Transfusion-requiring haemolytic anaemia after mitral-valve repair.
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Aged↗
Biomedical subjects
K Stoschitzky
Publications and source records attributed to K Stoschitzky.
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↗
[Current aspects of ACE inhibitor therapy from the cardiologic viewpoint].
From a cardiologist's view there are several established indications for the use of ACE-inhibitors like hypertension, heart failure and acute myocardial infarction. In other forms of coronary artery disease like stable and unstable angina and prevention of arteriosclerotic complications. ACE-inhibitors are under discussion. As antihypertensives ACE-inhibitors are about equally effective as calcium blockers, betablockers and diuretics without the negative effects on lipid metabolism and insulin sensitivity. Vascular and cardial remodelling are prevented with ACE-inhibitors at least to a certain degree. In heart failure ACE-inhibitors reduce morbidity and mortality, if left ventricular ejection fraction is reduced. In acute myocardial infarction ACE-inhibitors are indicated in overt heart failure, depressed left ventricular function and high-risk-patients. In silent ischaemia and secondary prevention ACE-inhibitors are under discussion.
Angiotensin-Converting Enzyme Inhibitors↗
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↗
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↗
[Hypertension and hemorheology].
A number of epidemiologic studies have provided evidence for an increased blood viscosity in hypertensive patients. Increased viscosity could result either from hemoconcentration, thus constituting a secondary phenomenon, or, alternatively, result directly from increased intracellular calcium concentrations in erythrocytes. The latter would augment the aggregating potential of these cellular blood compounds. This currently hypothetic view remains to be elucidated. Enhanced viscosity, however, may result in increased peripheral resistance and lead to hypertensive complications. The evaluation of antihypertensive therapy should therefore take possible effects upon blood viscosity into account.
Antihypertensive Agents↗
[What are the therapeutic consequences of evaluating hypertensive patients with 24-hour blood pressure monitors and blood pressure self-measurement?].
Arterial hypertension is an important risk factor for excessive cardiovascular morbidity and mortality due to its high prevalence of about 20% in the adult population. Causal readings, which have been obtained for diagnosis and control of treatment in hypertension are of limited value. They are not reproducable due to physiologic variability of blood pressure, which causes a rise of blood pressure, if a straining situation (e.g. in doctor's office) occurs (white-coat-hypertension). Furthermore, no correlation between causal readings and signs of endorgan-damage (EOD) such as left ventricular hypertrophy (LVH) can be observed. Especially the development of LVH comprises an independent risk factor and worsens prognosis. Results of ambulatory monitoring and self-measurement of blood pressure are reproducable and show an excellent correlation to EOD. Both methods are able to exclude white-coat-hypertension. Furthermore, ambulatory blood pressure monitoring allows to obtain blood pressure values during sleep, which may give further information concerning secondary hypertension, EOD and prognosis. Self measurement of blood pressure reinforces compliance of the patient and gives the possibility of self-titration and long-term control of antihypertensive drug treatment. The non-consensus concerning normal values is one limitation of both methods, but the cut-off level of office blood pressure recordings appears arbitrary, too. For optimal concomittance of hypertensives both methods have to reach more importance for diagnosis, evaluation of prognosis as well as treatment control.
Adult↗
Chiral aspects of beta-adrenoceptor antagonists.
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Adrenergic beta-Antagonists↗
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↗
Diminished vascular response to inhibition of endothelium-derived nitric oxide and enhanced vasoconstriction to exogenously administered endothelin-1 in clinically healthy smokers.
BACKGROUND: Smoking is a major risk factor for the development of atherosclerosis. Because endothelial dysfunction may be a marker for future atherosclerosis, we investigated the effects of smoking on endothelium-dependent control of vascular tone. METHODS AND RESULTS: The effects of brachial arterial infusions of NG-monomethyl-L-arginine (L-NMMA), a nitric oxide synthesis inhibitor; sodium nitroprusside; endothelin-1; and norepinephrine on forearm blood flow (strain-gauge plethysmography) were compared in 29 long-term smokers and 16 nonsmokers. The acute effects of smoking on systemic hemodynamics, plasma catecholamines, and forearm vascular responses to these compounds were investigated in smokers only. Smokers did not differ from nonsmokers (n = 16) regarding the vascular effects of sodium nitroprusside (n = 13) or vasoconstriction due to norepinephrine and endothelin-1 (n = 16). Low-dose endothelin-1-induced vasodilation, believed to reflect endothelial prostacyclin or nitric oxide release, was absent in smokers (n = 16), and their increase of forearm vascular resistance (FVR) after L-NMMA (n = 13) was impaired (35.6 +/- 27.9% versus 118.8 +/- 43.2%, P < .001). Short-term smoking (n = 11) increased blood pressure, heart rate, and plasma epinephrine concentrations (P < .05 or less); enhanced endothelin-1-induced vasoconstriction (delta FVR, 457 +/- 192% versus 254 +/- 143%, P < .01); and decreased norepinephrine-induced vasoconstriction (P < .05), but had no effect on the other interventions. CONCLUSIONS: Long-term smoking is associated with a diminished nitric oxide-dependent component of basal vascular tone and an impaired endothelium-dependent vasodilator response to low-dose endothelin-1 and short-term smoking enhances endothelin-1-induced vasoconstriction. Impaired endothelial control of vascular tone might reflect impairment of normal antiatherosclerotic endothelial functions in smokers, but the relevance of smoking-induced enhancement of endothelin-1 vasoconstriction remains to be determined.
Adult↗
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↗
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↗
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↗
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↗
[Specific and nonspecific effects of beta receptor blockers: stereoselectively different properties exemplified by (R)- and (S)-propranolol].
Beta adrenoceptor antagonists bind specifically to beta receptors in a reversible way, so they inhibit beta stimulating actions of beta mimetics such as epinephrine, norepinephrine, isoprenaline, etc. The effect of beta adrenoceptor antagonism depends on the extent of sympathetic activity and is most pronounced during work and stress. Most beta blockers are administered as racemic mixtures consisting of 50% of the (R)- and 50% of the (S)-enantiomer, but only one enantiomer (e.g. (S)-propranolol) exerts beta blocking activity in therapeutic doses while the other one (e.g. (R)-propranolol) does not. But there is also a number of non-beta blocking actions of beta adrenoceptor antagonists that show variable stereoselectivity. Propranolol is explored most extensively in this field: 1. Only (R)-propranolol inhibits the conversion of thyroxine to triiodothyronine. 2. Both (R)- and (S)-propranolol exert class 1 antiarrhythmic activity. 3. Both (R)- and (S)-propranolol decrease the intraocular pressure. In all these indications mentioned above, beta blockade as an unwanted effect could be avoided by administering optically pure (R)-propranolol instead of the racemic mixture. Stereoselectivity does not only influence the effects but also metabolism, protein-binding etc. of beta adrenoceptor antagonists. In fact, the (R)- and the (S)-enantiomer of a beta adrenoceptor antagonist are 2 substances with different pharmacodynamic and pharmacokinetic properties. Nevertheless, they are currently used as racemic mixtures in research as well as in therapy without being aware of stereoselective implications although there are nowadays methods available to separate and isolate the optically pure enantiomers of most beta adrenoceptor antagonists with high purity and on large scale at reasonable costs.
Adrenergic beta-Antagonists↗
Different stereoselective effects of (R)- and (S)-propafenone: clinical pharmacologic, electrophysiologic, and radioligand binding studies.
Propafenone is a class 1c antiarrhythmic agent with moderate beta-blocking activity as a result of a structural similarity to beta-adrenoceptor antagonists. In a randomized, double-blind crossover exercise study, eight healthy volunteers were examined before and 2 1/2 hours after oral administration of 300 mg (R,S)-, 150 mg (R)-, and 150 mg (S)-propafenone hydrochloride. The mean rate pressure product was significantly reduced by (R,S)-propafenone hydrochloride (-5.2%; p = 0.045) and half-dosed (S)-propafenone hydrochloride (-5.9%; p = 0.013), whereas the (R)-enantiomer caused no significant changes. There was a significant difference between the effects of (R)- and (S)-propafenone (p = 0.033). In beta-adrenoceptor-binding inhibition experiments with (S)-(125I)iodocyanopindolol in a sarcolemma-enriched cardiac membrane preparation, the eudismic ratio of (S)- over (R)-propafenone was 54. On the spontaneously beating Langendorff-perfused guinea pig heart, 3 x 10(-6) mol/L of both (R)- and (S)-propafenone resulted in significant changes (p less than 0.01) on His bundle conduction (+79% +/- 27% and +69% +/- 9%), as well as comparable decreases in the maximal rate of pacing with 1:1 conduction of the atrial (-54% +/- 10% and -57% +/- 8%) and ventricular myocardium (-42% +/- 6% and -43% +/- 6%), indicating equal effects in sodium channel-dependent antiarrhythmic class 1 activity. Thus (R)- and (S)-propafenone exert different beta-blocking actions but equal effects on the sodium channel-dependent antiarrhythmic class 1 activity. More specific antiarrhythmic class 1 therapy with reduction of beta-blocking side effects may be attained with optically pure (R)-propafenone hydrochloride instead of the currently used racemic mixture.
Administration, Oral↗
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↗
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↗