The serine protease inhibitor antithrombin III inhibits LPS-mediated NF-kappaB activation by TLR-4.

In Drosophila, the Toll family of proteins mediates the innate immune response. Toll is activated by Spaetzle, which is generated in response to pathogens via a serine protease cascade. We wished to investigate if lipopolysaccharides (LPS) might activate Toll-like receptor (TLR) 4 via a serine protease in humans. The serpin antithrombin III (ATIII) and the thrombin inhibitor hirudin both inhibited nuclear factor (NF)-kappaB activation by LPS and Lipid A. ATIII and hirudin were also able to inhibit LPS-induced NF-kappaB activation in cells stably transfected with TLR4. These results suggest that LPS may activate a mammalian serine protease, which generates a product required for TLR4 signalling.

The short- and long-term effects of bezafibrate in the rat.

Bezafibrate is a potent hypolipidemic agent, which causes marked proliferation of peroxisomes in rat liver. At the same dosage, bezafibrate is more effective in male than in female rats. This is probably related to divergent pharmacokinetics, which cause differences in drug level in serum and liver. The volume density of peroxisomes and several of their enzymes such as carnitine acetyl transferase and acyl-COA oxidase increase in a dose-related fashion. The hypolipidemic effect of bezafibrate, however, does not correlate with the used dosage. This implies that peroxisomal proliferation may play only a minor role in the hypolipidemic action of bezafibrate. In animals treated for 26 months with 300, 750, or 1500 ppm bezafibrate, the relative liver weight and serum triglycerides did not differ significantly from controls. Peroxisomal proliferation varied in different cells, being most prominent in single hepatocytes. The liver catalase activity was significantly reduced, but carnitine acetyl transferase was increased. Abnormal peroxisomes and mitochondria with longitudinal cristae were quite frequent. In one focus, catalase activity was severely diminished ahd peroxisomes were markedly reduced. The incidence of liver tumors was the same (1-3%) in treated animals as in controls.

Plasma cortisol levels before and during "low-dose" hydrocortisone therapy and their relationship to hemodynamic improvement in patients with septic shock.

OBJECTIVES: To compare cortisol levels during "low-dose" hydrocortisone therapy to basal and ACTH-stimulated endogenous levels and to assess whether clinical course and the need for catecholamines depend on cortisol levels and/or pretreatment adrenocortical responsiveness. DESIGN AND SETTING: Prospective observational study in a medical ICU of a university hospital. PATIENTS: Twenty consecutive patients with septic shock and a cardiac index of 3.5 l/min or higher, started on "low-dose" hydrocortisone therapy (100 mg bolus, 10 mg/h for 7 days and subsequent tapering) within 72 h of the onset of shock. MEASUREMENTS AND RESULTS: Basal total and free plasma cortisol levels ranged from 203 to 2169 and from 17 to 372 nmol/l. In 11 patients cortisol production was considered "inadequate" because there was neither a response to ACTH of at least 200 nmol/l nor a baseline level of at least 1000 nmol/l. Following the initiation of hydrocortisone therapy total and free cortisol levels increased 4.2- and 8.5-fold to median levels of 3,587 (interquartile range 2,679-5,220) and 1,210 (interquartile range 750-1,846) nmol/l on day 1, and thereafter declined to median levels of 1,310 nmol/l and 345 nmol/l on day 7. Patients with "inadequate" steroid production could be weaned from vasopressor therapy significantly faster, although their plasma free cortisol concentrations during the hydrocortisone treatment period did not differ. CONCLUSIONS: (a) During proposed regimens of "low-dose" hydrocortisone therapy, initially achieved plasma cortisol concentrations considerably exceed basal and ACTH stimulated levels. (b) Cortisol concentrations decline subsequently, despite continuous application of a constant dose. (c) "Inadequate" endogenous steroid production appears to sensitize patients to the hemodynamic effects of a "therapeutic rise" in plasma cortisol levels.

Kinetics and characteristics of an acute phase response following cardiac arrest.

OBJECTIVE: Inflammation and hypoxia are frequently associated, but their interaction is poorly understood. In vitro studies have shown that hypoxia stimulates the genes of acute phase proteins (APP) and cytokines known to induce APP. We decided to determine kinetics and potential determinants of an acute phase response after cardiac arrest and to assess whether isolated moderate hypoxia can induce APP in humans in vivo. DESIGN: Prospective, observational study in patients and human experiment. SETTING: Tertiary care university hospital. PATIENTS AND PARTICIPANTS: 22 patients after primarily successful cardiopulmonary resuscitation (CPR) and 7 healthy volunteers. INTERVENTIONS: None in patients; exposure of volunteers to simulated altitude (460 torr/6 h). RESULTS: Following CPR, type-1 APP (C-reactive protein, alpha 1-acidglycoprotein, serum amyloid A) and type-2 APP (haptoglobin, alpha 1-antitrypsin) increased consistently within 1-2 days and the 'negative' APP transferrin was downregulated. This APP response occurred irrespective of the cause of arrest, the estimated time of anoxia, clinical course or patient outcome and was not different in patients with and without infectious complications. Exposure of healthy volunteers to less severe but more prolonged hypoxia did not induce APP, although a time dependent increase of serum erythropoietin (EPO) was measurable under these conditions, indicating the activation of oxygen dependent gene expression. CONCLUSIONS: (i) A marked acute phase response occurs regularly after cardiac arrest, but within the complexity of this situation the severity of hypoxia is not a predominant determinant of this response. (ii) Despite in vitro evidence for similarities in the oxygen dependent regulation of APP and EPO production, the oxygen sensitivity of these proteins in vivo is different. (iii) Measurements of APP are not revealing regarding infectious complications in the early phase after CPR.

[Pharmacokinetics and tolerability of telenzepine in patients with compensated liver cirrhosis]. / Pharmakokinetik und Verträglichkeit von Telenzepin bei Patienten mit kompensierter Leberzirrhose.

Pharmacokinetics and Tolerability of Telenzepine in Patients with Chronic Liver Diseases. The pharmacokinetics and tolerability of the new selective muscarinic M1-antagonist telenzepine (BY 803; CAS 80880-90-6) were studied in 10 patients with compensated liver cirrhosis who were treated over 4 weeks with 3 mg at night. 3 mg telenzepine was well tolerated. There was no deterioration of laboratory parameters during the 4 weeks treatment course. Following a single oral dose of 3 mg telenzepine the mean maximal plasma level (cmax) averaged 5.7 (1.9-10.1) ng/ml. After repeated dosing 3 patients displayed different kinetic behaviour resulting in higher values of AUC on day 14/15 in comparison to day 1/2. tmax and cmax remained unchanged. It can be concluded that even in patients with compensated liver cirrhosis no significant accumulation of the compound will occur.

[Lowering of the plasma lipid concentration with lovastatin. A clinical study in patients with primary hypercholesterolemia]. / Senkung der Plasma-Lipidkonzentration durch Lovastatin. Ergebnisse einer klinischen Prüfung bei Patienten mit primärer Hypercholesterinämie.

A study of 27 patients (18 males and 9 females; median age 57 [35-70] years) with hypercholesterolaemia examined the lipid-reducing effect, clinical reliability and tolerance of lovastatin, an HMG-CoA-reductase inhibitor, given in a single evening dose. After a four-week period on placebo and a lipid-reducing diet the patients received 20 mg lovastatin for four weeks. If, at the end of this period, total cholesterol levels were still above 200 mg/dl, the dose was increased to 40 mg, after a further four weeks to 80 mg. After a three-month treatment period total cholesterol concentration in lovastatin-treated patients was 28% lower than in the placebo group (289.4 +/- 42.2 vs 208.0 +/- 39.9 mg/dl; P less than 0.0001). LDL-cholesterol concentration had fallen by 40% (215.1 +/- 44.4 vs 130.1 +/- 24.7 mg/dl; P less than 0.0001), while plasma triglyceride concentrations had fallen by 15% (166.3 +/- 71.8 vs 141.8 +/- 69.8 mg/dl; P less than 0.01). At the same time, HDL-cholesterol levels had risen by 12% (42.9 +/- 12.4 vs 47.9 +/- 18.2 mg/dl; P less than 0.01). These results confirm the marked lipid-reducing effect of lovastatin.