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S Läer

Publications and source records attributed to S Läer.

At least 19 recordsLinked to original sources
PubMed2001

Separation of carvedilol enantiomers in very small volumes of human plasma by capillary electrophoresis with laser-induced fluorescence.

A sensitive capillary electrophoretic method for the determination of carvedilol enantiomers in 100 microl of human plasma has been developed and validated. Carvedilol and the internal standard carazolol are isolated from plasma samples by liquid-liquid extraction using diethylether. A sensitive and selective detection is provided by helium-cadmium laser-induced fluorescence. The total analysis time is 17.5 min, about 30 min are needed for the sample preparation. The linearity of the assay ranges from 1.56 to 50 ng/ml per carvedilol enantiomer. The limits of quantification (LOQ) for the carvedilol enantiomers in 100 microl of human plasma are 1.56 ng/ml. The inter-day accuracy for R-carvedilol is between 95.8 and 103% (104% at LOQ) and for S-carvedilol between 97.1 and 103% (107% at LOQ); the inter-day precision values are between 3.81 and 8.64% (10.9% at LOQ) and between 5.47 and 7.86% (7.91% at LOQ) for R- and S-carvedilol, respectively. The small sample volume needed is especially advantageous for the application in clinical studies in pediatric patients. As an application of the assay concentration/time profiles of the carvedilol enantiomers in a 5-year-old patient receiving a test dose of 0.09 mg/kg carvedilol are reported.

Adrenergic alpha-Antagonists↗
PubMed2001

Small blood volumes from children for quantitative sotalol determination using high-performance liquid chromatography.

A sensitive high-performance liquid chromatographic method using fluorescence detection has been developed for sotalol determination in small plasma samples of children and newborns with limited blood volume. In sample sizes of 100 microl of plasma, sotalol was extracted using an internal standard and solid-phase extraction columns. Chromatographic separation was performed on a Spherisorb C6 column of 150x4.6 mm I.D. and 5 microm particle size at ambient temperature. The mobile phase consisted of acetonitrile-15 mM potassium phosphate buffer (pH 3.0) (70:30, v/v). The excitation wavelength was set at 235 nm, emission at 300 nm. The flow-rate was 1 ml/min. Sotalol and the internal standard atenolol showed recoveries of 107+/-8.9 and 97+/-8.1%, respectively. The linearity range for sotalol was between 0.07 and 5.75 microg/ml, the limit of quantitation 0.09 microg/ml. Precision values expressed as percent relative standard deviation of intra-assay varied between 0.6 and 13.6%, that of inter-assay between 2.4 and 14.4%. Accuracy varied between 86.1 and 109.8% (intra-assay) and 95.4 and 103.3% (inter-assay). Other clinically used antiarrhythmic drugs did not interfere. As an application of the assay, sotalol plasma concentrations in a 6-year-old child with supraventricular tachycardia treated with oral sotalol (3.2 mg/kg per day) are reported.

Anti-Arrhythmia Agents↗
PubMed2001

Determination of carvedilol in human cardiac tissue by high-performance liquid chromatography.

A new high-performance liquid chromatographic method has been developed for the determination of the beta-receptor blocker carvedilol in human cardiac tissue. After homogenizing tissue samples in a microdismembrator, carvedilol and the internal standard naftopidil are extracted with acetone. The extract is evaporated to dryness and reconstituted in a potassium acetate buffer of pH 3.5. Samples are cleaned up with solid-phase extraction columns. Carvedilol and the internal standard show recoveries of 69.8 +/- 12.2% and 63.9 +/- 9.34%, respectively. The linearity range for carvedilol is 0.01-0.35 ng/mg (parts per billion) tissue (wet weight), and the limit of quantitation is 0.01 ng/mg. The percentage coefficient of variation of the intra-assay varies between 1.45 and 5.38% and the interassay between 4.25 and 6.96%. To use as an application of the assay, the cardiac carvedilol tissue level in a patient on oral carvedilol therapy for congestive heart failure is reported.

Adrenergic beta-Antagonists↗
PubMed2000

Biochemical mechanism(s) of stunning in conscious dogs.

The mechanism(s) underlying contractile dysfunction in cardiac stunning is not completely understood. The expression and/or the phosphorylation state of cardiac Ca(2+) homoeostasis-regulating proteins might be altered in stunning. We tested this hypothesis in a well-characterized model of stunning. Conscious dogs were chronically instrumented, and the left anterior descending artery (LAD) was occluded for 10 min. Thereafter, reperfusion of the LAD was initiated. Tissues from reperfused LAD (stunned) and Ramus circumflexus (control) areas were obtained when left ventricular regional wall thickening fraction had recovered by 50%. Northern and Western blotting revealed no differences in the expression of the following genes: phospholamban, calsequestrin, sarco(endo)plasmic reticulum Ca(2+)-ATPase 2a, and the inhibitory subunit of troponin I (TnI). However, the phosphorylation state of TnI and phospholamban were reduced in the LAD area. Fittingly, cAMP levels were reduced by 28% (P < 0.05). It is concluded that the contractile dysfunction in cardiac stunning might be mediated in part by decreased levels of cAMP and subsequently a reduced phosphorylation state of phospholamban and TnI.

Animals↗
PubMed1999

Inositol-1,4,5-trisphosphate increase by diadenosine tetraphosphate in preparations from failing human myocardium.

In human ventricular trabeculae carneae 100 microM AP4A (diadenosine tetraphosphate) increased force of contraction to 162.8+/-15.7% of predrug value (n=9). This positive inotropic effect was accompanied by a prolongation of time parameters: time to peak tension and time of relaxation were prolonged by 7.8+/-1.3% and 14.9+/-3.8%, respectively (P<0.05). In the same trabeculae, AP4A increased IP3 (inositol-1,4,5-trisphosphate) content from 9.0+/-1.3 pmol/mg to 22.9+/-5.4 pmol/mg protein (n=5-9). In conclusion, the positive inotropic effect of AP4A in the human myocardium is likely due to an increase of IP3 mediated probably via Gq-coupled P2Y-purinoceptors. Because of the prominent role of Gq in the development of cardiac disease, these findings may lay the ground to further investigate the possible role of AP4A and/or related ligands (e.g. AP2A and AP3A) in heart failure.

Cardiomyopathies↗
PubMed1998

Receptor mechanisms involved in the 5-HT-induced inotropic action in the rat isolated atrium.

1. The effects of 5-hydroxytryptamine (5-HT) in rat cardiac preparations were studied. 5-HT up to 10 microM failed to affect contractility in papillary muscles. However, in electrically driven (1 Hz) left atria 5-HT exerted a positive inotropic effect that started at 1 microM and attained its maximum at 10 microM (312+/-50% of predrug value, n=8). 2. 5-HT 10 microM stimulated the content of inositol-1,4,5-trisphosphate but not of cyclic AMP in rat left atria. 3. Plasma and serum levels of 5-HT amounted to about 0.3 microM and 15 microM, respectively. 4. The selective 5-HT4 receptor antagonists GR 125487 (10 nM and 1 microM) and SB 203186 (1 microM) did not attenuate the positive inotropic effect of 5-HT in rat left atria. In contrast, the 5-HT2 receptor antagonist ketanserin (5 nM, 50 nM, 1 microM) resulted in a concentration-dependent diminution of the positive inotropic effect of 5-HT in rat left atria. 5. Reverse transcriptase polymerase chain reaction with specific primers detected mRNA of the 5-HT2A receptor in rat atria and ventricles, while expression of the 5-HT4 receptor was confined to atria. 6. It is suggested that the positive inotropic effect of 5-HT in electrically driven rat left atria is mediated by ketanserin-sensitive 5-HT2A receptors and not through 5-HT4 receptors.

Animals↗
PubMed1998

Long-term beta adrenoceptor-mediated alteration in contractility and expression of phospholamban and sarcoplasmic reticulum Ca(++)-ATPase in mammalian ventricle.

We studied the influence of prolonged administration of the beta adrenoceptor agonist isoproterenol on contractile parameters and expression of sarcoplasmic reticulum (SR) Ca(++)-ATPase and phospholamban, genes important for Ca++ uptake into the SR. Isoproterenol (Iso), 0.9% NaCl (Ctr), propranolol (Prop) or Iso plus Prop were administered to rats by subcutaneous infusion with osmotic minipumps for 1, 2, 3, 4, 8, 13 and 26 days, respectively. The positive inotropic effect of Iso was impaired in rats pretreated with Iso in vivo. Iso pretreatment shortened time to peak tension (TPT) by 28%, time of relaxation (RT) by 27% and total contraction time (TCT) by 27% compared with the appropriate controls (day 2). The shortening of time-dependent contractile indices started after 1 day of Iso pretreatment, reached a maximum after 2 days and remained reduced for 4 days. Longer treatment by Iso failed to affect time parameters, whereas the positive inotropic effect of Iso added to the isolated muscles persisted. The shortened contractile time parameters were accompanied by diminished mRNA and protein expression of phospholamban (PLB) and SR-Ca(++)-ATPase (SERCA). The mRNA levels for PLB and SERCA were maximally reduced by 31 +/- 1.3% and 41 +/- 1.4% in the Isopretreated group (2 days) respectively. The reduced mRNA levels were accompanied by reduced levels of the corresponding proteins. It is concluded that altered levels of PLB and SERCA probably account for the noted changes in contractile time parameters in the mammalian heart.

Animals↗
PubMed1997

Quantitation of diltiazem in human cardiac tissue using high-performance liquid chromatography.

A new high-performance liquid chromatographic method has been developed for the determination of diltiazem in human cardiac tissue. Tissue samples are homogenized and digested with trypsin solution. Diltiazem and the internal standard are extracted with acetone. The extract is evaporated to dryness and reconstituted in potassium phosphate buffer. Samples are then cleaned up with solid-phase extraction columns. Diltiazem and the internal standard show recoveries of 59% +/- 16 and 52% +/- 13. The linearity range is 0.12-2.25 ng/mg wet weight. The limit of quantitation is 0.12 ng/mg (w/w). The percentage coefficient of variation of intra-assay varies between 3.57 and 11.2, and that of interassay varies between 5.42 and 11.7. As an application of the assay, a diltiazem cardiac tissue level in a patient on oral therapy for supraventricular tachycardia is reported.

Calcium Channel Blockers↗
PubMed1997

Interaction between sotalol and an antacid preparation.

AIMS: The aim of the study was to investigate the pharmacokinetic interaction between sotalol and antacids, and its pharmacodynamic relevance. METHODS: In a randomized cross-over design with three treatment groups, six healthy volunteers received orally either 160 mg of sotalol alone (phase 1), or 160 mg sotalol plus 20 ml of a suspension of an antacid (MAH; magnesium hydroxide (1200 mg) and aluminium oxide (1800 mg)) (phase 2) or 160 mg sotalol plus the antacid given 2 h after sotalol administration (phase 3). Heart rate and plasma sotalol concentrations were measured before and 1, 2, 3, 4, 6, 8, 12 and 24 h after sotalol administration. Urinary sotalol excretion was measured for 24 h after sotalol application. RESULTS: Cmax of sotalol decreased from 1.22 +/- 0.22 mgl-1 (phase 1) to 0.89 +/- 0.29 mgl-1 (phase 2) and increased again to 1.27 +/- 0.18 mgl-1 in phase 3. A similar significant change was noted in AUC (15.6 +/- 2.75 mgl-1, 12.3 +/- 3.04 mg h l-1 and 15.0 +/- 2.06 mgl-1) and in the amount of cumulative urinary excretion (79.2 +/- 11.1 mg, 72.1 +/- 11.2 mg and 80.6 +/- 7.9 mg), respectively. tmax and elimination half-life (t1/2,z) of sotalol remained unchanged in the presence of MAH. After combined administration with MAH, the area under the heart rate curve of sotalol was reduced between 0 and 4 h when compared across treatments. CONCLUSIONS: Combined administration of sotalol and MAH decreased the serum sotalol levels. The interaction can be avoided by a two hour interval between application of these drugs.

Adsorption↗
PubMed1996

Determination of sotalol in human cardiac tissue by high-performance liquid chromatography.

A sensitive and quantitative reversed-phase HPLC method for the analysis of D,L-sotalol in human atria, ventricles, blood and plasma was developed. Sotalol was determined in about 100 mg of human right atria, left ventricles, and in 500 microliters of blood and plasma samples of patients undergoing coronary bypass surgery or heart transplantation. Patients were taking 80-160 mg of sotalol as an antiarrhythmic agent. Atenolol was used as an internal standard certifying high precision of measurement. Sotalol blood and plasma concentrations correlated linearly to the obtained signals from 26.5 ng/ml to 2.12 micrograms/ml. Sotalol tissue concentrations showed linearity between 0.27 ng/mg and 10.6 ng/mg wet weight. The limit of quantitation was 0.27 ng/mg at a signal-to-noise ratio of 10. Sotalol was extracted from homogenized tissue with a buffer solution (pH9) and the remaining pellet was extracted with methanol. The methanol extract was evaporated under nitrogen and reconstituted in buffer (pH3). The whole extract was cleaned by solid-phase column extraction, eluted with methanol, evaporated again, reconstituted in the mobile phase (acetonitrile-15 mM potassium phosphate buffer pH3, 17:83, v/v) and injected onto the HPLC column (Spherisorb C6 column, 5 microns, 150 x 4.6 mm I.D.). For the detection of sotalol, the UV wavelength was set to 230 nm. Recoveries of sotalol and atenolol in atria and ventricles were 65.6 and 75.0%, respectively. Intra- and inter-assay coefficients of variation for tissue concentrations were 3.38 and 6.14%, respectively. Intra- and inter-assay accuracy for determined tissue sotalol concentrations were 94.9 +/- 6.3 and 99.6 +/- 4.1%.

Adrenergic beta-Antagonists↗
PubMed1996

[Morphological and functional features of cytostatic drug resistance and the effects of MDR modulators].

Manifold mechanisms of resistance can be expressed by malignancies. Profound information on this aspect is a prerequisite for comprehensive individual chemotherapy. Based on both morphological and functional findings, the diagnosis of P-Glycoprotein (P-Gp) mediated Multidrug Resistance (MDR) can be verified. In order to describe minimum criteria for conclusive diagnosis, morphological and biochemical findings (Immunocytochemistry, RT-PCR, ultrastructural and Laser-Scan microscopy) and functional data (cytostatic drug transport, proliferation) were correlated in tumor cell lines of the MDR phenotype as opposed to cells with atypical resistance. Frequently, single features of MDR are found in atypical, P-Gp negative resistance. Accumulation deficits for mitoxantrone based on vesicular drug transport were found in P-Gp negative gastric carcinoma cell line EPG85-257RNOV. Nocodazole blocked microtubule formation which is essential for vesicle transfer from perinuclear regions to the periphery of the cytosol. Cytochalasin blocked exocytosis of drug containing vesicles. MDR modulators were ineffective. Alternatively, P-Gp mediated drug extrusion and exocytosis of drug containing vesicles may constitute complementary mechanisms of resistance. In gastric carcinoma cells EPG85-257DAU, MDR modulators do increase cytosolic daunorubicin load, but drug binding to nuclear target sites is still inhibited due to drug containment within vesicles. To complicate matters, MDR modulators may be functional even in MDR negative cells, as shown in a panel of melanoma cell lines. Data show that conclusive diagnosis of P-Gp-mediated MDR should be based on more than one experimental approach including immunocytochemistry, a sensitive assay such as RT-PCR and--whenever feasible--a functional test.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1995

The technique of endobronchial lidocaine administration does not influence plasma concentration profiles and pharmacokinetic parameters in humans.

This study investigated plasma concentration profiles, pharmacokinetic characteristics and side-effects of lidocaine following 3 different administration techniques. Sixty ASA I/II patients undergoing elective ENT-operations were randomised into 4 groups. Lidocaine 1% (1 mg/kg) was administered 50 min before the end of the operation, via a regular endotracheal tube (group 1), a suction-catheter deep endobronchially (group 2), or an EDGAR-(Endobronchial-Drug and Gas Application during Resuscitation)-tube characterized by a separate injection channel ending at the orifice of the tube (group 3). For the control group, a regular endotracheal tube was inserted without lidocaine administration (group 4). Anesthesia was induced with propofol (2 mg/kg), sufentanil (0.5 micrograms/kg), and vecuronium (0.08 mg/kg) and continued as total intravenous anesthesia with propofol (8 mg/kg/h) and oxygen in air (FiO2 = 0.33). A control and 13 blood samples were taken up to 180 min after lidocaine administration. Lidocaine plasma concentrations were determined using a fluorescence polarization immunoassay (TDxFLx). Heart rate, blood pressure, endtidal PcO2, and oxygen saturation were similar in all groups investigated. Ventilation was interrupted for 3.6 +/- 0.5 s in group 1 and 10.2 +/- 0.8 s in group 2, to administer lidocaine. Patients from group 3 were ventilated continuously because of a separate injection channel integrated in the EDGAR-tube. Sore throat was significantly increased in group 2 as compared with groups 1, 3 and 4. Asorption of lidocaine in groups 1-3 resulted in maximal mean plasma concentrations ranging from 0.78 to 0.85 micrograms/ml after 16.9 to 22.4 min.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1993

Effect of transient reduction of cerebral blood flow in normotensive rats on striatal dopamine-release.

Bilateral Clamping of both Carotid Arteries (BCCA) in normotensive rats is known to cause a transient reduction in cerebral blood flow. Using in vivo trans-striatal microdialysis and HPLC/ECD we measured the release of dopamine and DA-metabolites under these oligemic conditions. BCCA caused a substantial stimulation of striatal DA-release (40-fold) and a decrease of the outflow of DA-metabolites. The elevated DA-release returned to baseline levels before the onset of reperfusion. Upon reperfusion, DA-metabolites rose above their initial baseline values. Trans-striatal administration of glutamate-diethylester (GDEE, 10 mM) attenuated the oligemia-induced DA-release. A sudden reduction of blood flow appears to disrupt the compartmentation of dopamine in striatal dopaminergic nerve endings in a similar but more moderate manner as compared to ischemia.

3,4-Dihydroxyphenylacetic Acid↗