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Biomedical subjects

W Lindner

Publications and source records attributed to W Lindner.

At least 19 recordsLinked to original sources
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

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↗
PubMed1995

Stereoselective increase of plasma concentrations of the enantiomers of propranolol and atenolol during exercise.

OBJECTIVE: In vitro studies have shown that, like catecholamines, both propranolol and atenolol are taken up by and released from adrenergic cells. We performed this study to investigate whether this may also play a role in humans and whether stereoselective aspects are important. METHODS: This was a randomized, double-blind, placebo-controlled, crossover study of two groups of 12 healthy volunteers. Subjects received single oral doses of 80 mg (R,S)-, 40 mg (R)-, and 40 mg (S)-propranolol; 100 mg (R,S)-, 50 mg (R)-, and 50 mg (S)-atenolol; and placebo at intervals of 1 week. Exercise was performed at 4 and 9 hours after drug intake, and blood samples were taken before and at the end of each exercise period. The plasma concentrations of the (R)- and (S)-enantiomers of propranolol and atenolol, as well as those of epinephrine and norepinephrine, were determined by HPLC. RESULTS: Effects of exercise on the plasma levels of the enantiomers of propranolol and atenolol were similar. When the optically pure enantiomers were administered, exercise caused a marked and significant increase of the plasma concentrations of the (S)- but not of the (R)-enantiomers. When the drugs were administered in the racemic form, the plasma levels of both the (R)- and (S)-enantiomers were elevated to the same extent. The increase of norepinephrine levels during exercise was more pronounced than that of epinephrine and paralleled that of the (S)-enantiomers of the beta-blockers. CONCLUSION: Bearing the in vitro data in mind, we conclude that (S)-propranolol and (S)-atenolol are taken up into and released from adrenergic cells together with norepinephrine during exercise. The reason why the plasma concentrations of (R)-propranolol and (R)-atenolol are increased only during exercise in the presence of the corresponding (S)-enantiomers remains to be determined.

Administration, Oral↗
PubMed1995

Stereoselective vascular effects of the (R)- and (S)-enantiomers of propranolol and atenolol.

All beta-adrenergic antagonists have an asymmetric carbon atom, and most commercially available beta-blockers consist of (R)- and (S)-enantiomers in a fixed 1:1-ratio. The drugs are believed to be contraindicated when peripheral vascular disease exists, presumably due to unopposed alpha-adrenergic vasoconstriction. However, little is known about direct vascular effects of beta-blockers or of stereoselective effects on peripheral arteries. Therefore, we investigated the effects on forearm blood flow (FBF) of brachial artery infusions of the (R)- and (S)- enantiomers of propranolol and atenolol (2, 10, and 50 micrograms/min each) and their inhibitory effects on isoprenaline (Iso)-induced vasodilatation by forearm venous occlusion plethysmography in 12 healthy subjects. Only (R)-propranolol caused an increase in FBF (+21%, p < 0.05), whereas (S)-propranolol and (R)- and (S)-atenolol had no direct effect on peripheral arteries. Vasodilatation induced by Iso was abolished by (S)-propranolol and reduced by (R)-propranolol (-56%, p < 0.05) and (S)-atenolol (-68%, p < 0.05), whereas (R)-atenolol had no effect. Our results indicate that the optically pure (R)- and (S)-enantiomers of propranolol and atenolol do not exert direct vasoconstrictive effects. Furthermore, our results confirm that predominantly (S)-enantiomers have beta-adrenoceptor blocking effects, but they also show that neither the non-beta-blocking (R)-enantiomer of propranolol nor the (S)-enantiomer of the beta 1-selective agent atenolol is completely devoid of blocking effects on vascular beta 2-adrenoceptors.

Adult↗
PubMed1994

Stereoselective high-performance liquid chromatographic assay of (+/-)-delmopinol in plasma using solid-phase extraction, a chiral derivatizing agent and electrochemical detection.

An enantioselective HPLC bioanalytical method for (+/-)-delmopinol was established in order to elucidate the pharmacokinetic behaviour of this chiral drug. (+/-)-Delmopinol and (+/-)-M1652, a structurally related compound used as internal standard, were extracted from plasma by a solid-phase extraction procedure using CN cartridges. The enantiomers were derivatized with a chiral derivatizing agent (R,R)-O,O'-di-p-toluoyl tartaric acid anhydride yielding diastereomeric derivatives which were separated on a reversed-phase column with acetonitrile-0.1 M ammonium acetate buffer (65:35, v/v) pH 5.7 as mobile phase. The resolution values of the diastereomeric derivatives of (-)- and (+)-M1652 and of the derivatives of (-)- and (+)-delmopinol were 1.03 and 1.46, respectively. The limit of quantitation was approximately 3 pmol (1 ng)/enantiomer per 0.5 ml plasma using electrochemical detection (+0.75 V versus Pd/PdO reference electrode). The effectiveness of the derivatization was > 98% and the total recovery of (+/-)-delmopinol and of (+/-)-M1652 from plasma or serum was found to be approximately 50%. The assay was applied to enantioselective pharmacokinetic investigations in humans, rats and dogs but showing here only one concentration time curve of the (+)- and (-)-delmopinol in a human subject after administering (+/-)-delmopinol in form of an aqueous mouth wash solution for 60 s.

Anhydrides↗
PubMed1994

Direct enantioselective determination of (R)- and (S)-propranolol in human plasma. Application to pharmacokinetic studies.

In order to examine possible drug interactions of (R)- and (S)-propranolol a randomized, double blind, crossover study has been performed, administering orally single doses of 40 mg (R,S)- and of 20 mg (S)-propranolol. HCl three times daily over a week to reach steady state conditions. After the first single dose of 40 mg (R,S)-propranolol. HCl, the AUC0-infinity and Cmax values of the (S)-isomer were greater than those of the (R)-isomer: the ratio of AUC(S) over AUC(R) was 1.77 (P < 0.05) and that of Cmax 1.57 (P < 0.01). When (S)-propranolol.HCl was given as a single 20 mg dose, the AUC(S) value was a factor of 0.55 lower than that administration of 40 mg (R,S)-propranolol.HCl. At steady state, the AUC of (S)-propranolol was 1.52 times higher (P < 0.01) than that of the (R)-isomer after administration of 40 mg racemate, and comparing the (S)-isomer, the ratio was 1.21. Following administration of the first single dose of 40 mg of the racemate, the mean (SD) clearance of the (R)- and (S)-isomers was 110 (84) and 61 (37) ml min-1 kg-1, respectively; at steady state these values were 89 (55) and 57 (37) ml min-1 kg-1, respectively. Respective values for (S)-propranolol after single isomer administration (20 mg) were 86 (36) and 57 (25) ml min-1 kg-1 in single dose and steady state situations. The data are based on the quantitative analysis of (R)- and (S)-propranolol in plasma.(ABSTRACT TRUNCATED AT 250 WORDS)

Chromatography, High Pressure Liquid↗
PubMed1993

Stereoselective features of (R)- and (S)-atenolol: clinical pharmacological, pharmacokinetic, and radioligand binding studies.

In a randomized, double-blind, cross-over study in 12 healthy volunteers, the effects of single oral doses of 100 mg rac-atenolol were compared during exercise to those of equal amounts of the optically pure enantiomers, i.e., 50 mg (R)- and 50 mg (S)-atenolol. The mean rate pressure product decreased with rac-atenolol (-37%; P < 0.01) and half-dosed (S)-atenolol (-35%; P < 0.01) to the same extent, whereas (R)-atenolol caused no effect. Radioligand binding studies in beta-adrenergic receptors of the guinea pig heart yielded a eudismic ratio of 46 for (S)- to (R)-atenolol. The mean AUCs, maximal plasma concentrations, and plasma half-lives of the enantiomers were similar regardless of whether they were administered as optically pure enantiomers or as racemic mixture. On the other hand, the AUC of (R)-atenolol was 1.08-fold greater (P < 0.01) than that of the (S)-enantiomer. The reason for this finding remains unclear. We conclude that only (S)-atenolol, but not (R)-atenolol, contributes to the beta-blocking effect of currently used rac-atenolol since the same effect can be elicited with the (S)-enantiomer alone.

Adult↗
PubMed1993

Stereoselective HPLC bioanalysis of atenolol enantiomers in plasma: application to a comparative human pharmacokinetic study.

An enantioselective HPLC bioassay has been developed relying on extraction of (R)- and (S)-atenolol from alkalinized plasma or serum (pH > 12) into dichloromethane containing 5% (v/v) 1-butanol followed by an achiral derivatization of the drug with phosgene leading to (R)- and (S)-oxazolidine-2-one derivatives. Under these conditions there was quantitative conversion of the acetamido group to the corresponding nitrile. These stable derivatives were separated on a (R,R)-diaminocyclohexane-dinitrobenzoyl chiral stationary phase [(R,R)-DACH-DNB] using dichloromethane/methanol 98/2 as mobile phase. Determination limits of 0.5 ng for (R)- and 0.6 ng for (S)-atenolol could be achieved using fluorimetric detection. The assay was applied to a human pharmacokinetic study which was performed in a randomized cross-over, double-blind fashion in 12 healthy volunteers, administering single oral doses of 100 mg (R,S)-, 50 mg (R)-, and 50 mg (S)-atenolol. AUC0-24 and Cmax values of (R)-atenolol were slightly but significant higher than those of (S)-atenolol. The R/S ratios were 1.09 for AUC(R)/AUC(S) and 1.03 for Cmax (R)/Cmax(S) (P < 0.01) respectively after administration of the racemic drug. However, there were no difference between AUC, Cmax, and t1/2 values of each enantiomer, whether they were administered as single enantiomers or in the form of its racemic mixture.

Administration, Oral↗
PubMed1993

Enhancing in vivo effect of propranolol on human lymphocyte function is not due to stereospecific beta-adrenergic blockade.

Immunoenhancing in vivo effects of beta-adrenergic blockers have been previously ascribed to a reduced beta-receptor-mediated immunosuppression. In the present study using a whole blood stimulation assay, the effects of a five-day treatment with the purified (R)- or (S)-isomer of propranolol (3 x 40 mg/day) on the polyclonal in vitro responsiveness of peripheral blood lymphocytes (PBL) of normothyroid and hyperthyroid persons were assessed. It is shown that both isomers likewise exhibit a significant enhancing effect on the proliferative response of PBL to T and B cell mitogens, which strongly argues for nonspecific effects of propranolol to be responsible rather than a specific beta-adrenergic receptor blockade.

Adult↗
PubMed1992

Stereoselective release of (S)-atenolol from adrenergic nerve endings at exercise.

In-vitro studies have shown that atenolol, a beta-blocking agent, is stereoselectively taken up by and released from adrenergic nerve endings by membrane depolarisation. To investigate the potential importance of these findings, blood samples were taken at rest and after exercise testing from 10 patients (mean [SE] age 60 [3] years) receiving long-term treatment with racemic atenolol. At rest, mean plasma concentration of (R)-atenolol was higher than that of (S)-atenolol (ratio 1.14, p less than 0.01), but after exercise there was a stereoselective increase in (S)-atenolol concentration, which changed the ratio to 0.66 (p less than 0.01). Since (S)-atenolol but not (R)-atenolol causes clinically relevant beta-blockade, our findings may have importance for the management of patients receiving beta-blocking drugs.

Adrenergic Fibers↗
PubMed1992

Racemic (R,S)-propranolol versus half-dosed optically pure (S)-propranolol in humans at steady state: Hemodynamic effects, plasma concentrations, and influence on thyroid hormone levels.

In a randomized, double-blind, crossover study in 10 healthy volunteers the hemodynamic effects, drug plasma concentrations, and thyroid hormone profiles were compared after oral administration for 1 week of 40 mg t.i.d. racemic (R,S)-propranolol versus 20 mg t.i.d. optically pure (S)-propranolol. During exercise, both substances decreased heart rate (-14%, p less than 0.01), as well as the overall rate pressure product (-19%, p less than 0.01) to the same extent, indicating similar beta-blocking effects. After oral application of (R,S)-propranolol the maximal plasma concentration (Cmax) and the area under the plasma concentration-time curve (AUC) of (S)-propranolol were higher than those of (R)-propranolol (eudismic ratios (S)- over (R)-propranolol Cmax, 1.36 [p less than 0.01] and AUC, 1.42 [p less than 0.01]) despite dose-equivalence of both enantiomers in the administered racemic (R,S)-propranolol preparation indicating different pharmacokinetic properties. Mean values of Cmax and the AUC of (S)-propranolol did not differ significantly after 1 week of oral administration of 40 mg (R,S)-propranolol and 20 mg (S)-propranolol t.i.d., respectively. The ratio of triiodothyronine to thyroxine was decreased by (R,S)-propranolol (-25%, p less than 0.01) but not by (S)-propranolol, suggesting that only the (R)-enantiomer inhibits the conversion of thyroxine to triiodothyronine. Thus, half-dosed optically pure (S)-propranolol is an equally effective beta-adrenergic receptor antagonist compared with currently used racemic (R,S)-propranolol. By contrast, the conversion of thyroxine to triiodothyronine is inhibited by (R)-propranolol only.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1992

Stereoselective interactions of (R)- and (S)-propafenone with the cardiac sodium channel.

The specific interactions of both (R)- and (S)-propafenone with the cardiac sodium channel were studied with patch clamp techniques in the whole-cell recording mode at reduced extracellular Na+ on guinea pig ventricular cells. Both (R)- and (S)-propafenone (10 microM) shifted the membrane potential required for half-maximal steady-state inactivation (E0.5) of the cardiac sodium channel to considerably more negative membrane potentials [E0.5 = -70.8 +/- 2.9 mV for controls vs. -85 +/- 3.1 mV for (R)-propafenone and -91.9 +/- 1.7 mV for (S)-propafenone]. (S)-Propafenone at a concentration of 10 microM is more effective in shifting the h infinity curve of the cardiac sodium channel. Recovery from inactivation of the cardiac sodium current is prolonged by orders of magnitude by both stereoenantiomeric forms [time constants were estimated to be 38 +/- 15 ms at -90 mV vs. 46.5 +/- 14.3 s for (R)-propafenone and 74.2 +/- 37.9 for (S)-propafenone]. Development of block occurs mainly through the inactivated channel conformation for both (R)- and (S)-propafenone. Development of block of inactivated cardiac sodium channels occurs with time constants of 15.9 +/- 3.9 s for (R)-propafenone and 19.7 +/- 7.3 s for (S)-propafenone at 10 microM. Action potential duration and possible stereoselective interaction with ion transport systems other than sodium channels may influence the block developed by either (R)- or (S)-propafenone at a given concentration and beating frequency indirectly through the membrane potential.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Interaction of propafenone enantiomers with human alpha 1-acid glycoprotein.

The interaction of propafenone enantiomers with human alpha 1-acid glycoprotein was studied using high-performance liquid chromatography. Each of the two optical antipodes interacted with one class of high-affinity binding sites characterized by Ka(R) = (6.18 +/- 0.93) x 10(5) M-1, n(R) = 1.34 +/- 0.09 for the (R)-isomer and Ka(S) = (8.93 +/- 1.82) x 10(5) M-1, n(S) = 0.99 +/- 0.08 for the (S)-isomer. Nonspecific binding to secondary low-affinity high-capacity binding site(s) was only slightly greater in the case of the (S)-enantiomer (n'k'(S) = (1.06 +/- 0.09) x 10(4) M-1) compared to the (R)-enantiomer (n'k'(R) = (6.87 +/- 0.72) x 10(3) M-1). It was concluded that both enantiomers interact with common single class of high-affinity binding sites on AAG (along with nonspecific binding) exhibiting only slight stereoselectivity for propafenone.

Chromatography, High Pressure Liquid↗