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Biomedical subjects

O Paulsen

Publications and source records attributed to O Paulsen.

At least 37 records · Page 2Linked to original sources
PubMed1995

Cytotoxic effects of four antibiotics on endothelial cells.

Intravenous administration of antibiotics often causes local pain and thrombophlebitis at the site of injection. An in vitro model that could predict these effects would be of great value. In this study the effects of four antibiotics, benzylpenicillin, cefuroxime, dicloxacillin and erythromycin, have been evaluated on three types of endothelial cells in culture. The cell types employed were primary culture from human umbilical vein, primary culture from bovine aorta, and the cell line EA-hy 926, a hybride endothelial cell. These cells were exposed to antibiotics for 24 hr and subsequently toxic effects on cells were evaluated by three different assays. Benzylpenicillin was atoxic in all types of cells and in all assays, in contrast to the other antibiotics. The other three antibiotics exerted dose dependent toxic effects in all investigated cells when DNA-synthesis and total cell protein were used as toxicity assays but the results varied between the cell types. There were no significant differences between the effects of cefuroxime, dicloxacillin and erythromycin on bovine endothelial cells. In the other cell types, however, there were significant differences between some drugs but the outcome depended on the cell type. It is concluded that it is possible to show differences between the effect of antibiotics on endothelial cells, but the result depends on the cell type employed.

Animals↗
PubMed1995

Combined alpha-interferon and ribavirin treatment in chronic hepatitis C: a pilot study.

16 patients with chronic hepatitis C virus (HCV) infection were treated with a combination of interferon-alpha and ribavirin for 24 weeks in an open study. One patient declined further treatment due to depression after week 16 and did not complete further follow-up. A moderate decline was observed in hemoglobin and an increase in bilirubin level both reversible after discontinuing the treatment. 24 weeks after treatment cessation 9/15 (60%) evaluable patients had complete clearance of HCV-RNA as measured with PCR. HCV genotype did not seem to be correlated with response, but patients with sustained response to treatment had a significantly reduced number of HCV RNA copies/ml serum at treatment start compared with the other patients. These findings support the promising results of this combination therapy noted in other pilot studies.

Adult↗
PubMed1994

The quantal size at retinogeniculate synapses determined from spontaneous and evoked EPSCs in guinea-pig thalamic slices.

1. To determine the quantal size at retinogeniculate synapses, spontaneous and evoked excitatory postsynaptic currents (EPSCs) were recorded in twelve neurones of the dorsal lateral geniculate nucleus in guinea-pig thalamic slices using the whole-cell patch-clamp technique. We limited our study to the fast non-N-methyl-D-aspartate (NMDA) component of the EPSCs by adding the NMDA receptor antagonist DL-2-amino-5-phosphonovaleric acid to the perfusion medium. 2. Spontaneous EPSCs occurred at a frequency between 0.5 and 6.6 Hz (mean 2.5 Hz). The modal value of the peak conductance change of spontaneous excitatory events varied between cells from 102 to 179 pS. 3. EPSCs were evoked by electrical stimulation in the optic tract. The peak conductance change of EPSCs evoked by stimulation of a putative single input fibre ranged from 0.6 to 3.4 nS (mean 1.7 nS). 4. To resolve the quantal components of evoked EPSCs the external Ca2+ concentration was reduced and the external Mg2+ concentration increased for four cells. In this condition failures occurred and the amplitude histograms were multimodal with approximately equidistant peaks. 5. These multimodal histograms could be fitted by a sum of Gaussian functions with mean values corresponding to integer multiples of the modal value of the spontaneous EPSCs for the same cell. Thus, the quantal size of evoked EPSCs was the same as the modal value of spontaneous EPSCs. The mean of the apparent quantal conductance change was 138 pS. The estimated number of quanta released by stimulating a putative single input fibre in the control condition ranged from 4 to 27 (mean 13).(ABSTRACT TRUNCATED AT 250 WORDS)

2-Amino-5-phosphonovalerate↗
PubMed1994

Specificity of protein kinase inhibitor peptides and induction of long-term potentiation.

Previous studies have used synthetic peptide analogs, corresponding to sequences within the pseudosubstrate domain of protein kinase C (PKC) or the autoregulatory domain of Ca2+/calmodulin-dependent protein kinase II (CaMKII), in attempts to define the contribution of each of these protein kinases to induction of long-term potentiation (LTP). However, the specificity of these inhibitor peptides is not absolute. Using intracellular delivery to rat CA1 hippocampal neurons, we have determined the relative potency of two protein kinase inhibitor peptides, PKC-(19-36) and [Ala286]CaMKII-(281-302), as inhibitors of the induction of LTP. Both peptides blocked the induction of LTP; however, PKC-(19-36) was 30-fold more potent than [Ala286]CaMKII-(281-302). The relative specificity of PKC-(19-36), [Ala286]CaMKII-(281-302), and several other CaMKII peptide analogs for protein kinase inhibition in vitro was also determined. A comparison of the potencies of PKC-(19-36) and [Ala286]CaMKII-(281-302) in the physiological assay with their Ki values for protein kinase inhibition in vitro indicates that the blockade of induction of LTP observed for each peptide is attributable to inhibition of PKC.

Amino Acid Sequence↗
PubMed1993

Failure to induce long-term depression by an anti-correlation procedure in area CA1 of the rat hippocampal slice.

We have independently in our two laboratories re-examined the report by Stanton and Sejnowski (Nature, 339, 215-218, 1989) that single stimuli to a test pathway in area CA1 of the hippocampal slice, when delivered between short bursts of stimuli to a second, convergent pathway, produce an associative long-term depression (LTD) in the test pathway. While robust associative LTP was observed when stimuli to the two inputs were correlated in time, the anti-correlation procedure failed to induce LTD; rather, a trend towards potentiation was observed. This result was obtained using both submerged and interface chambers, and in two different strains of rat. A transient depression lasting for a few minutes could usually be elicited by strong tetanic stimulation; this depression was not restricted to activated pathways.

Animals↗
PubMed1993

Absolute bioavailability of an aqueous solution of 1-deamino-8-D-arginine vasopressin from different regions of the gastrointestinal tract in man.

The absolute bioavailability of an aqueous solution of 1-deamino-8-D-arginine vasopressin (dDAVP) from different regions of the gastrointestinal (GI) tract (stomach, duodenum, jejunum, ileum, colon, rectum) has been studied in 6 healthy, male volunteers aged 24 to 35 years, followed for 12 h after each drug administration. For i.v. administration the subjects received 4 micrograms dDAVP. For intestinal administration 400 micrograms dDAVP was directly applied to six distinct sites in the GI tract via two or four channel tubes with or without a distal occlusive balloon. Biological effects were assessed and plasma and urinary levels of dDAVP were measured using a specific, sensitive RIA. Urine osmolality remained elevated and diuresis decreased for 12 h following dDAVP administration irrespective of the site of application. After i.v. administration, the half-life of elimination of dDAVP was 60.0 min, plasma clearance 1.7 ml.min-1.kg-1, amount excreted in urine 2.0 micrograms and renal clearance was 0.8 ml.min-1.kg-1. The mean bioavailability (f) after gastric application was 0.19% (range 0.02-0.35%). f was 0.24% after duodenal application (range 0.04-0.62%), 0.19% after jejunal (range 0.01-0.41%), 0.03% after distal ileal (range 0.01-0.08%), 0.04% after proximal colonic (range 0.01-0.12%) and 0.04% after rectal (0.01-0.10%) application. The bioavailability was significantly higher in the three upper GI regions in comparison to the three lower regions. The bioavailability of dDAVP after gastric, duodenal and jejunal application was similar to that after swallowing a tablet in a previous study. Absorption from the ileum was lower than expected and no preferential site of absorption was found.

Adult↗
PubMed1993

Pharmacokinetics of 1-deamino-8-D-arginine vasopressin after various routes of administration in healthy volunteers.

OBJECTIVE: We investigated the pharmacokinetics and biological effects of 1-deamino-8-D-arginine vasopressin (dDAVP) in healthy adults after intravenous, subcutaneous, intranasal, peroral, sublingual and intrarectal administration. DESIGN: Eight normal volunteers were studied over an 8-hour period after each drug administration, separated by at least one week. For intravenous and subcutaneous administration, the subjects received 2 micrograms of dDAVP. The intranasal and sublingual doses were 20 micrograms and the rectal dose was 50 micrograms. Oral administration of dDAVP was effected with a 200-micrograms tablet. MEASUREMENTS: Plasma and urinary levels of dDAVP were measured using a specific and sensitive radioimmunoassay. RESULTS: A significant increase of urine osmolality was observed after all routes of administration, except the sublingual and intrarectal for up to 8 hours after administration. After intravenous administration, the half-life of elimination (t1/2) of dDAVP was 78 +/- 10 minutes. An extensive adsorption of dDAVP to the plastic syringe was found with intravenous but not with subcutaneous administration. Using the area under the curve of dDAVP from the subcutaneous administration as a reference, bioavailability was found to be 3.4% after intranasal administration and 0.1% after oral administration. After sublingual and intrarectal routes of administration no detectable dDAVP was found in the blood; however, low amounts were found in the total 24-hour urine. CONCLUSION: The bioavailability of dDAVP seems lower than previously reported after intranasal and oral administration.

Administration, Intranasal↗
PubMed1992

Efficacy and tolerance of roxithromycin in comparison with erythromycin stearate in patients with lower respiratory tract infections.

The efficacy and tolerance of roxithromycin 150 mg b.i.d. were compared with those of erythromycin stearate 500 mg b.i.d. in patients with lower respiratory tract infections. Out of 86 patients recruited for the study, 79 were evaluable for tolerance and 76 for efficacy. These patients were evenly distributed among the 3 investigational clinics, with 26, 25 and 28 patients, respectively. The diagnosis of lower respiratory tract infections was based on clinical, laboratory, radiological and/or physical findings and, when available, bacteriological and serological findings. The duration of treatment was 10 days, with follow-up at post-treatment visits directly after treatment and 6 weeks thereafter. The clinical outcome was satisfactory with no significant difference between the drugs. More patients reporting adverse events were on erythromycin than on roxithromycin (51.3% vs 17.5%; p = 0.003). The results suggest that roxithromycin is as effective as erythromycin stearate in the treatment of lower respiratory tract infections and causes fewer adverse effects.

Adult↗
PubMed1992

Effects of ketamine on sensory perception: evidence for a role of N-methyl-D-aspartate receptors.

The chiral forms of ketamine were applied as probes for N-methyl-D-aspartate receptor-mediated neurotransmission in humans. Both enantiomers, in clinically relevant concentrations, displaced [3H]dizocilpine (MK 801) from specific binding sites (phencyclidine sites) in membrane fractions of brain homogenates. (S)-Ketamine was at least 4 times as potent as (R)-ketamine in this respect. In healthy volunteers, the most obvious effect of subanesthetic doses of both enantiomers was altered sensory perception. (S)-Ketamine was 4 times as potent as (R)-ketamine in reducing pain perception and in causing auditory and visual disturbances. Both enantiomers caused proprioceptive disturbances (feelings of detachment from the body) and slightly reduced the ability to recall objects seen after administration of the drugs. The ability to recall objects seen immediately before drug exposure was unaffected. The results are in accordance with the hypothesis that inhibition of sensory perception by ketamine in subanesthetic concentrations is due to N-methyl-D-aspartate receptor blockade. It is suggested that N-methyl-D-aspartate receptor-mediated transmission is involved in the processing of sensory information in the human brain.

Adult↗
PubMed1989

Stereoselective interaction of omeprazole with warfarin in healthy men.

The effect of concomitant treatment with omeprazole (20 mg/day) on the plasma concentration and anticoagulation effect of warfarin was studied in 21 young healthy men. An initial three weeks' treatment with warfarin alone was administered to determine the doses required for the subjects' vitamin K-dependent coagulation factors to fall within 10-20% of the normal range, as determined by the Trombotest. Omeprazole and placebo were then administered concomitantly with warfarin for 2 weeks each in a double-blind, randomized, crossover fashion. Plasma concentrations of (R)- and (S)-warfarin, and Trombotest values were measured daily on weekdays throughout the crossover period. Omeprazole had no apparent effect on the mean (S)-warfarin plasma concentration (379 ng/ml with, versus 387 ng/ml without, omeprazole), but caused a slight (12%) although statistically significant increase in the mean (R)-warfarin concentration from 490 to 548 ng/ml (95% confidence interval for difference of means: 28-88). The Trombotest values exhibited large inter- and intrasubject variability during both omeprazole and placebo treatment; however, there was a small, although statistically significant decrease in the mean value from 21.1% without to 18.7% with omeprazole treatment (95% CI for difference of means: -4.6- -0.1). Those subjects with Trombotest values nearest the therapeutic range (5-15%) exhibited less change during omeprazole treatment, and no changes occurred that required a change in warfarin dosing. The interaction of omeprazole with warfarin was attributed to a stereoselective inhibition of the hepatic metabolism of the less potent (R)-warfarin enantiomer. The small effect of omeprazole on the anticoagulation activity of warfarin is not likely to be of clinical importance.

Adult↗
PubMed1989

No effect of terodiline on anticoagulation effect of warfarin and steady-state plasma levels of warfarin enantiomers in healthy volunteers.

The influence of terodiline (25 mg b.i.d.) on the anticoagulant effect and plasma levels of warfarin enantiomers was studied in 23 young healthy male volunteers. Racemic warfarin was first given for 24 days to determine the doses required for the subject's vitamin K-dependent coagulation factors to fall within 10-20% of the normal range, as determined by the Thrombotest. During continuous warfarin treatment (mean daily dose 5.3 mg, range 2.5-9.4 mg), terodiline or placebo was given for two weeks in a randomized and double-blind fashion, and then the drugs were crossed over and given for another two weeks. Terodiline did not influence the anticoagulant effect of warfarin or the plasma levels of the warfarin enantiomers. The results indicate that it should not be necessary to monitor patients on combined therapy with terodiline and warfarin more frequently than patients on warfarin monotherapy.

Adult↗
PubMed1989

Effects of N-acetylcysteine on human polymorphonuclear leukocytes.

N-acetylcysteine (NAC) at concentrations from 0.39 micrograms/ml to 100 micrograms/ml did not affect chemotaxis under agarose of human polymorphonuclear leukocytes (PMNLs). No reduction of phagocytic or bactericidal capacity was found in PMNLs exposed to NAC at the same concentrations. At high concentrations of NAC (25-100 micrograms/ml) a distinct inhibition of the chemiluminescent response to formylmetionyl-leucyl-phenylalanine (fMLP) known to be associated with mainly extracellular metabolic processes, was observed, consistent with the well known scavenger effects of the drug. The response to opsonized zymosan, which reflects mainly intracellular metabolic activity, was less marked. At a still higher concentration of NAC (500 micrograms/ml), a distinct effect on both intra- and extracellularly generated chemiluminescence could be demonstrated. The lack of inhibitory effects on phagocytosis and intracellular killing in spite of the effects on chemiluminescence indicates that NAC has no negative influence on the antimicrobial activity of PMNLs.

Acetylcysteine↗
PubMed1989

Pharmacokinetic comparison of two models of endocarditis prophylaxis with amoxycillin.

From studies on prophylaxis against experimental streptococcal endocarditis using amoxycillin in a single dose, it has been deduced that serum concentrations above 0.12 mg/l should be maintained for at least 10 h after antibiotic administration. Since concentrations above this level are reported to occur following an oral dose of 3 g of amoxycillin, this doses for prophylaxis has become widely accepted in USA and the UK, and presently also in Sweden. Nevertheless, in individuals who cannot tolerate a high single dose of amoxycillin, there is need for an alternative dosage regimen. In the present study, we have compared the pharmacokinetics in 12 healthy volunteers, of a single dose of 3 g of amoxycillin with those of 1 g as single dose or combined with 1 g of probenecid. The combination resulted in an AUC twice as large as that achieved after 1 g of amoxycillin, and was slightly, but not significantly, larger than that after 3 g. However, amoxycillin concentrations above 0.12 mg/l were sustained for almost 14 h with the combination as compared to 10.4 hours following 3 g of amoxycillin only (p less than 0.001). Thus, the combination should be a convenient alternative in patients unable to tolerate a higher oral dose of amoxycillin, and in situations when an antibacterial effect of longer duration is desired.

Adult↗
PubMed1989

No effect of omeprazole-induced hypoacidity on the bioavailability of amoxycillin or bacampicillin.

The absorption of ampicillin esters is reported to decrease when gastric acidity is inhibited because of hydrolysis of the esters, or by lowered solubility at a higher pH. No such information on the hydroxylated derivative amoxycillin is available. This was investigated in 8 fasting volunteers, who received 800 mg bacampicillin or 1000 mg amoxycillin on 4 study days, separated by at least 1 week. Each ampicillin derivative was administered on 1 occasion as a single drug, and on another after 1 week's pretreatment with the potent acid inhibitor omeprazole. Bacampicillin was absorbed more rapidly than amoxycillin, and serum peak concentrations were higher. After induced hypoacidity, peak concentrations of both antibiotics appeared to be slightly delayed, and those of bacampicillin significantly reduced. Nevertheless, both the areas under the plasma concentration curves, and the half lives of elimination of the antibiotics were unaffected. Hypoacidity as such does not reduce the bioavailability of amoxycillin or bacampicillin.

Adult↗
PubMed1988

No effect of roxithromycin on pharmacokinetic or pharmacodynamic properties of warfarin and its enantiomers.

The macrolide antibiotics are metabolized by cytochrome P-450 enzymes in the liver and interactions with similarly metabolized compounds have been described. Simultaneous treatment with erythromycin and warfarin is known to decrease warfarin clearance and prolong prothrombin time. Roxithromycin (RU 28965), a new erythromycin derivative with improved pharmacokinetic properties, might then, because of structure similarity, be expected to interact with warfarin. In 21 healthy volunteers, the effect of orally administered roxithromycin (150 mg b.i.d.) on warfarin steady-state kinetics, and the effects of warfarin on roxithromycin kinetics, were investigated in a double-blind, randomized study versus placebo. Since the warfarin enantiomers, R- and S-warfarin have both different potency and different metabolism, the ratio between the enantiomers with and without roxithromycin, was also determined. In this study, mean AUC for warfarin increased slightly from day 14 of warfarin treatment to day 28, but no difference was found between the roxithromycin group and the placebo group, and no change appeared in the ratio between the warfarin enantiomers. A moderate increase in dosage was needed to maintain hypocoagulability during warfarin medication, but there was no difference between the roxithromycin group and the placebo groups, respectively. In addition, roxithromycin kinetics appeared to be unaffected by warfarin treatment.

Adult↗
PubMed1988

Short-term exposure to bilirubin reduces synaptic activation in rat transverse hippocampal slices.

We evaluated the feasibility of using the in vitro transverse rat hippocampal slice as a model to study the effect of bilirubin on neuronal activity. Bilirubin in concentrations from 100 mumol/liter to 1 mmol/liter with bovine serum albumin as a stabilizer caused a significant decrease in the slope of the field excitatory postsynaptic potentials, concomitant with a significant increase in the peak latency of the population spike. These changes were partially reversible when bilirubin was removed from the incubation fluid. A partially reversible shift to the right of the presynaptic fiber volley/field excitatory postsynaptic potential relationship was interpreted as an expression of a reduction in synaptic activation. A partially reversible shift to the left of the field exitatory postsynaptic potential population spike relationship was interpreted as an expression of increased postsynaptic excitability. In conclusion the in vitro rat hippocampal slice was used successfully to study the effect of bilirubin on neuronal activity. A depressive effect of bilirubin was observed.

Action Potentials↗