CNI-1493 attenuates hemodynamic and pro-inflammatory responses to LPS.

The increased production of pro-inflammatory cytokines and nitric oxide have been postulated to contribute to the deleterious sequella of LPS administration. To date, clinical strategies to control these responses using individual specific inhibitors have been disappointing. The aim of the present study was to determine whether a tetravalent guanylhydrazone compound (CNI-1493) attenuates LPS-induced stress responses by suppressing multiple inflammatory mediators. Rats were injected intravenously with either CNI-1493 (10 mg/kg) or vehicle (1 mL NaCl) 60 min prior to the injection of LPS (100 microg/100 g body weight). LPS produced a 20% decrease in mean arterial blood pressure and a significant increase in circulating TNF-alpha levels as well as in tissue content of TNF-alpha, IL-1beta, and IL-6. This was associated with a marked increase in lung and gut apoptosis and myeloperoxidase (MPO) activities as well as with an increase in lung and spleen nitric oxide end products (NOx). Pretreatment with CNI-1493 attenuated the LPS-induced drop in mean arterial blood pressure (MABP) and blunted (40%) the rise in circulating TNF-alpha levels. CNI-1493 attenuated the LPS-induced increase in tissue cytokine (TNF-alpha, IL-1beta, and IL-6) content in lung and spleen but did not alter that of liver or gut. CNI-1493 pretreatment protected both lung and gut from LPS-induced apoptosis and in addition attenuated the rise in MPO activity in the gut. These results suggest diverse effects of CNI-1493 that are tissue specific and that confer protection against the hemodynamic and inflammatory responses to LPS.

Spectroscopic imaging of the uptake kinetics of human brain ethanol.

Previous measurements of the ratio of brain to venous blood alcohol have ranged from 21-100%, depending on the experimental model, pulse sequence, and the concentration reference used. The goal of this study was to evaluate the uptake kinetics and visibility of brain ethanol in comparison to venous blood levels using a pulse sequence that minimizes uncertainties due to differences in J-modulation, T(1), and T(2) between ethanol and the concentration standard. This was achieved using a short TE (24 msec) spin echo sequence with a semiselective refocusing pulse to minimize J-modulation losses of the ethanol. Brain ethanol levels were measured with 10-min time resolution using a 16 x 16 spectroscopic imaging matrix with nominal voxels of 1.44 cc. During the course of the study, the brain/blood alcohol ratio declined from a value of 1.54 +/- 0.74 at 35 min after drinking to a final value of 0.93 +/- 0.16 at 85 min postdrinking. Magn Reson Med 42:1019-1026, 1999.

Measurements of human brain ethanol T(2) by spectroscopic imaging at 4 T.

Previous MRS measurements of ethanol in human brain have yielded a range of transverse relaxation times for ethanol methyl resonance at 1.5 T (200-380 ms). To determine the T(2) of the methyl proton resonance of ethanol in human brain, 8 x 8 spectroscopic images were acquired at 16 different TE values. A frequency-selective refocusing pulse was used to suppress J-modulation of the ethanol triplet, permitting nonintegral multiples of 1/J to be used for TE values. The measured T(2) values for the methyl resonances of ethanol, creatine, and N-acetyl aspartate in mixed tissues were 82 +/- 12, 148 +/- 20, and 227 +/- 25 ms, respectively. Regression analysis of the measured T(2) as a function of gray matter content indicates a shorter T(2) value for ethanol in pure white matter compared to that in pure gray matter. Magn Reson Med 44:35-40, 2000.