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  • 1
    Electronic Resource
    Electronic Resource
    Springer
    European journal of clinical pharmacology 24 (1983), S. 7-14 
    ISSN: 1432-1041
    Keywords: oxprenolol ; coronary heart disease ; normals ; pharmacodynamics ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The plasma concentration profile of oxprenolol after intravenous bolus injection, during intravenous infusion and following sustained oral administration was studied in a total of 106 patients with coronary heart disease. Speed of onset of pharmacodynamic activity, as measured by suppression of isoprenaline tachycardia, was discernible within a few seconds of central injection and complete within 5 min in all patients; variability in response was small. Following both i.v. bolus and intravenous infusion, plasma oxprenolol concentrations showed considerable between patient variability The plasma concentration/time profile observed in 16 patients following single intravenous oxprenolol bolus therapy was substantially higher, particularly during the early distribution phase, than observed and predicted volunteer data. Higher plasma oxprenolol concentrations were also attained during the more extended time sampling of the infusion studies; these findings would be compatible with reduced oxprenolol clearance in patients with ischaemic heart disease. During chronic oral therapy there was a many-fold between-subject variability in plasma concentration achieved following a given ingested dose. Correlation of antagonism of exercise tachycardia inhibition with plasma oxprenolol concentration in 15 male volunteers demonstrated near complete blockade of exercise stimulation of chronotropic beta-adrenoceptors at an average plasma oxprenolol concentration of 150 ng/ml. In coronary heart disease, such plasma concentrations can most conveniently be achieved by a 4 mg oxprenolol intravenous bolus with simultaneous infusion of 0.05 mg/kg/h; however, these studies provide sufficient information to allow alternative regimens to be derived should lesser plasma concentrations be considered desirable.
    Type of Medium: Electronic Resource
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  • 2
    ISSN: 1432-1041
    Keywords: nicardipine ; angina pectoris ; haemodynamic ; pharmacokinetics ; radionuclide studies
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Pharmacokinetic, haemodynamic and radionuclide studies explored the acute pharmacokinetic and pharmacodynamic actions of nicardipine in patients with coronary heart disease. Nicardipine infusion resulted in dose-related reductions in systolic and diastolic blood pressure and an increased heart rate. Pharmacodynamic activity was evident between 12 and 24 min following 5 and 10 mg i.v. nicardipine but by 3–6 min following the higher doses of 15 and 20 mg; hypotensive activity persisted for up to 2 h. Post-infusion nicardipine concentrations declined biexponentially; however the limited data precluded formal compartmental analysis. Plasma clearance ranged from 5–12 ml/min/kg, and appeared lower than previously reported volunteer data. The haemodynamic actions of nicardipine (10 mg infusion over 10 min) in 6 patients undergoing diagnostic catheterization were reductions in systolic, diastolic and mean systemic arterial pressure and systemic vascular resistance index. Heart rate and stroke volume index increased, and there was a small but statistically significant increase in pulmonary artery occluded pressure. Radionuclide parameters were measured in 20 patients with stable angina, at rest and during supine bicycle exercise, before and 3–5 min after nicardipine 10 mg intravenously. The left ventricular ejection fraction increased by 4% at rest but not during exercise. The left ventricular rest and exercise ejection and filling rates both increased with a concurrently reduced left ventricular ejection time. There was a highly significant inverse relationship between baseline exercise ejection fraction and the response to nicardipine; ejection fraction increased with low initial values but was either unchanged or fell with higher initial values. These data suggest that the acute effects of nicardipine in stable coronary artery disease probably reflect a reduction in left ventricular afterload and an associated augmentation of cardiac pumping performance. The acute circulatory profile of nicardipine appears sufficiently promising to warrant longer-term studies in ischaemic heart disease.
    Type of Medium: Electronic Resource
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  • 3
    ISSN: 1432-1041
    Keywords: beta-blocking drugs ; coronary artery disease ; myocardial infarction ; haemodynamic response
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Theoretically the increased sympathoadrenal activity following acute myocardial infarction might augment the haemodynamic impact of beta-adrenoceptor blockade. To evaluate this question 32 haemodynamic studies were performed to compare the effects of equivalent beta-blocking doses of propranolol (8 mg i.v.) and pindolol (0.8 mg i.v.) in patients with a recent acute myocardial infarction (A.M.I.) or stable coronary artery disease (and a presumptive low sympathetic state). In stable coronary artery disease there were clear differences between the haemodynamic impact of propranolol and pindolol. Propranolol decreased both heart rate (ΔHR −7 beat/min) and cardiac index (ΔCI −0.4l/min/m2), with an increased pulmonary artery occluded pressure (ΔPAOP +4 mmHg) and systemic vascular resistance index (ΔSVRI +358 dyn · s · cm−5 m2). However an equivalent beta-blocking dose of pindolol increased PAOP (ΔPAOP +3 mmHg) leaving other variables unchanged. These differential actions of propranolol and pindolol have previously been ascribed to the intrinsic synpathomimetic activity (I.S.A.) of pindolol maintaining cardiac pumping function in a low sympathetic state. In contrast following myocardial infarction, both drugs reduced cardiac index to a significantly greater extent compared with stable coronary artery disease (ΔCI propranolol −0.8l/min/m2; pindolol −0.4l/min/m2;p〈0.05); propranolol also reduced the systemic arterial blood pressure (Δsystolic −10 mmHg; Δmean −5 mmHg;p〈0.05). The haemodynamic relevance of the I.S.A. of pindolol appeared attenuated following A.M.I. These data are compatible with experimental evidence of sympathetic nervous activation following coronary occlusion; the resulting hyperadrenergic state appears to condition an augmented haemodynamic response to beta-blocking drugs irrespective of their ancillary pharmacological properties. The implications of these findings for clinical therapy warrant further examination.
    Type of Medium: Electronic Resource
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  • 4
    Electronic Resource
    Electronic Resource
    Springer
    European journal of clinical pharmacology 19 (1981), S. 323-327 
    ISSN: 1432-1041
    Keywords: metoprolol ; coronary heart disease ; haemodynamics ; i.v. metoprolol ; dose-response effect
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The haemodynamic effects of intravenous metoprolol, over the dose-range 2.5–20 mg, were studied in 12 patients with coronary heart disease. The pharmacodynamic activity of the drug was confirmed by the suppression of exercise systolic pressure and tachycardia. There were statistically significant dose-response reductions in systolic and diastolic pressures, heart rate and cardiac output together with a dose-related increase in pulmonary wedge pressure. In patients with coronary heart disease intravenous metoprolol should probably not exceed the doses used in this study and should be administered with caution in patients with impairment of pumping function.
    Type of Medium: Electronic Resource
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  • 5
    ISSN: 1432-1041
    Keywords: coronary heart disease ; beta-blockade ; haemodynamics ; propranolol ; pindolol ; intrinsic sympathomimetic activity ; partial agonist activity
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary To determine whether the depression of left ventricular pumping activity associated with beta-blockade alone could be offset by a substantial degree of partial agonist activity, the haemodynamic dose-response effects of intravenous propranolol and pindolol were compared in a randomised between-group saline controlled study in twenty patients with angiographically proven coronary artery disease. The intravenous doses of propranolol (2–16 mg) and pindolol (0.2–1.6 mg) used were selected on the basis of published reports of equivalence in terms of exercise blockade of chronotropic beta-adrenoceptors. Following four intravenous boluses of each drug, administered according to a cumulative log-dosage schedule, there was a log-linear increase in the plasma concentrations of each drug. The range of plasma concentrations achieved were those which have been shown to be associated with substantial attenuation of sympathetic stimulation of cardiac beta-adrenoceptors. At rest propranolol resulted in dose-related linear reductions in heart rate and cardiac output and linear increases in left heart filling pressure and systemic vascular resistance compared with saline-controlled measurements. The only statistically significant change at rest after pindolol was a small increase in the left heart filling pressure. The calculated systemic vascular resistance was increased after propranolol but unchanged after pindolol. During supine bicycle exercise the systolic blood pressure increased less after propranolol than after saline or pindolol. The increments in all other measured haemodynamic variables during exercise were equally influenced by the two drugs. Propranolol resulted in a significantly greater depression of the relationship between left heart filling pressure and cardiac output at rest and during exercise than an equivalent beta-blocking dose of pindolol. The contrasting haemodynamic profile of the two drugs is explicable by the partial agonist stimulation of the heart by pindolol directly maintaining left ventricular pumping activity and simultaneously lowering afterload by stimulating vasodilator beta2-adrenoceptors in peripheral arteriolar resistance vessels. In patients with impairment of left ventricular function due to coronary heart disease who require intravenous beta-blocking therapy, partial agonist activity in a beta-blocking drug may be haemodynamically advantageous.
    Type of Medium: Electronic Resource
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  • 6
    ISSN: 1432-1041
    Keywords: beta-receptor blocking drugs ; myocardial infarction ; haemodynamic effects ; propranolol ; pindolol ; intrinsic sympathomimetic activity
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The relevance of the intrinsic sympathomimetic activity (ISA) of beta-blocking compounds to the clinical therapeutics of acute myocardial infarction was evaluated in 20 patients with an uncomplicated acute myocardial infarction by comparing the haemodynamic effects of equivalent beta-blocking doses of propranolol (non-cardioselective; no ISA) and pindolol (non-cardioselective; 50% ISA). Consecutive eligible male patients admitted to a Coronary Care Unit were randomised following a 1 h control period to two separate studies. In Study 1 the short-term dose-response effects of propranolol (1–8 mg) or pindolol (0.1–0.8 mg) were assessed. In Study 2 comparison of the effects of single i.v. propranolol (8 mg) and pindolol (0.8 mg) doses was undertaken over 6 h. Haemodynamic variables and thermodilution cardiac output were subsequently recorded to compare the effects of each drug on the circulation. The plasma concentrations of propranolol and pindolol were in the recognised therapeutic range. Both drugs were clinically well-tolerated, the changes induced in haemodynamic variables following each drug demonstrated effective beta-blockade. Within the limits of the experimental protocol, these data did not suggest definite haemodynamic advantage for ISA of pindolol in acute myocardial infarction. These findings are perhaps due to sympathetic activation in acute myocardial infarction attenuating the haemodynamic impact of ISA.
    Type of Medium: Electronic Resource
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  • 7
    Electronic Resource
    Electronic Resource
    Springer
    Cardiovascular drugs and therapy 11 (1997), S. 57-61 
    ISSN: 1573-7241
    Keywords: beta-blockade ; comparison ; partial agonism ; chronotropy ; inotropy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract A double-blind, randomized, placebo-controlled comparison of metoprolol (50 mg) and celiprolol (200 mg) was undertaken in nine normal volunteers. Rest and exercise (supine bicycle) hemodynamics were assessed at 0, 2, 4, 6, and 8 hours following single oral doses of medication administered at weekly intervals. The influence of the ancillary pharmacological properties of metoprolol and celiprolol on cardiac pumping indices was assessed from heart rate and peak aortic acceleration (pkA − Exerdop). Following placebo, the heart rate and pkA increased progressively with exercise duration and workload. Following metoprolol 50 mg, the heart rate (−9.7 beat/min at 75 watts exercise) and pkA decreased. The blunting of acceleration was greater at higher exercise workloads (−6.7 m/sec2 at 75 watts exercise). Celiprolol reduced heart rate (−6.9 beat/min at 75 watts exercise) without a change in pkA. The heart rate/pkA relationship showed significant parallel displacement, downwards after metoprolol but upwards after celiprolol. Thus, for a given heart rate increment there was a greater decrease in pkA after metoprolol compared with celiprolol. The different ancillary pharmacological profiles of metoprolol and celiprolol resulted in contrasting hemodynamic profiles. The observed differences in the heart rate/pkA relationships may be attributable to the peripheral actions of these agents. The therapeutic relevance of the better maintained cardiac pumping indices on celiprolol for ischemic patients with impaired cardiac function warrants further investigation.
    Type of Medium: Electronic Resource
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  • 8
    Electronic Resource
    Electronic Resource
    Springer
    Cardiovascular drugs and therapy 7 (1993), S. 45-53 
    ISSN: 1573-7241
    Keywords: diuretics ; hemodynamics ; chronic heart failure ; furosemide ; piretanide ; torasamide ; bumetanide
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary In chronic heart failure diuretic drugs improve central hemodynamic variables and cardiac pumping secondary to altered plasma and extracellular volumes; humoral markers of these changes include increased plasma renin and aldosterone levels. The latter increases are maximal over the first week but decline with chronic therapy. The plasma alpha-ANP levels show a reciprocal effect; these data are compatible with a rapid contraction of the plasma volume which is sustained during chronic therapy. The acute hemodynamic actions of diuretic agents reflect both immediate and direct vascular actions and also effects secondary to diuresis (volume redistribution). At rest substantial reductions in pulmonary “wedge” pressure (−29%), with a consequent fall in cardiac output (−10%), are described. Total systemic vascular resistance initially increases but “reverse autoregulation” over subsequent weeks returns this elevation gradually towards control values. Tolerance to these initial hemodynamic effects does not occur with maintained therapy; moreover, echocardiographic markers of contractility and exercise capacity may increase. The early venodilator effects of diuretic drugs can be attributed to prostaglandin release and the initial pressor actions to activation of the renin angiotensin system; these vascular actions may have limited relevance to long-term beneficial effects on hemodynamics. Direct pulmonary vasodilation and improved pulmonary compliance remain an interesting finding. Although most patients are both symptomatically and hemodynamically improved at rest, the actions during exercise are more varied. Some individuals with severely impaired left ventricular function show little hemodynamic improvement, whereas those with milder dysfunction usually benefit; in the main this is probably related to the latter being on a steeper cardiac function curve. The impact of diuretic therapy on the underlying disease process is unclear; however, there is little convincing evidence of remodelling or improvement in intrinsic performance (as distinct from that induced by altered loading conditions).
    Type of Medium: Electronic Resource
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  • 9
    ISSN: 1573-7241
    Keywords: heart rate variability ; scatterplot ; nonlinear ; beta-adrenoceptor ; partial agonist
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract There is evidence that the processes regulating heart rate variability (HRV) reflect nonlinear complexity and show “chaotic” determinism. Data analyses using nonlinear methods may therefore reveal patterns not apparent with the standard methods for HRV analysis. We have consequently used two nonlinear methods, the Poincaré plot (scatterplot) and cardiac sequence (quadrant) analysis, in addition to the standard time-domain summary statistics, during a normal volunteer investigation of the effects on HRV of some agents acting at the cardiac beta-adrenoceptor. Under double-blind and randomized conditions (Latin square design), 25 normal volunteers received placebo, salbutamol 8 mg (β2-adrenoceptor partial agonist), pindolol 10 mg (β2-adrenoceptor partial agonist), or atenolol 50 mg (β1-adrenoceptor antagonist). Single oral doses of medication (at weekly intervals) were administered at 22:30 hours, with sleeping heart rates recorded overnight. The long-term (SDNN, SDANN) and short-term (rMSSD) time-domain summary statistics were reduced by salbutamol 8 mg and increased by atenolol 50 mg compared with placebo. The reductions in both SDNN and SDANN were greater after salbutamol 8 mg compared with pindolol 10 mg. The reduced HRV after pindolol 10 mg differed from the increased HRV following atenolol 50 mg. The Poincaré plot, constructed by plotting each RR interval against the preceding RR interval, was measured using a reproducible computerized method. Scatterplot length and area were reduced by salbutamol 8 mg and increased by atenolol 50 mg compared with placebo; scatterplot length and area were lower after pindolol 10 mg compared with atenolol 50 mg. Geometric analysis of the scatterplots allowed width assessment (i.e., dispersion) at fixed RR intervals. At the higher percentiles (i.e., 90% of scatterplot length: low HR), salbutamol 8 mg reduced and atenolol 50 mg increased dispersion; at lower percentiles (i.e., 10%, 25%, and 50% length), atenolol 50 mg and pindolol 10 mg increased dispersion compared with placebo and salbutamol 8 mg. Cardiac sequence analysis (differences between three adjacent beats; ΔRR vs. ΔRRn+1) was used to assess the short-term patterns of cardiac acceleration and deceleration. Four patterns were identified: +/+ (a lengthening sequencing), +/− or −/+ (balanced sequences), and finally −/− (a shortening sequence). Cardiac acceleration episodes (i.e., number of times ΔRR and ΔRRn+1 were both changed) were increased in quadrants −/− and +/+ following pindolol 10 mg and salbutamol 8 mg; the beat-to-beat difference (ΔRRn+1) was reduced after salbutamol 8 mg compared with the three other groups. These results demonstrated a shift towards sympathetic dominance (β-adrenoceptor partial agonist salbutamol 8 mg) or parasympathetic dominance (β1-adrenoceptor antagonist atenolol 50 mg); pindolol 10 mg exhibited HR-dependent effects, reducing HRV at low but increasing variability at high prevailing heart rates. These nonlinear methods appear to be valuable tools to investigate HRV in health and to study the implications of perturbation of HRV with drug therapy in disease states.
    Type of Medium: Electronic Resource
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  • 10
    Electronic Resource
    Electronic Resource
    Springer
    Cardiovascular drugs and therapy 14 (2000), S. 433-440 
    ISSN: 1573-7241
    Keywords: heart rate variability ; scatterplot ; compactness ; beta-adrenoceptor agonist antagonist
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract This article compares different methods of scatterplot analysis to assess the optimal methodology. The scatterplot (Poincaré plot) is a nonlinear heart rate variability method where a “return map” is constructed by plotting each current cycle against the previous beat (RR vs. RRn−1). Geometric analysis of the scatterplot allows short-term and long-term heart rate variability (HRV) to be assessed. A three-dimensional construct is also possible, where the third axis represents the density of values, at any given RR vs. RRn−1 intersection. Topological methods of analysis can compute the density distribution function or compactness of a dataset. Scatterplots that otherwise appear very similar in the two-dimensional plot may be clearly differentiated using this approach. Correct characterization may improve the ability of scatterplot analysis to predict outcomes in cardiovascular disease. We have assessed two computational approaches that take account of scatterplot density, namely, the heart rate variability fraction and the compactness measure. Scatterplots were constructed from three double-blind and randomized placebo controlled studies conducted in a total of 49 healthy subjects. Single oral doses of antagonists (atenolol 50 mg [β-1, propranolol 160 mg [β-1 and β-2], and ICI 118,551 25 mg [β-2]) or agonists (xamoterol 200 mg [β-1], salbutamol 8 mg [β-2], prenalterol 50 mg [β-1 and β-2], and pindolol 10 mg [mainly β-2] of the cardiac β-adrenoceptor were studied. Salbutamol, pindolol, and xamoterol increased compactness and reduced HRV fraction significantly compared with placebo. However, when compared with the more conventional scatterplot parameters, these newer density methods were found to be less discriminating. An alternative approach to improve scatterplot discrimination, using the combination of several scatterplot features, is under investigation.
    Type of Medium: Electronic Resource
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