Alpha-1 Acid Glycoprotein as a Biomarker for Subclinical Illness and Altered Drug Binding in Rats.

Alpha-1 acid glycoprotein (AGP) is a significant drug binding acute phase protein that is present in rats. AGP levels are known to increase during tissue injury, cancer and infection. Accordingly, when determining effective drug ranges and toxicity limits, consideration of drug binding to AGP is essential.

Calculating safety margins using total plasma concentration versus unbound plasma concentration - does it make a difference?

Safety margin, a key aspect of any non-clinical toxicity studies, is calculated by dividing the systemic exposure (AUC) at NOAEL (No Adverse Effect Level) in toxicity studies by the clinical exposure. The validity of using total plasma concentration (C) to calculate AUC is often discussed, as it is the unbound plasma concentration (C) that elicits the pharmacological and toxicological effects. Data regarding plasma protein binding across species was collected for 114 MSD small molecule compounds which had been discontinued from development either due to non-clinical toxicity or due to clinical Adverse Effects.

Nicotinamide prevents apoptosis in human cortical neuronal cells.

In previous studies, the free radical generating toxin tertiary butylhydroperoxide (t-BuOOH) was found to induce significant cell death in human cortical neuronal cells (HCN2 cells). Pretreatment with the poly (ADP-ribose) polymerase (PARP) inhibitor nicotinamide was able to prevent HCN2 cell death. In this study it is observed that apoptosis is induced following the addition of t-BuOOH at 6 h as indicated by TUNEL-positive cells.

The soy isoflavone, genistein, protects human cortical neuronal cells from oxidative stress.

Genistein, a soy isoflavone, has been shown to mimic the pharmacological actions of the endogenous steroid estrogen with which it has structural similarities. There is now evidence that the genistein can prevent disorders-like heart diseases, cancer and diabetes as well. However, very few studies have looked at the effect of genistein on the central nervous system.

A comparative study of the effect of oxidative stress on the cytoskeleton in human cortical neurons.

Cytoskeleton disruption is a process by which oxidative stress disrupts cellular function. This study compares and contrasts the effect of oxidative stress on the three major cytoskeleton filaments, microfilaments (MFs), microtubule (MT), and vimentin in human cortical neuronal cell line (HCN2). HCN2 cells were treated with 100 microM tertiary butylhydroperoxide (t-BuOOH), a free radical generating neurotoxin for 1, 3, or 6 h.

The effect of tertiary butylhydroperoxide and nicotinamide on human cortical neurons.

It is well known that the generation of oxygen radicals can cause neuronal death by both apoptosis and necrosis, which may lead to the onset of neurodegenerative diseases. In previous in vivo studies, nicotinamide was found to prevent both DNA fragmentation and apoptosis that were induced by free radical generating toxins like tertiary butylhydroperoxide (t-BuOOH). Nicotinamide is a precursor for NAD and is an inhibitor of the enzyme poly(ADP-ribose) polymerase (PARP).

Nicotinamide protects HCN2 cells from the free radical generating toxin, tertiary butylhydroperoxide (t-BuOOH).

In previous studies with mice the oxygen radical generating neurotoxin tertiary butylhydroperoxide (t-BuOOH) was used to mimic the oxidative injury that has been implicated in neurodegenerative diseases. In addition, previous studies have shown that the poly (ADP-ribose) polymerase (PARP) inhibitor nicotinamide is able to prevent DNA fragmentation and apoptosis that is induced by t-BuOOH in mouse brain. However, the molecular mechanism(s) by which nicotinamide is able to protect human brain cells at the cellular level is not clear.