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Biomedical subjects

W Lindner

Publications and source records attributed to W Lindner.

At least 55 records · Page 3Linked to original sources
PubMed1999

Capillary electrophoretic study of cisplatin interaction with nucleoside monophosphates, di- and trinucleotides.

cis-Diamminedichloroplatinum(II) (cisplatin) is applied against different kinds of cancer although toxic side effects are known. Screening systems for alternative compounds with higher effectiveness but minimizing toxic side effects are required. We investigated the adduct formation of cisplatin with nucleoside monophosphates, di- and trinucleotides. Capillary electrophoretic separations were performed in a sodium phosphate buffer using an instrument equipped with a diode array detector. Adduct formation results in a significant shift of lambda(max) to lower energy compared to free nucleotides. Therefore, UV spectra are an important tool for peak identification. We could separate and identify all four common nucleotides and their major platinum adducts in a single run demonstrating the suitability of CE for these kinds of investigations. Furthermore, kinetic studies of these reactions are performed.

Cisplatin↗
PubMed1999

Enantioselective anion exchangers based on cinchona alkaloid-derived carbamates: influence of C8/C9 stereochemistry on chiral recognition.

Four diastereomeric chiral stationary phases (CSPs) based on quinine, quinidine, epiquinine, and epiquinidine tert-butyl carbamate selectors were synthesized and evaluated under ion exchange HPLC conditions with a set of racemic N-acylated and N-oxycarbonylated alpha-amino acids as selectands. The enantioseparation potential of quinine- and quinidine-derived CSPs proved to be far superior to that of their C9-epimeric congeners. The absolute configuration of C9 stereogenic center of the cinchonan backbone of these selectors was identified as the structural feature controlling the elution order. Guided by an X-ray structure of a most favorable selector-selectand complex and the observed chromatographic enantioseparation data, a chiral recognition model was advanced. The contributions of ion-pairing, pi-pi donor-acceptor, hydrogen bonding and steric interactions were established as crucial factors.

Antimalarials↗
PubMed1999

Enantiomeric separation of N-protected amino acids by non-aqueous capillary electrophoresis using quinine or tert-butyl carbamoylated quinine as chiral additive.

A capillary electrophoretic (CE) method for the enantioseparation of N-protected chiral amino acids was developed using quinine and tert-butyl carbamoylated quinine as chiral selectors added to nonaqueous electrolyte solutions (NACE). A series of various N-derivatized amino acids were tested as chiral selectands, and in order to optimize the CE enantioseparation of these compounds, different parameters were investigated: the nature of the organic solvent, the combination of different solvents, the nature and the concentration of the background electrolyte, the selector concentration, the capillary temperature, and the applied voltage. The influence of these factors on the separation of the analyte enantiomers and the electroosmotic flow was studied. Generally, with tert-butyl carbamoylated quinine as chiral selector, better enantioseparations were achieved than with unmodified quinine. Optimum experimental conditions were found with a buffer made of 12. 5 mM ammonia, 100 mM octanoic acid, and 10 mM tert-butyl carbamoylated quinine in an ethanol-methanol mixture (60:40 v/v). Under these conditions, DNB-Leu enantiomers could be separated with a selectivity factor (alpha) of 1.572 and a resolution (Rs) of 64.3; a plate number (N) of 127,000 and an asymmetry factor (As) of 0.93 were obtained for the first migrating enantiomer.

Amino Acids↗
PubMed1999

Influence of beta-blockers on melatonin release.

OBJECTIVE: Melatonin is a mediator in the establishment of the circadian rhythm of biological processes. It is produced in the pineal gland mainly during the night by stimulation of adrenergic beta1- and alpha1-receptors. Sleep disturbances are common side-effects of beta-blockers. The influence of specific beta-blockade as well as that of combined alpha-and beta-blockade on melatonin production has not been investigated in humans before. METHODS: We performed a randomized, double-blind, placebo-controlled, cross-over study in 15 healthy volunteers. Subjects received single oral doses of 40 mg (R)-propranolol, 40 mg (S)-propranolol, 50 mg (R)-atenolol, 50 mg (S)-atenolol, 25 mg (R,S)-carvedilol, 120 mg (R,S)-verapamil or placebo at 1800 hours. Urine was collected between 2200 hours and 0600 hours, and 6-sulfatoxy-melatonin (aMT6s), the main metabolite of melatonin which is almost completely eliminated in urine, was determined by radioimmunoassay (RIA). RESULTS: Mean nocturnal excretion of aMT6s in urine after intake of the drugs was as follows (in microg): placebo 26; (R)-propranolol 24 (-7%, NS); (S)-propranolol 5 (-80%, P < 0.001); (R)-atenolol 27 (+7%, NS); (S)-atenolol 4 (-86%, P < 0.01); (R,S)-carvedilol 23 (-10%, NS); (R,S)-verapamil 29 (+14%, NS). These data show that only the specifically beta-blocking (S)-enantiomers of propranolol and atenolol decrease the nocturnal production of melatonin whereas the non-beta-blocking (R)-enantiomers have no effect. Unexpectedly, (R,S)-carvedilol which inhibits both alpha- and beta-adrenoceptors does not decrease melatonin production. CONCLUSION: These findings indicate that beta-blockers decrease melatonin release via specific inhibition of adrenergic beta1-receptors. Since lower nocturnal melatonin levels might be the reason for sleep disturbances, further clinical studies should investigate whether or not oral administration of melatonin might avoid this well-known side-effect of beta-blockers. The reason why (R,S)-carvedilol does not influence melatonin production remains to be determined.

Adrenergic beta-Antagonists↗
PubMed1999

A severely affected infant with absence of cysteinyl leukotrienes in cerebrospinal fluid: further evidence that leukotriene C4-synthesis deficiency is a new neurometabolic disorder.

Leukotrienes are potent oxygenated metabolites derived from the 5-lipoxygenase pathway of arachidonic acid metabolism. They comprise the cysteinyl leukotrienes (LTC4, LTD4, LTE4) and LTB4. The rate limiting step in the formation of cysteinyl leukotrienes is the conversion of LTA4 to LTC4 catalyzed by the enzyme LTC4 synthase. Recently, the first inborn error of leukotriene synthesis, LTC4-synthesis deficiency, has been identified in a patient with a fatal developmental syndrome. We report on an additional infant presenting with severe muscular hypotonia, symmetrical extension in the lower extremities and psychomotor retardation who died at the age of 6 months. Despite intensive investigations no specific diagnosis could be made. Leukotrienes were subsequently analyzed in the cerebrospinal fluid. Concentrations of LTC4, LTD4 and LTE4 were below the detection limit (< 5 pg/ml) whereas LTB4 was found to be in the upper normal range. The absence of cysteinyl leukotrienes with normal LTB4 concentration in cerebrospinal fluid is unique and seems to be pathognomonic for LTC4-synthesis deficiency. Our patient most likely represents the second case described so far with this condition. This report provides further evidence that LTC4-synthesis deficiency represents a new neurometabolic disorder.

Fatal Outcome↗
PubMed1999

Delivery room management of extremely low birth weight infants: spontaneous breathing or intubation?

OBJECTIVE: To study the effect of two different delivery room (DR) policies on the rate of endotracheal intubation and mechanical ventilation (EI/MV) and short term morbidity in extremely low birth weight infants (ELBWI; <1000 g, >/=24 weeks). METHODS: Retrospective cohort study of 123 inborn ELBWIs born in 1994 and in 1996. DR policies have changed. Until 1994, ELBWIs were intubated immediately after delivery when presenting the slightest signs of respiratory distress or asphyxia after initial resuscitation using a face mask and a handbag. During 1995, the guidelines for respiratory support were changed. In 1996, continuous (15 to 20 seconds), pressure controlled (20 to 25 cm H2O) inflation of the lungs using a nasal pharyngeal tube, followed by continuous positive airway pressure (CPAP; 4 to 6 cm H2O) was applied to all ELBWIs immediately after delivery to establish a functional residual capacity and perhaps to avoid EI/MV. In addition to the changes in respiratory support, the prevention of conductive and evaporative heat loss was improved in 1996. For analysis of morbidity and mortality, infants were matched for gestational age and birth weight. RESULTS: The rate of EI/MV in the DR decreased from 84% in 1994 to 40% in 1996. In 1996, 25% of the ELBWIs were never intubated (7% in 1994), but 35% of the ELBWIs needed secondary EI/MV, primarily because of respiratory distress syndrome (RDS). Initial ventilator settings, ventilator days, mortality, and morbidity were not different between ELBWIs with EI/MV in the DR and infants with secondary EI/MV attributable to RDS in the intensive care unit. ELBWIs with no EI/MV that was caused by RDS had a lower morbidity (ie, bronchopulmonary dysplasia, intraventricular hemorrhage >grade 2 and/or periventricular leukomalacia), mortality, and fewer hospital days (mean: 79 vs 105 days). The incidence of gastrointestinal adverse effects like feeding intolerance or necrotizing enterocolitis was not increased in 1996. PaCO2 was significantly higher at admission to the neonatal unit in ELBWIs with CPAP in 1996 (54 +/- 15 mm Hg, 7.2 +/- 2.0 kPa) compared with infants with EI/MV in 1994 (38 +/- 11 mm Hg, 5.1 +/- 1. 5 kPa. A total of 26% of spontaneously breathing infants had hypercapnia (PaCO2 >/=60 mm Hg [8.0 kPa]), compared with 7% of infants with EI/MV in 1994. Within the first few hours of life, PaCO2 decreased to 46 (32 to 57) mm Hg (6.1 [4.3 to 7.6] kPa) in never intubated ELBWIs (n = 17), but increased to 70 (57 to 81) mm Hg (9.3 [7.6 to 10.8] kPa) in ELBWIs (n = 14) with RDS and secondary EI/MV (age 5.5 [1 to 44] hours). CONCLUSIONS: In our setting, the individualized intubation strategy in the DR restricted EI/MV to those ELBWIs who ultimately needed it, without increasing morbidity or mortality in infants with secondary EI/MV attributable to RDS. We speculate that an individualized intubation strategy of the ELBWI is superior to immediate intubation of all ELBWIs with slight signs of respiratory distress after birth.

Cohort Studies↗
PubMed1998

On-column formation of arsenic-glutathione species detected by size-exclusion chromatography in conjunction with arsenic-specific detectors.

The 'retention analysis method', which is based on size-exclusion chromatography (SEC) in conjunction with an arsenic-specific detector (graphite furnace atomic absorption spectrometer, GFAAS), was used to study the effect of pH (range 2.0-10.0), temperature (4, 25 and 37 degrees C), and the concentration of glutathione in the mobile phase (0.5-7.5 mM) on the formation of arsenic-glutathione species after injection of sodium arsenite using phosphate-buffered saline solutions as mobile phases. The formation of arsenic-GSH species was facilitated by low temperatures (4 degrees C), pH 6.0-8.0 and high concentrations of glutathione (7.5 mM) in the mobile phase. Simulating the physicochemical parameters found inside human red blood cells (approximately 3.0 mM glutathione, 37 degrees C, pH 7.4) and hepatocytes (approximately 7.5 mM glutathione, 37 degrees C, pH 7.4), SEC-GFAAS provided evidence for the formation of arsenic-glutathione species under these conditions. In addition, the 'chelating agent', sodium DL-2,3-dimercapto- -propanesulfonate (1.0 and 2.0 mM) was demonstrated to bind arsenous acid stronger in the presence of glutathione (7.5 mM) under these conditions (PBS buffer, pH 7.4, 37 degrees C).

Arsenic↗
PubMed1998

Tension pneumopericardium in a preterm infant without mechanical ventilation: a rare cause of cardiac arrest.

A preterm infant with a gestational age of 32 weeks developed a tension pneumopericardium during the second day of life. The infant was treated with nasal continuous positive airway pressure and was not mechanically ventilated before pneumopericardium occurred. After emergency pericardiocentesis, two recurrences of pneumopericardium without clinical deterioration were diagnosed by X-ray during a 2-d observation period. A continuous pericardial drainage was positioned and was successfully removed on the seventh day of life after weaning from the ventilator. Tension pneumopericardium may occur even in non-ventilated newborns and should be considered as a rare but important differential diagnosis of cardiac arrest.

Disease-Free Survival↗
PubMed1997

Computerized optimization of the high-performance liquid chromatographic enantioseparation of a mixture of 4-dinitrophenyl amino acids on a quinine carbamate-type chiral stationary phase using DRYLAB.

A method is proposed for the sensitive chiral analysis of amino acid enantiomers by high-performance liquid chromatography (HPLC). Thus the enantiomers of a mixture of seven racemic amino acids were resolved as their DNP derivatives from each other and from the peak of the hydrolyzed reagent, employing a quinine carbamate-based chiral anion exchange-type chiral stationary phase (CSP) and aqueous buffered mobile phases. However, the initial isocratic chromatogram yielded many peak overlaps although the corresponding enantiomers were well resolved. Therefore, the separation of the complex mixture had to be optimized; we utilized the commercial computer method development software DRYLAB. First, the influence of the manifold mobile phase parameters and chromatographic conditions (pH, type and content of organic modifier, buffer concentration, temperature, type of co-ion, etc.) on retention and resolution was studied by isocratic elution. Furthermore, with such optimized conditions linear and multi-segmented organic modifier and buffer salt gradients, respectively, were simulated with the computer program and experimentally verified. Average errors of prediction of retention times lay between 2 and 8%. Finally, a highly improved HPLC gradient method resulted in almost all components being baseline separated and equally spaced and accelerated by a factor of more than 3 compared to the initial run.

Amino Acids↗
PubMed1996

Comparison of the Hummel-Dreyer method in high-performance liquid chromatography and capillary electrophoresis conditions for study of the interaction of (RS)-, (R)- and (S)-carvedilol with isolated plasma proteins.

The Hummel-Dreyer method in capillary zone electrophoresis was compared with the corresponding high-performance liquid chromatographic (HPLC) variant in order to study the interaction of racemic carvedilol and its individual enantiomers with isolated human plasma proteins [alpha 1-acid glycoprotein (AGP) and human serum albumin (HSA)]. The binding parameters characterizing the high-affinity binding site of AGP evaluated by using capillary electrophoresis [Ka(RS) = (3.01 +/- 1.15).10(6) l/mol; Ka(S) = (2.13 +/- 0.53).10(6) l/mol; Ka(R) = (4.88 +/- 1.57).10(6) l/mol] were in good accordance with those obtained by HPLC [Ka(RS) = (3.88 +/- 1.74).10(6) l/mol: Ka(S) = (1.80 +/- 0.53) x 10(6) l/mol; Ka(R) = (5.43 +/- 2.53).10(6) l/mol]. Relatively small quantitative differences have been observed considering the attachment of (R)-carvedilol to the secondary low-affinity binding sites on alpha 1-acid glycoprotein by comparing these two methods. In general, the Hummel-Dreyer method applied to capillary zone electrophoresis conditions was verified to be an efficient and fast technique for reliable description of quantitative binding parameters of hydrophobic drugs.

Adrenergic beta-Antagonists↗
PubMed1996

Drug-protein binding sites. New trends in analytical and experimental methodology.

In the last few years, continuous progress in instrumental analytical methodology has been achieved with a substantial increase in the number of new, more specific and more flexible methods for ligand-protein assays. In general, the methods used for drug-protein binding studies can be divided into two main groups: separation methods (enabling the calculation of binding parameters, i.e. the number of binding sites and their respective affinity constants) and non-separation methods (describing predominantly qualitative parameters of the ligand-protein complex). This review will be focussed particularly on recent trends in the development of drug-protein binding methods including stereoselective and non-stereoselective aspects using chromatography, capillary electrophoresis and microdialysis as compared to the "conventional approach" using equilibrium dialysis, ultrafiltration or size exclusion chromatography. The advantages and limitations of various methods will be discussed including a focus on "optimal" experimental strategies taking into account in vitro, ex vivo and/or in vivo studies. Furthermore, the importance of some particular aspects concerning the drug binding to proteins (covalent binding of drugs and metabolites, stereoselective interactions and evaluation of binding data) will be outlined in more detail.

Animals↗
PubMed1996

Organochlorine pesticide analysis in oil seeds and vegetable oil: simplification of silica gel clean-up and elimination of chlorinated solvents.

For the determination of organochlorine pesticides (OCPs) in vegetable oils and oil seed samples, a solid-phase extraction method is described, modified from that developed by Steinwandter, with silica gel columns activated with a 10% water content. In comparison to the method developed by Steinwandter, we reduced the amount of solvents and chemicals required for sample preparation and substituted dichloromethane by the much less toxic tert-butylmethyl ether in the eluent mixture. In this manner the sample preparation technique becomes more convenient, cheaper and ecologically more justifiable. Under the specified sample preparation and elution conditions 1 g silica gel retained about 16 mg triglycerides whereas the OCPs were quantitatively eluted. The recoveries for hexachlorobenze, (HCB) alpha-HCH, Lindane (gamma-HCH) gamma-HCH, Heptachlor, Heptachlorepoxid, o,p'-DDE, p,p'-DDE, Dieldrin, o,p'-DDT, p,p'-DDT were between 75 and 90%. The reproducibility of the total method was excellent as well as its ruggedness.

Chromatography, Gas↗
PubMed1996

Are there stereoselective electrophysiologic effects of intravenously administered (S)- or (R)-propafenone hydrochloride in patients with supraventricular tachycardia?

OBJECTIVE: The electrophysiological effects of intravenously administered pure (S)- and (R)-propafenone hydrochloride has been determined for the first time in humans-12 patients with supraventricular tachycardia. METHODS: Measurements were performed before and during drug therapy. RESULTS: (S)- and (R)-propafenone prolonged the AH interval from 82 to 107 ms and 75 to 84 ms, respectively, and significantly increased the V nodal Wenckebach cycle length by 58 ms and 37 ms, respectively. The AV nodal effective refractory period in both groups was increased significantly to the same extent (45 vs 42 ms). Sinus node recovery times were not significantly influenced by either enantiomers. Both (S)- and (R)-propafenone significantly prolonged the HV interval to the same extent (from 41 to 51 ms, and 42 to 53 ms). Changes in the electrophysiological characteristics of the myocardium were more pronounced in the atria than in the ventricles. Only (S)-propafenone significantly increased the atrial effective refractory period from 204 to 230 ms, and the ventricular effective refractory period from 225 to 241 ms compared to (R)-propafenone (from 221 to 239 ms, and from 219 to 222 ms, respectively). There was a more pronounced electrophysiological effect on AV nodal conduction of (S)- than (R)-propafenone, probably as a result of its beta-blocking activity. CONCLUSION: The electrophysiological effects of (S)-compared to (R)-propafenone were not very pronounced, so it still remains questionable whether one of the enantiomers might be clinically superior to the other, or to the racemic mixture.

Adult↗
PubMed1996

Exercise increases plasma concentrations of (R)- and (S)-propranolol.

OBJECTIVE: We recently reported a highly stereoselective increase in plasma concentrations of (S)-atenolol during exercise which is most likely due to a release of the drug from adrenergic cells. The objective of the present study was to investigate the influence of physical exercise on plasma concentrations of the (R)- and (S)-enantiomers of propranolol. METHODS: Blood samples were taken immediately before and at the end of exercise in 12 patients receiving chronic treatment with racemic (R, S)-propranolol. Plasma concentrations of (R)- and (S)-propranolol were determined by HPLC. RESULTS: In contrast to atenolol, mean plasma concentrations of (S)-propranolol were significantly higher (+20%) than those of (R)-propranolol at rest. During exercise there was an increase in plasma concentrations of both (R)-propranolol (+129%) and (S)-propranolol (+109%). CONCLUSION: Based on information from in vitro studies we conclude that the increase in plasma concentrations of (S)-propranolol during exercise is caused by a release of the drug from adrenergic nerves, whereas the reason for the increase in (R)-propranolol remains to be determined. This release of the beta-adrenoceptor blocking (S)-enantiomer directly at the synaptic gaps might be one reason for the poor correlation between plasma concentration and effect of beta-adrenoceptor antagonists repeatedly described in the literature.

Adrenergic beta-Antagonists↗
PubMed1996

Quantification of rate-dependent effects of verapamil, diltiazem, and digoxin on atrioventricular conduction.

The calcium channel blocking agents, verapamil and diltiazem, and the digitalis compound, digoxin, caused drug specific rate-dependent changes of the atrioventricular conduction time (AVCT). The purpose of this study was to investigate this rate adaptation of the AVCT in isolated guinea pig hearts perfused by the method of Langendorff to get an insight in drug-specific binding kinetic to the respective channel. In the presence of 10 nM verapamil, 30 nM diltiazem, or 0.6 nM digoxin, the atrioventricular conduction time was prolonged to a comparable degree during sinus rhythm. The drug-specific time constant, characterizing the rate-dependent adaptation of the AVCT, in the presence of a substance was comparable if evaluated after abruptly changing the heart rate from the pacing cycle length of 240 ms to 180 ms (tau-on) or from 180 to 240 ms (tau-off). The adaptation of the AVCT in the presence of verapamil (tau-on = 178 +/- 45 beats, tau-off = 125 +/- 33 beats, mean +/- SEM) was more pronounced than in the presence of digoxin (tau-on = 144 +/- 24 beats, tau-off = 98 +/- 15 beats) or diltiazem (tau-on = 70 +/- 11 beats, tau-off = 98 +/- 15 beats). In conclusion, the differences in the rate adaptation of the AVCT may be explained by the drug-specific association and dissociation kinetic to the calcium channel, slow in the case of verapamil, and fast in the case of dilitiazem, whereas this phenomenon in the presence of digoxin may be explained by its direct effects on passive membrane properties.

Adaptation, Physiological↗