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Biomedical subjects

W Lindner

Publications and source records attributed to W Lindner.

At least 91 records · Page 5Linked to original sources
PubMed1990

The effect of D- versus L-propranolol in the treatment of hyperthyroidism.

The purpose of this study is to determine whether there is a difference in treatment of hyperthyroidism using either the D- or L-isomer of propranolol. Two groups of 20 patients with overt hyperthyroidism received either 120 mg L- or D-propranolol each for a period of 5 days. In the D-propranolol administered group there was a significant decrease in TT3 and fT3 plasma levels and in the ratio of TT3 to TT4; however, a significant increase occurred in rT3 values up to day 5. On the other hand, L-propranolol treatment resulted in a less pronounced decrease in TT4 and TT3 values, while all other thyroid hormone levels remained unchanged as, above all, did the T3/T4 ratio. The well known effect of D,L-propranolol upon peripheral conversion of T4 to T3 is thus not due to the beta-blocking action of L-propranolol but is mainly conditioned by the D-isomer which has no beta-blocking action itself.

Adult↗
PubMed1990

Stroke volume and left ventricular output in preterm infants with patent ductus arteriosus.

To assess the effect of patent ductus arteriosus (PDA) on left ventricular output (LVO) we studied stroke volume (SV), LVO, and heart rate (HR) in 21 very low birth wt preterm neonates with clinically symptomatic PDA before and after surgical ligation. Six additional infants were also studied before PDA with left-to-right shunt was detectable by the pulsed Doppler technique. Gestational age (median and range) was 28 (24-32) wk. SV was measured by duplex Doppler and M-mode echocardiography, and LVO was calculated as product of SV and HR. LVO was 419 (305-562) mL/min/kg during symptomatic PDA. It decreased to 246 (191-292) mL/min/kg after ligation (n = 21, p less than 0.001). SV was 2.69 (1.98-4.10) mL/kg during symptomatic PDA decreasing to 1.63 (1.22-1.98) mL/kg after ductal closure (n = 21, p less than 0.001). HR did not change after ductal closure. In the six infants with three examinations, LVO and SV were normal before detectable ductal left-to-right shunt and after ligation, but LVO was increased by 59.5 +/- 23% (mean +/- SD) (p less than 0.05), and SV by 60 +/- 32% (p less than 0.05) during symptomatic PDA. In conclusion, preterm neonates with RDS, requiring mechanical ventilation, increased LVO during symptomatic PDA by increasing their SV, and not by changing their HR.

Cardiac Output↗
PubMed1989

Enantioselective drug monitoring of (R)- and (S)- propranolol in human plasma via derivatization with optically active (R,R)-O,O-diacetyl tartaric acid anhydride.

A sensitive high-performance liquid chromatographic method was developed for the stereoselective assay of (R)- and (S)-propranolol in human plasma. The method involves diethyl ether extraction of the drugs and a racemic internal standard, N-tert.-butylpropranolol, followed by derivatization of the compounds with the chiral reagent (R,R)-O,O-diacetyl tartaric acid anhydride. The resulting diastereomeric derivatives were separated isocratically on a reversed-phase column. Quantitation was achieved by the peak-height ratio method with reference to the internal standard. The assay was accurate and reproducible in the concentration range 1-100 ng of (R)- and (S)-propranolol per ml plasma, using fluorescence detection at lambda ex 290 nm and lambda em 335 nm. The applicability of this method was demonstrated for the determination of concentration-time profiles of propranolol enantiomers in the course of comparative pharmacokinetic studies.

Administration, Oral↗
PubMed1989

Quantification of midodrine and its active metabolite in plasma using a high performance liquid chromatography column switching technique.

An automated column-switching HPLC system is described for the simultaneous determination of midodrine, an alpha-adrenergic stimulating drug, and its active metabolite, ST-1059. Serum or plasma (850 microliters) is directly injected onto a RP18 (30 micrograms particle size) pre-column (9 x 4 mm ID) which acts as an on-line liquid-solid extractor and analyte enrichment system. The injection is followed by washing steps. The fraction containing the analytes is transferred onto an analytical RP18 column via step gradient elution where the final analysis is performed. Fluorescence detection is used (lambda ex 290 nm and lambda em 322 nm), and method detection limits of 0.8 ng/mL plasma were reached. These were sufficiently low to determine the plasma concentration-time profiles for both compounds following oral administration of 2.5 mg and 5 mg midodrine hydrochloride. The assay in serum or plasma was linear in the range of 1 to 15 ng analyte/mL, the recovery was greater than 95%, and the reproducibility was sufficient. The assay was rugged and was maintained by routinely changing the home-made, dry packed pre-column every 20th serum injection.

Chemical Phenomena↗
PubMed1989

Pharmacokinetic data of propranolol enantiomers in a comparative human study with (S)- and (R,S)-propranolol.

The pharmacokinetics of (S)-propranolol were compared after the oral administration of a 40 mg dose of the pure enantiomer and an 80 mg dose of a racemic mixture of (R,S)-propranolol. The results of this study indicate that the bioavailability of (S)-propranolol, as expressed by the mean area under the concentration-time curve (AUC) and maximum serum concentration, is lower after 40 mg of the optically pure drug than after the racemic drug.

Adult↗
PubMed1989

Stereoselective hemodynamic effects of (R)-and (S)-propranolol in man.

In a randomized, double-blind, placebo-controlled, cross-over study 24 healthy volunteers were examined before and 2 h after oral administration of 80 mg (R,S)-, 40 mg (R)- and 40 mg (S)-propranolol.HCl; 8 of them received placebo in an additional run. During exercise on a bicycle ergometer and a rest period the rate pressure product was decreased by 80 mg (R,S)-propranolol.HCl (-32.8% p less than 0.0001) and 40 mg (S)-propranolol.HCl (-32.3%; p less than 0.0001), whereas 40 mg (R)-propranolol.HCl as well as placebo showed no effect. Corresponding binding inhibition experiments using (-)-(125I)iodocyanopindolol in a sarcolemma-enriched cardiac membrane preparation yielded a eudismic ratio of 179 for (S)- over (R)-propranolol. 2 h after oral application, stereospecific HPLC analysis revealed different individual concentrations in plasma of (R)- 22.3 +/- 21.7 ng/ml) and (S)-propranolol (30.4 +/- 26.9 ng/ml) when 80 mg of (R,S)-propranolol.HCl was administered. The plasma levels were similar when 40 mg of the pure enantiomer of (R)- (22.7 +/- 20.3 ng/ml) or (S)-propranolol.HCl (28.7 +/- 22.5 ng/ml) was applied. (R)- and (S)-propranolol are two substances with different pharmacodynamic and pharmacokinetic properties. As there are methods available to produce the optically pure enantiomers, they should be used rather than the racemic mixture.

Adult↗
PubMed1989

Synthetic peptide antisera: their production and use in the cloning of matrix proteins.

Small amounts (0.1-1.0 nmole) of purified (greater than 90%) proteins isolated from small quantities of connective tissues can readily be microsequenced and 20 to 40 N-terminal amino acids determined. A synthetic peptide (10 or more amino acids long) can be produced and either injected directly into rabbits for antiserum production (generally peptides greater than 20 amino acids in length) or conjugated to a carrier protein prior to injection. The antisera have proven useful in the isolation of cDNA clones, for both locating clones producing the protein in expression libraries and in the subsequent confirmation of the sequence (preferably using a part of the sequence not directly used in the production of the original antiserum).

Animals↗
PubMed1988

Ophthalmic artery blood flow velocity in healthy term and preterm neonates.

Ophthalmic artery blood flow velocity (OA-BFV, cm/s), cerebral blood flow velocity (C-BFV, cm/s), and cardiac output (ml/min) were measured by pulsed Doppler sonography in 15 healthy term and 10 well preterm (26-35 wk) infants in the first week of life. OA-BFV did not increase with increasing gestational age (preterm: peak systolic BFV 29 +/- 5 cm/s, mean BFV 7.2 +/- 1.5 cm/s; term: peak systolic BFV 27 +/- 5 cm/s, mean BFV 6.6 +/- 1.3 cm/s), unlike C-BFV (preterm: peak systolic BFV 34 +/- 8 cm/s, mean BFV 9.4 +/- 2.3 cm/s; term: peak systolic BFV 43 +/- 9 cm/s, p less than 0.05; mean BFV 11 +/- 3.0 cm/s, p less than 0.05) and cardiac output (preterm 329 +/- 128 ml/min, term 732 +/- 112 ml/min; p less than 0.001). The ratio of OA-BFV/C-BFV was significantly higher in preterm than in term infants (p less than 0.01). In preterm infants, but not in term infants, there was a positive linear correlation of OA-BFV to C-BFV (r = 0.88). We conclude that it is possible to measure opthalmic artery blood flow velocity in neonates by pulsed Doppler sonography. Gestational age has different effects on OA-BFV and on C-BFV. Although it is a point of discussion if blood flow velocities are reflecting absolute blood flow, Doppler assessment of OA-BFV could be a tool for monitoring risk factors for retinopathy of prematurity.

Blood Flow Velocity↗
PubMed1987

Purification, properties, and genetic location of Escherichia coli cytidine 5'-monophosphate N-acetylneuraminic acid synthetase.

N-Acetylneuraminic acid cytidylyltransferase (EC 2.7.7.43) (CMP-NeuAc synthetase) catalyzes the formation of cytidine monophosphate N-acetylneuraminic acid. We have purified CMP-NeuAc synthetase from an Escherichia coli O18:K1 cytoplasmic fraction to apparent homogeneity by ion exchange chromatography and affinity chromatography on CDP-ethanolamine linked to agarose. The enzyme has a specific activity of 2.1 mumol/mg/min and migrates as a single protein and activity band on nondenaturing polyacrylamide gel electrophoresis. The enzyme has a requirement for Mg2+ or Mn2+ and exhibits optimal activity between pH 9.0 and 10. The apparent Michaelis constants for the CTP and NeuAc are 0.31 and 4 mM, respectively. The CTP analogues 5-mercuri-CTP and CTP-2',3'-dialdehyde are inhibitors. The purified CMP-N-acetylneuraminic acid synthetase has a molecular weight of approximately 50,000 on sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The gene encoding CMP-N-acetylneuraminic acid synthetase is located on a 3.3-kilobase HindIII fragment. The purified enzyme appears to be identical to the 50,000 Mr polypeptide encoded by this gene based on insertion mutations that result in the loss of detectable enzymatic activity. The amino-terminal sequence of the purified protein was used to locate the start codon for the CMP-NeuAc synthetase gene. Both the enzyme and the 50,000 Mr polypeptide have the same NH2-terminal amino acid sequence. Antibodies prepared to a peptide derived from the NH2-terminal amino acid sequence bind to purified CMP-NeuAc synthetase.

Amino Acid Sequence↗
PubMed1987

Structural characterization of pertussis toxin A subunit.

The relationship between the structure of the A subunit of pertussis toxin and its function was analyzed. Limited tryptic digestion of the A subunit converted the protein to two stable fragments (Mr = 20,000 and 18,000). Antibodies raised to synthetic peptides homologous to regions in the A subunit were used to map these fragments. Both fragments were shown to contain the NH2-terminal portion but not the COOH-terminal portion of the A subunit. While these fragments exhibited NAD glycohydrolase activity, they were unable to reassociate with the B oligomer of the toxin. Thus the COOH-terminal portion of the A subunit does not contain the residues which are required for the NAD glycohydrolase activity of the toxin. However, this region of the molecule may be important for maintaining the oligomeric structure of the toxin. These results suggest that the A subunit of pertussis toxin is similar in structure to the A subunit of cholera toxin. In addition, antibodies raised to a synthetic peptide identical to residues 6-17 of the A subunit of pertussis toxin will bind to the A subunit of cholera toxin.

Animals↗
PubMed1987

Automated synthesis and use of N-chloroacetyl-modified peptides for the preparation of synthetic peptide polymers and peptide-protein immunogens.

A method to incorporate N-chloroacetyl moieties at the amino termini of synthetic peptides using a standard program with an automated peptide synthesizer has been developed. The N-chloroacetyl-modified peptides react well with sulfhydryl containing proteins such as 4-mercaptobutyrimide-modified bovine serum albumin to form stable protein-peptide conjugates. By incorporating cysteine into the synthetic peptide, autopolymerization or cyclization of the synthetic peptide occurs by reaction of the free sulfhydryl with the chloroacetyl group. N-Chloroacetyl-derivatized peptides may be useful as reagents for potential peptide immunogens and vaccines.

Acetylation↗
PubMed1987

Stereochemistry of aromatic phenytoin hydroxylation in various drug hydroxylation phenotypes in humans.

Phenytoin pharmacokinetics exhibit large intersubject differences and coinheritance of phenytoin metabolism with known drug hydroxylation polymorphisms was therefore suspected. To study the inherited enzymatic mechanisms underlying phenytoin disposition in humans, we have investigated the rate and the stereochemical course of aromatic phenytoin hydroxylation in subjects with and without genetic drug hydroxylation deficiencies for mephenytoin or debrisoquine. For the separate analysis of S- and R-enantiomers of 5-(4-hydroxyphenyl)-5-phenylhydantoin (HPPH; the major phenytoin metabolite), a chiral ligand exchange chromatography system was used. The S-enantiomer of HPPH was the major urinary phenytoin metabolite irrespective of the various drug hydroxylation phenotypes studied. By contrast, the formation of the HPPH R-enantiomer was significantly decreased in poor metabolizer phenotypes of mephenytoin leading to a bimodal distribution of the urinary HPPH S/R-ratio in humans which was correlated closely with the mephenytoin hydroxylation index. Thus, HPPH S/R-values greater than 40 are likely to occur in S-mephenytoin hydroxylation-deficient phenotypes. Analysis of HPPH S/R-ratios in urine samples in a population of 122 randomly selected epileptic patients under chronic phenytoin treatment showed that product-stereoselective aromatic phenytoin hydroxylation is preserved after chronic drug administration. In subjects with and without genetic S-mephenytoin hydroxylation deficiency, extensive HPPH formation was confirmed by a pronounced NIH-shift of the tritium isotope during the product-stereoselective hydroxylation of the pro-S phenyl ring of phenytoin. Substrate-stereoselective glucuronidation of R- and S-HPPH (and related enantiomeric hydantoin metabolites) could be excluded based on identical urinary excretion of p.o. administered pure metabolite enantiomers.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1985

Heart rate and systolic time intervals in healthy newborn infants: longitudinal study.

To determine the influence of heart rate (HR) on systolic time intervals (STI) in neonates, serial measurements of right ventricular (RVSTI) and left ventricular systolic time intervals (LVSTI) were made on 30 healthy term newborn infants at age 4-8 h, 24-30 h, eight days, and four weeks. STI was related to HR and age. Age-related changes were similar to previously reported results. The preejection periods (RPEP and LPEP) significantly shortened with increasing age, whereas the right and left ventricular ejection times (RVET and LVET) were unrelated to age. RPEP was unrelated to HR, but tended to be prolonged in restless infants. With increasing HR, RVET decreased and RPEP/RVET increased in all age groups, but less at four weeks. A rise in HR of 50/min resulted in an increase of RPEP/RVET by 26% of the mean value at age 4-8 h and by 20% at four weeks. In 14 infants, RVSTI was recorded during a change in HR. In all these infants, RPEP and RPEP/RVET increased with increasing HR. We conclude that HR-related changes of RVSTI in neonates are different from those in older subjects. It should be considered that in neonates elevated values of RPEP/RVET, suggesting increased pulmonary vascular resistance, may be caused by high HR and unrest.

Age Factors↗
PubMed1984

Detection of 4-hydroxynonenal as a product of lipid peroxidation in native Ehrlich ascites tumor cells.

4-Hydroxynonenal, which is a major product of lipid peroxidation in rat liver microsomes, was detected in native Ehrlich ascites tumor cells. Its formation was stimulated either by ferrous ions or by Fe(II)-histidinate. The identification was based on chromatographic (TLC/HPLC) and ultraviolet-spectroscopic evidence using synthetic 4-hydroxynonenal as reference. Highest values of 4-hydroxynonenal concentration (about 0.1 microM in the cell suspension) after 30 min of incubation were observed with Fe(II)-histidinate as stimulant. Saturation was already reached after an incubation period of 10 min. The results confirm the expectation by Schauenstein and Esterbauer (in Submolecular Biology and Cancer, Ciba Foundation Series 67 (1979) pp. 225-244, Excerpta Medica, Amsterdam) that endogenous lipid peroxidation gives rise to a distinct intracellular level of alpha, beta-unsaturated aldehydes. A simple hypothetical mechanism for the formation of 4-hydroxynonenal from n-6-polyunsaturated fatty acids is presented.

Aldehydes↗
PubMed1984

Tartaric acid derivatives as chiral sources for enantioseparation in liquid chromatography.

Based on a systematic review of the usage of tartaric acid as a chiral source to resolve enantiomeric compounds, a concept is presented for synthesizing new chiral stationary phases utilizing tartaric acid derivatives as the chiral selector. The results indicate that the conformational change of one of the three optically active centres of the chiral selector strongly affects its enantioselectivity for certain types of compound.

Journal Article↗
PubMed1984

Trace analysis of 2,4,5,TP and other acidic herbicides in wheat using multicolumn-HPLC.

In continuation of our work dealing with multicolumn HPLC (MC-HPLC) techniques and their applicabilities for tracing a few compounds out of complex multicomponent matrices a residue analysis of the herbicides 2,4,5T and MCPA (phenoxyacids) in wheat is described. A simple plant extract with aqueous basic buffer is loaded in quantities of several 100 microliters onto a strong anion exchanger (column 1,C1) performing extraction of the acidic compounds, while the neutral and cationic substances are eluted thus attaining on-column trace enrichment. Via mobile phase selection (pH change) elution from C1 is possible, the fraction (zone-cut) containing the compounds of interest is transferred onto C2 (reversed phase, RP2 and RP18) on which peak compression is performed followed by (step)gradient elution. Detection limits in the lower ppb range are routinely obtained. A MC-HPLC chromatographic setup separation of eleven acidic herbicides in a formulation is also shown.

2,4,5-Trichlorophenoxyacetic Acid↗