Lack of pharmacokinetic interaction between linezolid and antacid in healthy volunteers.

Several antibiotics show significant pharmacokinetic interactions when they are given orally concomitantly with antacids. The objective of this study was to evaluate the effects of antacid (containing magnesium) on the pharmacokinetics of linezolid. A single dose of 600 mg linezolid was given orally alone and 10 min after administration of the antacid Maalox 70mVal, which contains 600 mg magnesium hydroxide and 900 mg aluminum hydroxide, to nine healthy males and nine healthy females in a crossover and randomized study. Linezolid plasma concentrations were determined by high-performance liquid chromatography, and pharmacokinetic parameters were calculated for both treatments. Coadministration with antacids did not change the pharmacokinetics of linezolid. The ratios (90% confidence intervals) of the individual values of the area under the concentration-time curve and the maximum concentration in plasma (C(max)) (linezolid plus antacid versus linezolid alone) were 1.01 (0.99 to 1.02) and 0.99 (0.96 to 1.02), respectively. Likewise, no significant difference in any of the other pharmacokinetic parameters was observed between the treatment groups (the time to C(max), lag time, volume of distribution [V/F], and clearance [CL/F]). However, a significant sex difference was observed for AUC, C(max), V/F, and CL/F; and these differences could be almost completely explained by the differences in body weight between males and females. No clinically relevant adverse effects were detected under either condition. The coadministration of antacids had no effect on the pharmacokinetics of linezolid. This demonstrates that the oral absorption of linezolid was not affected by the presence of antacids containing magnesium hydroxide and aluminum hydroxide. Antacids can be safely administered together with linezolid.

Ectopic parvalbumin expression in mouse forebrain neurons increases excitotoxic injury provoked by ibotenic acid injection into the striatum.

A neuroprotective role for Ca(2+)-binding proteins in neurodegenerative conditions ranging from ischemia to Alzheimer's disease has been suggested in several studies. A key phenomenon in neurodegeneration is the Ca(2+)-mediated excitotoxicity brought about by the neurotransmitter glutamate. To evaluate the relative ability to resist excitotoxicity of neurons containing the slow-onset Ca(2+)-binding protein parvalbumin (PV), we injected the glutamate agonist ibotenic acid (IBO) into the striatum of adult mice ectopically expressing PV in neurons. Striatal ibotenic acid injection results in local nerve cell loss and reactive astrogliosis. Light microscopic evaluation, carried out after a delay of 2 and 4 weeks, reveals an enlarged and accelerated neurodegenerative process in mice ectopically expressing neuronal PV. Thus, PV is not neuroprotective, it rather enhances nerve cell death. This result implicates that the increase in cytosolic Ca(2+)-buffering capacity in the transgenic mice impairs other systems involved in Ca2+ sequestration. In addition, ultrastructural morphometric analysis shows that in neurons the mitochondrial volume is reduced in mice ectopically expressing neuronal PV. This is paralleled by a reduction in the amount of the mitochondrial marker enzyme cytochrome c oxidase subunit I (COXI). We conclude that alterations in the Ca(2+) homeostasis present in mice ectopically expressing neuronal PV are more deleterious under excitotoxic stress and largely outweigh the potential benefits of an increased Ca(2+)-buffering capacity resulting from PV.

Effect of inherent epileptic seizures on brain injury after transient cerebral ischemia in Mongolian gerbils.

Subthreshold excitotoxic stimuli such as brief cerebral ischemia or chemically induced seizures modulate brain injury resulting from subsequent transient ischemia. Depending on the delay between the two insults, either tolerance or cumulative damage will develop. We were interested whether non-chemically induced inherent epileptic seizures as they occur in Mongolian gerbils have an effect on the outcome of a transient global ischemia, i.e., whether they are an interfering variable in ischemia experiments. Occurrence of spontaneous seizures in adult male gerbils was registered with a video-controlled seizure monitoring system. Bilateral occlusion of common carotid arteries was carried out 2 h or 24 h after the last generalized seizure. After 4 days survival, the extent of ischemia-induced neuronal damage and glial activation were assessed in the hippocampus and striatum. No significant difference in the ischemia induced nerve cell loss was observed in cresyl violet stained sections between the 2-h or 24-h interval gerbils. Neuronal expression of endothelial nitric oxide synthase in CA1 disappeared with neuronal degeneration. Distribution and degree of upregulation of glial fibrillary acidic protein as marker for astrocytes did not differ between the two groups. We concluded that non-chemically induced inherent epileptic seizures neither protect the gerbil brain from injury nor augment the degree of damage resulting from transient forebrain ischemia. Thus, inherent epileptic seizures do not influence the outcome of the insult, making the gerbil a reliable model for studies on transient brain ischemia.

Interleukin-6 receptor expression and localization after transient global ischemia in gerbil hippocampus.

Ischemia results in increased interleukin-6 (IL-6) expression in the brain. To prove a connection between IL-6 upregulation and IL-6 receptor (IL-6R) expression following ischemia, we analyzed cell-type specific expression changes of IL-6R using transient global ischemia in the gerbil as a model. In sham operated animals, IL-6R mRNA and protein were mainly detected in hippocampal pyramidal cells and interneurons. After ischemia, IL-6R was expressed in neurons but there was no increase during the peak IL-6 expression. Neuronal IL-6R mRNA and protein decreased in parallel with pyramidal cell death, starting 2 days after ischemia. Double-labeling experiments revealed that in postischemic hippocampus IL-6R was not present in GFAP-reactive astrocytes but that the surviving parvalbumin containing interneurons expressed IL-6R mRNA.