Activity of LY333328 in experimental meningitis caused by a Streptococcus pneumoniae strain susceptible to penicillin.

In a rabbit model of Streptococcus pneumoniae meningitis single doses of 10 and 2.5 mg of the glycopeptide LY333328 per kg of body weight reduced bacterial titers in cerebrospinal fluid (CSF) almost as rapidly as ceftriaxone at 10 mg/kg/h (changes in log CFU, -0.29 +/- 0.21 and -0.26 +/- 0.22 versus -0.34 +/- 0.15/ml/h). A dose of 1 mg/kg was bacteriostatic (change in log CFU, 0.01 +/- 0.11/ml/h). In two animals receiving LY333328 at a dose of 40 mg/kg the bacterial titers were reduced by 0.54 and 0.51 log CFU/ml/h. The penetration of CSF by LY333328 was 1 to 5%. The concentrations of lipoteichoic and teichoic acids in CSF and neuronal damage were similar in ceftriaxone- and LY333328-treated animals.

Idebenone protects hepatic microsomes against oxygen radical-mediated damage in organ preservation solutions.

The ability of the benzoquinone coenzyme Q-10 or its derivative QSA-10 (idebenone) to protect against lipid peroxidation and protein damage mediated by the pro-oxidative system NADPH/ADP/Fe3+ was tested in a rat liver microsomal model incubated in University of Wisconsin (UW) or histidine-tryptophan-ketoglutarate (HTK) solutions. Lipid peroxidation, as followed by direct determination of lipid hydroperoxides and by monitoring of malondialdehyde equivalents, was 1.8-fold enhanced in HTK and 3-fold attenuated in UW compared with HEPES buffer. Function and integrity of microsomal enzymes were investigated using glutathione S-transferase and cytochrome P-450 IIIA activity as assessed by lidocaine N-deethylation to monoethylglycinexylidide as well as by Western blot analysis of the cytochrome P-450 IIIA protein. Glutathione S-transferase activity was reduced by about 70% in HEPES compared with 50% in HTK and 36% in UW. Cytochrome P-450 IIIA was inactivated by about 75% in HEPES and HTK, compared with 55% in UW. The enzyme inactivation was paralleled by a loss of immunoreactive cytochrome P-450 IIIA protein. Supplementation of HTK with 0.1 mumol/L QSA-10 offered complete protection against lipid peroxidation, compared with 100 mumol/L with Q-10. QSA-10 (20 mumol/L) prevented protein damage in both preservation solutions, whereas Q-10 (20 mumol/L) offered only partial protection in UW and had no effect in HTK. The use of QSA-10 during liver transplantation may therefore have the potential of increasing the efficacy of organ preservation, maintaining donor organ quality, and preventing reperfusion injury. It is suitable for human use and has energy-conserving properties in addition to its antioxidant nature.

Investigations into the haemorheological significance of postprandial and fasting hypertriglyceridaemia.

Two study designs were conceived to evaluate the rheological significance of hypertriglyceridaemia. We first investigated the course of serum- (SV) and plasma viscosity (PV) and erythrocyte aggregation in serum (SEA) and plasma (PEA) of healthy normolipidaemic individuals over 4 h after a fatty rich meal, in native material and after removal of triglyceride rich lipoproteins by centrifugation. Secondly, blood from patients with untreated hypertriglyceridaemia was investigated under fasting conditions. PEA and SEA increased in parallel with postprandial triglycerides (+135 mg dl-1), but the effect on PEA was more pronounced (+0.8 abs% increase; 2 h after the meal) as compared to SEA (+0.4 abs% increase). PV and SV increased in parallel to the same extent (+0.05 mPas). In the triglyceride poor infranatant no significant changes occurred. In fasting plasma PEA and PV were significantly lower (1.1 abs% and PV 0.04 mPas respectively) in infranatant than in native plasma, while only small differences in triglyceride (mostly VLDL) were observed. This phenomenon was barely detectable in serum samples. We conclude that triglyceride rich lipoproteins have a profound influence on haemorheological parameters, and that fibrinogen in particular, potentiates the effect of large fasting VLDL on plasma viscosity and erythrocyte aggregation.

Investigations on the carcinogenicity of dipyrone in rats.

A carcinogenicity study with dipyrone (metamizol methanesulfonate) was conducted in male and female Wistar rats. The compound was administered with the feed for a period of 24 months in doses of 0, 1000, or 3000 ppm, followed by a 6-month recovery period (without compound administration). The rats in the high-dose group, especially the females, showed a statistically significant body weight gain retardation which was not correlated with reduced feed consumption. The chronic administration of dipyrone did not influence the survival of the rats. No treatment-related changes in clinical signs and hematological parameters occurred. The absolute and relative weights of thyroids and pituitaries in the high-dose males were increased statistically significantly but were still within the normal range of the rat strain used. Histological examination of the animals which died intercurrently or were killed in extremis or at the end of the recovery period did not reveal any nonneoplastic or neoplastic changes which were compound related under the test conditions used. All of the tumors in all groups of animals were considered spontaneous in nature. Dipyrone did not show carcinogenic potential in rats in this study.