Sensible approaches for reducing clinical trial costs.

Background: Over the past decade, annual funding for biomedical research has more than doubled while new molecular entity approvals have declined by one third.

Objective: To assess the value of practices commonly employed in the conduct of large-scale clinical trials, and to identify areas where costs could be reduced without compromising scientific validity.

Methods: In the qualitative phase of the study, an expert panel recommended potential modifications of mega-trial designs and operations in order to maximize their value (cost versus scientific benefit tradeoff).

Glucocorticoids stimulate cholesteryl ester formation in human smooth muscle cells.

The aim of the present study was to investigate the effect of synthetic glucocorticoid dexamethasone (Dex) on cholesterol esterification in cultured human smooth muscle cells (SMC). In labeled SMC, Dex stimulated the esterification of [3H]cholesterol in a dose-dependent manner. This effect was specific for glucocorticoid hormones and could be inhibited by cycloheximide (3 ng/mL), actinomycin D (10(-5) mol/L), and the specific glucocorticoid antagonist RU 486 (10(-8) mol/L).

Comparative study of the activity and composition of HDL3 in Russian and American men.

Previous studies conducted within the framework of the Lipid Research Clinics Program showed a strong inverse correlation between high-density lipoprotein cholesterol (HDL-C) level and coronary heart disease (CHD) risk in American male populations, whereas in Russian populations such a correlation was less pronounced. It was assumed that HDL was less protective of CHD in Russian than in American males. This study compared the functional activity and lipid composition of HDL3 isolated from the blood plasma of men with low, normal, and high HDL-C levels from Moscow (Russia) and Seattle (United States) populations.

The GTP-binding regulatory proteins, Gs and G(i), are altered in erythrocyte membranes of patients with ischemic heart disease resulting from coronary atherosclerosis.

Acute ischemic heart disease is associated with alterations in the cardiac adenylate cyclase system response, although the specificity and mechanism of these events are unknown. We studied the characteristics of inhibitory (G(i)) and stimulatory (Gs) GTP-binding regulatory proteins (G proteins) of adenylate cyclase in erythrocyte membranes of patients (n = 16) with nonacute ischemic heart disease resulting from coronary atherosclerosis. Gs was measured by reconstitution with the resolved catalytic unit of adenylate cyclase and by cholera toxin-catalyzed ADP-ribosylation of a 42-kD protein; G(i) was tested as a 41-kD substrate of pertussis toxin-catalyzed ADP-ribosylation.

Effect of VLDL on the inhibition of arachidonic acid transformation by dexamethasone in cultured smooth muscle cells.

Very-low-density lipoproteins (VLDL) induce a dose-dependent reduction (up to 55%) in the number of specific binding sites and about a 2-fold increase in binding affinity for [3H]dexamethasone in human and rat smooth muscle cells (SMC). Maximal effect of VLDL was achieved within 3-5 h at a lipoprotein concentration 60 micrograms protein/ml. Lipoprotein-mediated reduction in the number of [3H]dexamethasone binding sites resulted in partial loss of cellular sensitivity to hormone action: dexamethasone (1 x 10(-6) M) inhibited the transformation of [14C]arachidonic acid (AA) into metabolites to a lesser extent in SMC preincubated with VLDL (11.

Reduced sensitivity of cultured skin fibroblasts from familial hypercholesterolemic patients to glucocorticoids.

Cultured human skin fibroblasts, obtained from patients with homozygous familial hypercholesterolemia (FH), exhibited cholesterol synthesis that was 2.5-3-fold more intensive than in cells from healthy donors (normal cells). The study of the glucocorticoid [3H]-dexamethasone specific binding (glucocorticoid receptors, GcR) to the cells showed reduced number of binding sites (8 x 10(3) vs 120 x 10(3) binding sites/cell) and reduced Kd value (5.

Prostacyclin-mediated effect of high density lipoproteins as cellular cholesterol acceptors on aortic smooth muscle cells.

Low (LDL) and high (HDL) density lipoproteins stimulate prostacyclin (PGI2) synthesis in cultured rabbit and human aortic smooth muscle cells. In this respect, the efficacy of HDL exceeded that of LDL, HDL3 being the most effective. HDL3 obtained from hypoalphacholesterolemic patients' serum had a lesser stimulative effect on PGI2 synthesis as compared with HDL3 of normolipidemic subjects.

A sensitive and rapid method for determination of pyrophosphatase activity.

A new, rapid and sensitive method of measuring the rate and amount of PPi hydrolysis is described. The method is based on registration of small pH changes, caused by decrease of hydrogen-ion concentration during the pyrophosphatase reaction. With this detected value of hydrogen-ion concentration change and the buffering capacity of each reaction mixture determined by titration, the rate and amount of PPi hydrolysis can be calculated.