Safety, dosing, and pharmaceutical quality for studies that evaluate medicinal products (including biological products) in neonates

The study of medications among pediatric patients has increased worldwide since 1997 in response to new legislation and regulations, but these studies have not yet adequately addressed the therapeutic needs of neonates. Additionally, extant guidance developed by regulatory agencies worldwide does not fully address the specificities of neonatal drug development, especially among extremely premature newborns who currently survive. Consequently, an international consortium from Canada, Europe, Japan, and the United States was organized by the Critical Path Institute to address the content of guidance. This group included neonatologists, neonatal nurses, parents, regulators, ethicists, clinical pharmacologists, specialists in pharmacokinetics, specialists in clinical trials and pediatricians working in the pharmaceutical industry. This group has developed a comprehensive, referenced White Paper to guide neonatal clinical trials of medicines-particularly early phase studies. Key points include: The need to base product development on neonatal physiology and pharmacology while making the most of knowledge acquired in other settings; the central role of families in research; and the value of the whole neonatal team in the design, implementation and interpretation of studies. This White Paper should facilitate successful clinical trials of medicines in neonates by informing regulators, sponsors, and the neonatal community of existing good practice

Pediatric Hypertension

XVI, 600 p. 67 illus., 22 illus. in color.online

Decreased low-density lipoprotein receptor function and mRNA levels in lymphocytes from uremic patients

Decreased low density lipoprotein receptor function and mRNA levels in lymphocytes from uremic patients. The mechanisms by which renal failure causes hyperlipoproteinemia remain unclear. To investigate the potential role of the low-density lipoprotein (LDL) receptor in lipoprotein metabolism in uremia we measured LDL receptor function in peripheral blood mononuclear cells (PBMC) from uremic patients and control subjects using a functional assay in which proliferation of lectin-stimulated PBMC in the presence of lovastatin was dependent upon internalization of exogenous cholesterol via a functional LDL receptor. The amount of LDL required to reverse 50% of lovastatin-induced inhibition of proliferation in PBMC from uremic patients was significantly greater (3.6 ± 1.8 µg/ml, N = 33, P < 0.05) than controls, (1.99 ± 0.6 µg/ml, N = 37). Abnormal LDL receptor function in four uremic patients normalized following renal transplantation. To investigate the molecular basis for LDL receptor dysfunction, we directly quantitated LDL receptor messenger RNA (mRNA) in PBMC from uremic patients and control subjects using a ribonuclease protection assay. LDL receptor mRNA expression in uremic patients was 0.42 ± 0.08 (N = 10), significantly lower (P < 0.015) than in normal subjects, 0.71 ± 0.08 (N = 14). These data suggest that an acquired defect in LDL receptor function in PBMC from uremic patients exists which may be due to decreased LDL receptor expression. These abnormalities, if present in other tissues, could contribute to the aberrant lipoprotein metabolism which is a consistent feature of uremia