[Clinical pharmacokinetics of anti-infective drugs in extracorporeal membrane oxygenation]. / Klinische Pharmakokinetik der Antiinfektiva bei extrakorporaler Membranoxygenierung.

Extracorporeal membrane oxygenation (ECMO) is becoming more and more clinically important. The extracorporeal circuit for membrane oxygenation consists of a pump, a membrane oxygenator and large volume tubing. The ECMO device forms an additional compartment, which can absorb drugs with high lipophilia and protein binding. Thus, ECMO affects the volume of distribution and the clearance. As a consequence, the pharmacokinetic-pharmacodynamic (pk-pd) target parameters cannot be achieved. The selection of an appropriate substance and the mode of application, combined with therapeutic drug monitoring (TDM), can significantly improve the therapeutic outcome of critically ill patients.

Cardiovascular response to group I metabotropic glutamate receptor activation in NTS.

Glutamate is the proposed neurotransmitter of baroreceptor afferents at the level of the nucleus tractus solitarius (NTS). Exogenous glutamate in the NTS activates neurons through ionotropic and metabotropic glutamate receptors (mGluRs). This study tested the hypothesis that group I mGluRs in the NTS produce depressor, bradycardic, and sympathoinhibitory responses. In urethan-anesthetized rats, unilateral 30-nl microinjections of the group I-selective mGluR agonist 3,5-dihydroxyphenylglycine (DHPG) into the NTS decreased mean arterial pressure, heart rate, and lumbar sympathetic nerve activity. The dose of drug that produced 50% of the maximal response (ED50) was 50-100 microM. The response to microinjection of equal concentrations of DHPG or the general mGluR agonist 1-aminocyclopentane-1S,3R-dicarboxylic acid (ACPD) produced similar cardiovascular effects. The cardiovascular response to injection of DHPG or ACPD was abolished by NTS blockade of mGluRs with alpha-methyl-4-carboxyphenylglycine (MCPG). Blockade of ionotropic glutamate receptors with kynurenic acid did not attenuate the response to DHPG or ACPD injection. These data suggest that DHPG and ACPD activate mGluRs in the NTS and do not require ionotropic glutamate receptors to produce their cardiovascular response. In the NTS the group I mGluRs produce responses that are consistent with excitation of neurons involved in reducing sympathetic outflow, heart rate, and arterial pressure.

Effects of acetaminophen and ibuprofen on renal function in anesthetized normal and sodium-depleted dogs.

In certain conditions, renal prostaglandins (PGs) are important determinants of kidney function. Under these "renal PG-dependent states," pharmacological inhibition of vasodilatory PG may result in excessive renal vasoconstriction and adversely affect kidney function. The purposes of this study were to determine whether acetaminophen (Acet), a weak PG-synthesis inhibitor, influences kidney function in the renal PG-dependent state of anesthesia and sodium depletion. Comparisons were made with ibuprofen (Ibu). Measurements of PGE2 excretion were used to assess renal PG synthesis. Acet (15 mg/kg) and Ibu (10 mg/kg) both decreased renal blood flow and glomerular filtration rate by approximately 20-30% in normal, anesthetized, sodium-replete dogs. Although Acet produced similar changes in renal blood flow and glomerular filtration rate in the low-sodium dogs, Ibu caused a significantly greater renal vasoconstriction (64 +/- 10%) in these animals. Both Acet and Ibu inhibited urinary PGE2 excretion in sodium-replete and low-sodium dogs. Ibu tended to have a greater and more prolonged effect than did Acet. These results suggest that Acet alters PGE2 excretion and kidney function under renal PG-dependent conditions; the effects, however, are less severe than those seen with Ibu.

Nitric oxide inhibition causes an exaggerated pressor response in Yucatan miniature swine.

The involvement to nitric oxide (NO) in cardiovascular and renal function was evaluated in 12 anesthetized Yucatan miniature swine. The effect of NO blockade on blood pressure was measured in six additional conscious swine. In the anesthetized swine, mean arterial pressure (MAP), heart rate, glomerular filtration rate (GFR), and urinary excretion of water, sodium, and potassium were measured after systemic inhibition of NO synthesis by NG-nitro-L-arginine methyl ester (L-NAME), and were compared with values for a control period. After NO synthesis blockade, MAP increased by 63 +/- 5 mm Hg, a far greater increase than those observed in rats, dogs, domestic swine, or humans. The changes in GFR, urine flow rate (UFR), and sodium excretion (UNaV) were time-dependent. The GFR decreased to 50 +/- 6% of control values immediately after L-NAME administration, but returned to control values within 1 h. Significant increases in UFR and UNaV were observed only during the third experimental period, 40 to 60 min after drug infusion. In the conscious swine, L-NAME administration increased MAP by 24 +/- 4 mm Hg. Administration of the sympatholytic hexamethonium bromide fully reversed the increase of MAP in anesthetized and conscious swine. These findings indicate that NO has an important role in the maintenance of cardiovascular and renal function in Yucatan miniature swine. The exaggerated pressor response to NO blockade in miniature swine appears to involve the sympathetic nervous system.

Inhibition of angiogenesis and murine tumour growth by laminarin sulphate.

LAM S5 is a polysulphated derivative of the glucan laminarian that inhibits basic fibroblast growth factor (bFGF) binding and the bFGF-stimulated proliferation of fetal bovine heart endothelial (FBHE) cells. This report demonstrates that LAM S5 has anti-angiogenic activity, as shown by inhibition of tubule formation by endothelial cells cultured on Matrigel and inhibition of vascularisation of the chick chorioallantoic membrane. In addition, LAM S5 caused a tumour growth delay of the murine RIF-1 tumour of 2.6 days (P = 0.01).

The mechanism of folding of pancreatic ribonucleases is independent of the presence of covalently linked carbohydrate.

The role of asparagine-linked oligosaccharides for the mechanism of protein folding was investigated. We compared the stability and folding kinetics for two sets of pancreatic ribonucleases (RNases) with identical amino acid sequences and differences in glycosylation. First the folding of RNases A (carbohydrate free) and B (a single N-linked oligosaccharide) from bovine pancreas was investigated. The kinetics of refolding were identical under a wide range of conditions. The rate of unfolding by guanidinium chloride was decreased in RNase B. In further experiments the folding of porcine RNase (three carbohydrate chains at Asn-21, -34, and -76) was compared with the corresponding data for the deglycosylated protein. Even for this RNase with almost 40% carbohydrate content the mechanism of refolding is independent of glycosylation. Although the folding mechanism is conserved, the rates of individual steps in folding are decreased about 2-fold upon deglycosylation. We interpret this to originate from a slight destabilization of folding intermediates by carbohydrate depletion. In control experiments with nonglycosylated bovine RNase A it was ascertained that treatment with HF (as used for deglycosylation) did not affect the folding kinetics. The in vitro folding mechanism of glycosylated RNases apparently does not depend on the presence of N-linked oligosaccharide chains. The information for the folding of glycoproteins is contained exclusively in the protein moiety, i.e. in the amino acid sequence. Carbohydrate chains are attached at chain positions which remain solvent exposed. This ensures that the presence of oligosaccharides does not interfere with correct folding of the polypeptide chain.