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Biomedical subjects

R Nau

Publications and source records attributed to R Nau.

108 records · Page 6Linked to original sources
PubMed1992

Penetration of rifampicin into the cerebrospinal fluid of adults with uninflamed meninges.

The penetration of rifampicin into CSF was studied in seven patients who had undergone external ventriculostomy for occlusive hydrocephalus without major disturbance of the blood-CSF barrier. After the first dose of rifampicin 600 mg i.v. over 3 h, blood and CSF concentrations were determined serially by HPLC. Peak CSF concentrations obtained 0-8 h (median = 1 h) after the end of the infusion ranged from 0.57 to 1.24 mg/L (median = 0.73 mg/L). Elimination from CSF was slower than from serum (T1/2 beta CSF: 9.1-21.0 h (median = 14.5 h, n = 5); T1/2 beta serum: 2.2-5.8 h (median = 3.6 h, n = 7)). Based on the ratios of the areas under the concentration-time curves in CSF and serum, the overall penetration of rifampicin into CSF was 0.13-0.42 (median = 0.22). These results demonstrate effective CSF penetration and favourable pharmacokinetics of rifampicin in the absence of meningeal inflammation. They support the use of rifampicin as part of a combination therapy not only for tuberculosis of the central nervous system (CNS), but also for staphylococcal and listerial infections of the CNS in which there may be little meningeal inflammation.

Aged↗
PubMed1992

Low blood-to-cerebrospinal fluid passage of sorbitol after intravenous infusion.

BACKGROUND AND PURPOSE: Compared with mannitol, the osmotherapeutic agent sorbitol is less prone to accumulate in the blood and the same quantity may be infused in a smaller volume. Because of these advantageous characteristics, we studied the pharmacokinetics of sorbitol in serum and cerebrospinal fluid. METHODS: Six patients (five women and one man; age range, 46-70 years) with an external ventriculostomy and suffering from brain edema due to cerebrovascular disease received sorbitol as part of their therapy. Before and after the first dose of 50 g infused over 20 minutes, sorbitol concentrations in serum and cerebrospinal fluid were determined repeatedly using an enzymatic procedure. RESULTS: Maximal sorbitol concentrations ranged from 2,705 to 5,821 (median, 3,227) mg/l in serum compared with 6.7-130.7 (median, 19.5) mg/l in cerebrospinal fluid. Cerebrospinal fluid maxima were observed 0.17-3 hours after the end of the infusion. Sorbitol elimination in serum was adequately described by a two-compartment pharmacokinetic model (distribution half-life, 0.05-0.14 hour; elimination half-life, 0.23-0.61 hour). Elimination in cerebrospinal fluid followed a single-exponential decay and was considerably slower than that in serum (half-life, 1.3-7.7 hours). CONCLUSIONS: The maximal cerebrospinal fluid concentration/maximal serum concentration ratio was low for sorbitol, thus suggesting a small potential risk of inducing an increase of intracranial pressure after osmotherapy (rebound effect).

Aged↗
PubMed1990

[Listeriosis of the central nervous system].

Listeriosis of the CNS is an inflammatory disease of the central nervous system that occurs mostly sporadically or occasionally as a limited epidemic. The pathogens are generally ingested with the food. Whether or not the infection becomes manifest in an exposed person depends on the number of pathogens ingested, on the virulence of the Listeria strain and on the individual disposition. It appears to be of decisive importance for an infection that the cellular immunodefense mediated by the T cells is disturbed; however, even persons without any previous disease worth mentioning may be affected. The characteristics of the various CNS manifestations are demonstrated via the case histories of 12 own patients (acute meningitis and meningoencephalitis, brain stem encephalitis, brain abscess, meningoencephalitis with infected cerebral infarct, chronic recidivating encephalitis). Early neurological focal signs and symptoms, combined with CSF findings atypical for bacterial CNS disease, should not be taken lightly and may point to listeriosis even though they are not specific for CNS listeriosis. The decisive criterion is the proof of the pathogen in the blood or CSF or the proof of antibody titre changes in the serum. Recent CSF diagnostic methods such as CSF lactate determination and the identification of IgG-positive B lymphocytes are useful in differentiating between viral and noninflammatory CNS disease; most important for follow-up are repeat CSF examinations. High-dosage ampicillin or amoxycillin treatment combined with gentamycin is the therapy of choice in CNS listeriosis. The bactericidal effect achieved thereby is desirable especially if immunodefense is disturbed. Prognosis of CNS listeriosis depends on the underlying disease in each case. The high mortality even among persons who had been healthy before the infection, is at least in part due to delayed diagnosis.

Adolescent↗
PubMed1990

Penetration of ciprofloxacin into the cerebrospinal fluid of patients with uninflamed meninges.

Nine patients with external ventriculostomy and suffering from hydrocephalus, due to non-inflammatory central nervous system diseases, were given ciprofloxacin (200 mg twice daily iv). Ciprofloxacin concentrations in serum and CSF were measured by HPLC. Single-dose pharmacokinetics were determined in three patients, and 60 and 600 min post-dose levels after repeated administration in six patients. CSF concentrations were maximal 60-120 min after the end of the infusion. The CSF elimination half-life was 260-430 min compared with 145-170 in serum. Post-dose levels at 60 min ranged from 0.042 to 0.223 mg/l (median = 0.110). Repeated administration did not lead to substantial increases in serum and CSF concentrations. With respect to MIC90 values reported for bacteria involved in CNS infections, the CSF concentrations of ciprofloxacin obtained under our experimental conditions would be considered subtherapeutic. Thus ciprofloxacin therapy of CNS infections may be inadequate when only minor impairment of the blood-CSF barrier exists.

Adult↗
PubMed1990

Meningoencephalitis with septic intracerebral infarction: a new feature of CNS listeriosis.

The broad spectrum of CNS listeriosis is expanded by the observation of an intracerebral infarction associated with meningoencephalitis. Sequential CCT scans in a 66-year-old immuno-compromised woman led to the clinical diagnosis of brain abscess. Autopsy revealed an infected intracerebral infarction most probably due to temporal occlusion of the middle cerebral artery by septic microemboli or septic endothelial damage.

Aged↗
PubMed1987

Binding of vasoactive intestinal polypeptide to dispersed enterocytes results in rapid removal of the NH2-terminal histidyl residue.

Specific binding sites for 125I-labelled vasoactive intestinal polypeptide (VIP) (half-maximal inhibition at 1.5 +/- 0.2 nM VIP) were identified on dispersed porcine enterocytes. Radioactivity bound to the cell surface was internalized. At 37 degrees C, a steady state was achieved after 45 min with a ratio of internalized to cell surface-bound radioactivity of approximately 1:2 but at 10 degrees C, no radioactivity appeared intracellularly. Incubation of VIP with cells in the absence of inhibitors of proteolysis for as short a time as 30 s at 37 degrees C led to the formation of [des-His1]VIP by the action of amastatin- and bestatin-sensitive aminopeptidase(s). This metabolite was formed in the presence of sodium azide and when incubations were performed at 10 degrees C suggesting that internalization was not a prerequisite for degradation. As [des-His1]-VIP has only 1% of the bioactivity of VIP, formation of this metabolite will effectivily terminate the action of VIP in the epithelial layer of the intestine.

Amino Acids↗
PubMed1987

Appraisal of modifiable hospitalization risks.

Nine prevention experts rated hospitalization risks of 64 hypothetical healthy adults between 20 and 65 years old. There was substantial agreement among seven out of the nine experts. Pairwise correlations between any two of the experts ranged between 0.66 and 0.86. Decision analytic tools were used to model the average of the experts' ratings. The panel of experts provided us with the factors used, the relationship between the factors, and the relative importance of each factor. An index based on this information was highly correlated with the judgments of seven experts. Thus, we concluded that the scoring procedure can simulate the experts' judgments. Next, the index was used in an interactive computer program to assess modifiable health risks of individuals. This program is provided along with the paper to facilitate further research on validity and impact of the program.

Adult↗
PubMed1987

Conversion of neuropeptide K to neurokinin A and vesicular colocalization of neurokinin A and substance P in neurons of the guinea pig small intestine.

The highest concentration of neurokinin A-like immunoreactivity and substance P-like immunoreactivity in the guinea pig small intestine was associated with the myenteric plexus-containing longitudinal muscle layer. Chromatographic analysis of extracts of this tissue demonstrated the presence of neurokinin A and neuropeptide K but the probable absence of neurokinin B. A fraction of synaptic vesicles of density 1.133 +/- 0.003 g/ml was prepared from the myenteric plexus-containing tissue by density gradient centrifugation in a zonal rotor and was enriched 29 +/- 12-fold in the concentration of neurokinin A-like immunoreactivity and 43 +/- 13-fold in the concentration of substance P-like immunoreactivity. This fraction was separated from the fraction of vasoactive intestinal peptide-containing vesicles (density, 1.154 +/- 0.009 g/ml). Chromatographic analysis of lysates of the vesicles indicated the presence of neurokinin A but not neuropeptide K. It is postulated that beta-pre-protachykinin is processed to substance P, neurokinin A, and neuropeptide K in the cell bodies of myenteric plexus neurons but that conversion of neuropeptide K to neurokinin A takes place during packaging into storage vesicles for axonal transport. The data are consistent with the proposal that neurokinin A and substance P are stored in the same synaptic vesicle, but the possibility of cosedimentation of different vesicles of very similar density cannot be excluded.

Animals↗
PubMed1986

Specific binding and proteolytic inactivation of bradykinin by membrane vesicles from pig intestinal smooth muscle.

A preparation of closed membrane vesicles derived from the longitudinal and circular smooth muscle of pig small intestine was enriched eight-fold in the activity of 5'-nucleotidase and six-fold in the activity of peptidyl dipeptidase A relative to the tissue homogenate. The membrane vesicles specifically bound [3H]bradykinin and the concentration of bradykinin required to inhibit 50% binding was 0.76 +/- 0.05 nM. This concentration was not significantly different from the corresponding concentration of lysyl-bradykinin (0.45 +/- 0.13 nM) but was less (P less than 0.05) than the concentration of methionyl-lysyl-bradykinin (1.25 +/- 0.10 nM). The concentration of des-Arg9 bradykinin (7.5 microM) required for 50% inhibition was greater than 10(3) times less than bradykinin indicating the presence of a B2-type receptor. The membrane vesicles also degraded bradykinin and the principal metabolite was identified as bradykinin. Des-Arg1 bradykinin, des-Arg9 bradykinin and bradykinin were also formed in low yield. Cleavage of the Pro7-Phe8 bond was inhibited by phosphoramidon but not by enalapril or captopril indicating that proteolytic inactivation of bradykinin in the muscle layer of the intestine is mediated through endopeptidase 24.11 ("enkephalinase") but not through peptidyl dipeptidase A ("angiotensin-converting enzyme").

5'-Nucleotidase↗
PubMed1986

Proteolytic inactivation of substance P and neurokinin A in the longitudinal muscle layer of guinea pig small intestine.

Membrane vesicles, showing a 21 +/- 2-fold enrichment in the activity of 5'-nucleotidase and a 11 +/- 4-fold enrichment in the activity of angiotensin-converting enzyme relative to homogenate, were prepared from the myenteric plexus-containing longitudinal muscle layer of guinea pig ileum. Incubation of the vesicles with substance P and neurokinin A led to degradation of the peptides, and metabolites were isolated by reverse-phase HPLC and identified by amino acid composition. Cleavages of substance P between Glu6-Phe7, Phe7-Phe8, and Gly9-Leu10 and of neurokinin A between Gly8-Leu9 were observed and could be inhibited in a dose-dependent manner by phosphoramidon, an inhibitor of neutral endopeptidase 24.11. Formation of these metabolites was not completely inhibited by this agent, indicating that a phosphoramidon-insensitive form of endopeptidase 24.11 was present in the gut. Substance P was resistant to degradation by aminopeptidases, but neurokinin A was a substrate for bestatin-sensitive aminopeptidase(s), so that the neurokinin A (3-10) fragment represented the predominant metabolite in the chromatograms. The rate of formation of all the metabolites was not inhibited by enalapril and not enhanced by an increased Cl- concentration, indicating that angiotensin-converting enzyme was unimportant in the degradation process. Degradation of neurokinin A by the vesicles (Km 30 microM; Vmax 7.2 +/- 0.8 nmol min-1 mg of protein-1) was more rapid than degradation of substance P (Km 25 microM; Vmax 4.4 +/- 0.4 nmol min-1 mg of protein-1).

Aminopeptidases↗
PubMed1985

Proteolytic inactivation of substance P in the epithelial layer of the intestine.

Metabolites of substance P, produced by incubation with isolated epithelial cells and with purified brush border and basolateral membrane from pig small intestine, were isolated by high performance liquid chromatography and identified by amino acid analysis. Rapid cleavages between Gln6-Phe7, Phe7-Phe8 and Gly9-Leu10 and oxidation of the methionine residue at position 11 were observed with cells and with both membrane fractions. Formation of substance P3-11' indicative of the action of dipeptidylaminopeptidase IV (EC 3.4.14.5), was observed only at high substrate concentration. Proteolytic degradation was inhibited by phosphoramidon and by EDTA but was insensitive to chloride ion concentration and to captopril. These observations suggest that inactivation of substance P in the epithelial layer of the gut is mediated through endopeptidase-24.11 (EC 3.4.24.11) in the cell-surface membrane and that degradation by angiotensin-converting enzyme (EC 3.4.15.1), although present in high concentration in the mucosa, is unimportant.

Amino Acids↗
PubMedDate not supplied

Release of teichoic and lipoteichoic acids from 30 different strains of Streptococcus pneumoniae during exposure to ceftriaxone, meropenem, quinupristin/dalfopristin, rifampicin and trovafloxacin.

The release of teichoic acids (TA) and lipoteichoic acids (LTA) from 30 different strains of Streptococcus pneumoniae during exposure to ceftriaxone, meropenem, quinupristin/dalfopristin, rifampicin and trovafloxacin at concentrations of 10 micrograms/ml and of the respective MIC was determined by an enzyme immunoassay. At 10 micrograms/ml the most rapid and intense release was detected during treatment with the beta-lactam antibiotics ceftriaxone and meropenem, the lowest release was seen with rifampicin and quinupristin/dalfopristin. Trovafloxacin delayed the release of TA/LTA. The maximum concentrations of TA/LTA, however, during trovafloxacin treatment were almost as high as those during exposure to ceftriaxone and meropenem. During exposure to the MIC, ceftriaxone, meropenem, rifampicin and trovafloxacin released significantly higher amounts of TA/LTA than during exposure to 10 micrograms/ml (p < 0.01). Only quinupristin/dalfopristin released small amounts of TA/LTA at the low and high concentration. In conclusion, at high concentrations antibiotics that do not affect the bacterial cell wall released less pro-inflammatory compounds from S. pneumoniae than ceftriaxone and meropenem. This may be of value in the treatment of meningitis and sepsis.

Animals↗
PubMedDate not supplied

Rifabutin for experimental pneumococcal meningitis.

Rifabutin is a lipophilic antibacterial with high in vitro activity against many pathogens involved in bacterial meningitis including pneumococci. Resistance to beta-lactam antibiotics in pneumococci is not associated with a decreased sensitivity to rifabutin (30 strains from Germany with intermediate penicillin resistance; MIC range of penicillin: 0.125-1 mg/l, MIC of rifabutin: < 0.008-0.015 mg/l). Rifabutin at doses of 0.625, 1.25, 2.5, 5 and 10 mg/kg/h i.v. was investigated in a rabbit model of meningitis using a Streptococcus pneumoniae type 3 (MIC/MBC of rifabutin: 0.015/0.06 mg/l). The bacterial density in CSF at the onset of treatment was 7.3 +/- 0.6 log CFU/ml (mean +/- SD). Rifabutin decreased bacterial CSF titers in a dose-dependent manner [delta log CFU/ml/h (slope of the regression line log CFU/ml vs. time) at a dose of 0.625 mg/kg/h: -0.16 +/- 0.06 (n = 3), at 1.25 mg/kg/h: -0.20 +/- 0.12 (n = 4), at 2.5 mg/kg/h: -0.24 +/- 0.04 (n = 4), at 5 mg/kg/h: -0.31 +/- 0.10 (n = 8), and at 10 mg/kg/h: -0.29 +/- 0.10 (n = 5)]. At high doses rifabutin was as active as ceftriaxone at 10 mg/kg/h (delta log CFU/ml/h: -0.29 +/- 0.10, n = 10). Two and 5 h after initiation of therapy, CSF TNF-alpha activities were lower with rifabutin 5 mg/kg/h than with ceftriaxone (medians 2 vs. 141 U/ml, p = 0.005 at 2 h; median 51 vs. 120 U/ml 5 h after initiation of therapy, p = 0.04). This did not result, however, in a decrease of indicators of neuronal damage. In conclusion, intravenous rifabutin was bactericidal in experimental pneumococcal meningitis. Provided that a well-tolerated i.v. formulation will be available it may qualify as a reserve antibiotic for pneumococcal meningitis, in particular when strains with a reduced sensitivity to beta-lactam antibiotics are the causative pathogens.

Animals↗