters were determined in human serum albumin (HSA), alpha1-acid glycoprotein (AAG) and in pooled serum from six healthy volunteers. Concentrations of lerisetron ranging from 50 ng/ml to 2 microg/ml were used.

Effects of indomethacin and diclofenac on cerebral blood flow in hypercapnic conscious rats.

Cerebral blood flow (CBF) was measured in conscious rats treated with indomethacin, diclofenac or the vehicle for indomethacin during hypercapnia of three different degrees. Similar values were found for CBF in rats treated with diclofenac or vehicle and there was a direct correlation between CBF and the arterial blood carbon dioxide values. In contrast, indomethacin completely blocked the increase of CBF during hypercapnia.

Cardiac output redistribution induced by noradrenaline in two murine tumor models.

The response of tumor vessels to vasoactive substances could provide useful information on experimental tumor biology. We have studied the effects of noradrenaline (20 micrograms/kg i.v.

Distribution of cardiac output during development of two metastasizing murine tumors.

The study of cardiac output (CO) distribution to tumors and metastases is of interest for a better understanding of tumor biology and for pharmacological approaches. A radioactive microsphere method was developed to asses CO distribution in C57BL/6J mice bearing syngeneic 3LL or BALB/c mice with JWS. At the initial stages of cancer growth, the CO relative fractions per g of tissue (%CO/g) to 3LL and JWS were similar to those in surrounding tissues.

Effects of aspirin and indomethacin on cerebral circulation in the conscious rat: evidence for a physiological role of endogenous prostaglandins.

The purpose of this work was to evaluate the effects of equipotent doses of two different inhibitors of cyclo-oxygenase, indomethacin and aspirin, on cerebral blood flow and cerebral vascular resistances in the conscious undisturbed rat, using the reference sample radioactive microsphere method. We found that both, aspirin (50 mg/kg) and indomethacin (5 mg/kg) at 3, 15 and 60 min after their intravenous administration, increased cerebral vascular resistances and decreased cerebral blood flow to a similar extent. Both drugs completely abolished the hypotensive effect of 5 mg/kg i.