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1

Digitale Medien

The effects of chronic dosing on the β1 and β2-adrenoceptor antagonism of betaxolol and atenolol (1991)

Lipworth, B. J. ; Irvine, N. A. ; McDevitt, D. G.

Springer

European journal of clinical pharmacology 40 (1991), S. 467-471

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ISSN: 1432-1041

Schlagwort(e): Betaxolol ; atenolol ; nadolol ; cardioselectivity ; β-adrenocepter antagonism

Quelle: Springer Online Journal Archives 1860-2000

Thema: Chemie und Pharmazie , Medizin

Notizen: Summary Six normal subjects were given once daily treatment for 15 days with placebo (PL), betaxolol 10 mg (B10), 40 mg (B40); atenolol 100 mg (A100); and nadolol 40 mg (N40). Measurements of β1-adrenoceptorblockade (reduction of exercise heart rate) and of β2-adrenoceptor-blockade (attenuation of isoprenaline induced finger tremor) were made after the first, eighth and fifteenth doses of each drug. Plasma concentrations showed dose related increases between 10 mg and 40 mg doses of betaxolol, and there was significant drug accumulation at steady state compared with after single dosing. The reduction in exercise heart rate (EHR) with B10 was less in comparison with all other treatments. There were no significant differences in effects between single and chronic-dosing for any of the treatments (% reduction EHR compared with placebo, on days 1 and 15): B10 (18.2, 19.0), B40 (28.6, 26.5); A100 (22.7, 23.1); N40 (26.6, 23.8). Dose-ratios for attenuation of isoprenaline-induced finger tremor (IT100) were significantly greater with B40 compared with B10 or A100 (no dose-ratio for finger tremor could be calculated for N40). There were no differences between single and chronic-dosing (IT100 dose-ratios on days 1 and 15): B10 (3.0, 2.5), B40 (4.4, 5.3); A100 (3.0, 3.0). The attenuation of isoprenaline-induced chronotropic response (IH25) by N40 was significantly greater in comparison with all other treatments. IH25 dose-ratios (on days 1 and 15) were as follows: B10 (2.8, 3.6), B40 (5.1, 5.8); A100 (3.6, 3.6); N40 (19.0, 17.4). Thus, despite drug accumulation after chronic-dosing, there was no evidence of any increase in either β1 or β2-adrenoceptor antagonism at steady-state in comparison with after single-dosing. The apparent dissociation between plasma concentration and β-adrenoceptor antagonism after chronic-dosing my be a consequence of β-adrenoceptor up-regulation, resulting in partial attenuation of β-blockade.

Materialart: Digitale Medien

URL: http://dx.doi.org/10.1007/BF00315224

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2

Digitale Medien

β-Blockers and psychometric performance: Studies in normal volunteers (1985)

McDevitt, D. G.

Springer

European journal of clinical pharmacology 28 (1985), S. 35-38

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ISSN: 1432-1041

Schlagwort(e): atenolol ; benzodiazepines ; nadolol ; propranolol ; psychomotor tests ; β-adrenoceptor antagonists ; lipophilicity

Quelle: Springer Online Journal Archives 1860-2000

Thema: Chemie und Pharmazie , Medizin

Notizen: Summary Tests of psychometric function were performed in young, normal volunteers taking several β-adrenoceptor antagonists. With single doses of atenolol, a cardioselective hydrophilic β-blocker, dosedependent effects were apparent and were maximal at a dose of 200 mg. The lipophilic non-selective β-blocker, propranolol, also produced significant impairment of psychomotor tests but these were inversely related to dose, the longest effects being at a dose of 40 mg but with little effect at 320 mg. Subsequently, a multisubject comparison of propranolol and atenolol confirmed these findings and showed the effects to be of the same order of magnitude as those produced by diazepam. Chronic administration of atenolol 100 mg, nadolol 80 mg and diazepam 5 mg daily for seven days showed some effects with all drugs during the test period; however, these were sporadic rather than persistent. Overall, β-Blockers do appear to have central effects in man which can be demonstrated by psychomotor tests. However, the relevance of these central effects to maintenance therapy and skilled performance is unclear.

Materialart: Digitale Medien

URL: http://dx.doi.org/10.1007/BF00543708

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3

Digitale Medien

Comparison of the efficacy and systemic effects of 4 mg and 8 mg formulations of salbutamol controlled release in patients with asthma (1990)

Lipworth, B. J. ; Clark, R. A. ; Dhillon, D. P. ; [weitere]

Springer

European journal of clinical pharmacology 39 (1990), S. 281-285

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ISSN: 1432-1041

Schlagwort(e): salbutamol ; asthma ; beta-adrenoceptor ; controlled release formulation ; adverse effects

Quelle: Springer Online Journal Archives 1860-2000

Thema: Chemie und Pharmazie , Medizin

Notizen: Summary The purpose of the present study was to compare the efficacy and systemic effects of 4 mg and 8 mg doses of salbutamol controlled release (SCR) after single dosing and at steady state in patients with asthma. Fifteen asthmatic patients (Age 36 y, FEV1 85% predicted) were given SCR 4 mg and 8 mg twice daily for 7 days in a randomised double-blind cross-over design, with at least 7 days washout between treatments. There were no differences between the bronchodilator effects of 4 mg and 8 mg doses. There was no evidence of tolerance to the bronchodilator effects after chronic dosing. Morning and evening PEFR measurements also showed improvements during treatment with SCR 4 mg and SCR 8 mg, although there were no differences between the two formulations. Both doses of SCR caused significant objective tremor responses which were maintained after chronic dosing. The 8 mg dose produced a larger tremor response after single dosing, but not at steady-state. Subjective tremor occurred in 7 patients with SCR 8 mg, and in 2 patients with SCR 4 mg. There were no cardiac arrhythmias on Holter ECG monitoring. These results suggest that the 8 mg dose of SCR was no more effective than the 4 mg formulation, and was associated with more systemic adverse effects.

Materialart: Digitale Medien

URL: http://dx.doi.org/10.1007/BF00315111

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4

Digitale Medien

Pharmacokinetics, efficacy and adverse effects of sublingual salbutamol in Patients with asthma (1989)

Lipworth, B. J. ; Clark, R. A. ; Dhillon, D. P. ; [weitere]

Springer

European journal of clinical pharmacology 37 (1989), S. 567-571

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ISSN: 1432-1041

Schlagwort(e): salbutamol ; sublingual ; oral ; inhaled ; pharmacokinetics

Quelle: Springer Online Journal Archives 1860-2000

Thema: Chemie und Pharmazie , Medizin

Notizen: Summary Administration of drugs by the sublingual route provides rapid systemic absorption and avoids first-pass metabolism. The purpose of the present study was to assess the pharmacokinetics, efficacy and adverse effects of standard salbutamol tablets given by this route to patients with asthma. Seven asthmatic patients were given either sublingual salbutamol tablet 2 mg (SL), swallowed tablet 2 mg (O), metered dose inhaler 200 µg (MDI) or placebo (PL), in a randomized single-blind cross-over design. Airways responses (FEV1, FVC, PEFR), finger tremor (Tr), heart rate (HR), plasma potassium (K) and plasma salbutamol were measured over a 6 h period following drug administration. There were highly significant changes in FEV1 with MDI, O and SL routes compared with PL, although the response to MDI was greater and more rapid than with O or SL. There were similar findings for FVC and PEFR responses. There were no adverse effects with MDI, whereas both 0 and SL produced significant tremor responses. There were no differences between O and SL for any of the pharmacodynamic parameters. In addition, pharmacokinetic profiles for O and SL were also similar apart from an initial delay in absorption with SL. There were however, no significant differences in any of the pharmacokinetic parameters, between O and SL. This suggests that buccal absorption of salbutamol was negligible, and that systemic absorption occurred after swallowing of the dissolved sublingual tablet. These results show that sublingual administration of salbutamol tablet has no clinical benefit over the oral route.

Materialart: Digitale Medien

URL: http://dx.doi.org/10.1007/BF00562546

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5

Digitale Medien

Evaluation of the metabolic responses to inhaled salbutamol in the measurement of beta2-adrenoceptor blockade (1989)

Lipworth, B. J. ; McFarlane, L. C. ; Coutie, W. J. ; [weitere]

Springer

European journal of clinical pharmacology 37 (1989), S. 297-300

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ISSN: 1432-1041

Schlagwort(e): atenolol ; salbutamol ; beta-adrenoceptor antagonists ; cardioselectivity ; metabolic response

Quelle: Springer Online Journal Archives 1860-2000

Thema: Chemie und Pharmazie , Medizin

Notizen: Summary The aim of the present study was to evaluate whether metabolic responses to inhaled salbutamol may be used to measure the cardioselectivity of beta-adrenoceptor antagonists. We therefore studied the effects of oral doses of atenolol 50 mg, 100 mg, 200 mg (A50, A100, A200), propranolol 40 mg (P40), and placebo (Pl) on the hypokalaemic (K) and hyperglycaemic (Glu) responses to inhaled salbutamol in five healthy subjects. Increasing doses of atenolol were associated with a progressive attenuation of ΔK compared with placebo: −0.72 mmol·l−1 (Pl) vs −0.20 mmol·l−1 (A200). However, ΔK with A200 was significantly different from the response with P40: +0.12 mmol·l−1. There were partial reductions in the hyperglycaemic response with the beta-adrenoceptor antagonists, although this was only significant (compared with Pl) for P40: ΔGlu 1.92 mmol·l−1 (Pl) vs 0.76 mmol·l−1 (P40). These results show that beta2-adrenoceptor blockade by atenolol is a dose-dependent phenomenon, which may be measured by the attenuation of salbutamol-induced hypokalaemia. However, beta2-adrenoceptor blockade by atenolol 200 mg was less than that by propranolol 40 mg. The glucose response to salbutamol was only partially blocked by propranolol and may therefore not be suitable to assess beta2-adrenoceptor antagonism.

Materialart: Digitale Medien

URL: http://dx.doi.org/10.1007/BF00679788

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6

Digitale Medien

Beta-adrenoceptor responses to inhaled salbutamol in normal subjects (1989)

Lipworth, B. J. ; McDevitt, D. G.

Springer

European journal of clinical pharmacology 36 (1989), S. 239-245

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ISSN: 1432-1041

Schlagwort(e): beta-adrenoceptor ; salbutamol ; airways response ; tremor ; haemodynamic response ; metabolic response

Quelle: Springer Online Journal Archives 1860-2000

Thema: Chemie und Pharmazie , Medizin

Notizen: Summary The aim of the present study was to quantify and compare the airways and systemic beta-adrenoceptor responses to inhaled salbutamol in normal subjects. Seven non-atopic, normal subjects were given cumulative doubling doses of inhaled salbutamol (100 µg to 4000 µg) or placebo in a single-blind cross-over design. Airways (sGaw, FEF 50%, FEF 25%), tremor, haemodynamic and metabolic responses were measured at each dose increment. There were dose-related changes in sGaw, FEF 50% and FEF 25% up to a plateau at 1.0 mg. Analysis of individual responses showed that most subjects required either 1.0 or 2.0 mg for maximum bronchodilatation, independent of the parameter of airflow. There was no correlation between maximum response and baseline airway calibre. In contrast to airways effects, systemic beta-adrenoceptor responses did not occur until 500 µg, and a ceiling in the dose-response curve was not reached. Therer were significant correlations between air-ways, tremor and haemodynamic responses, and between different metabolic variables. The intraindividual variability was greatest for tremor and sGaw, although this was small in comparison to the size of maximum change with salbutamol. The converse applied to the hypomagnesaemic response.

Materialart: Digitale Medien

URL: http://dx.doi.org/10.1007/BF00558154

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7

Digitale Medien

The biochemical effects of high-dose inhaled salbutamol in patients with asthma (1989)

Lipworth, B. J. ; Clark, R. A. ; Fraser, C. G. ; [weitere]

Springer

European journal of clinical pharmacology 36 (1989), S. 357-360

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ISSN: 1432-1041

Schlagwort(e): salbutamol ; asthma ; metabolism ; potassium ; glucose

Quelle: Springer Online Journal Archives 1860-2000

Thema: Chemie und Pharmazie , Medizin

Notizen: Summary We have studied the biochemical effects of high doses of inhaled salbutamol in 14 asthmatic patients age 38 years, FEV1 62%. Cumulative doubling doses of inhaled salbutamol were given every 20 min as follows: 100 µg, 200 µg, 500 µg, 1000 µg, 2000 µg, 4000 µg. Plasma glucose, potassium, and magnesium were measured at each step of the doseresponse curve. Salbutamol produced significant hypokalaemic and hyperglycaemic effects, but no significant change in magnesium. There were linear log-dose responses for both glucose (r/it=0.58) and potassium (r=−0.46). There were wide individual variations in maximum responses to salbutamol 4000 µg (as means and 95% confidence intervals): Δ glucose 1.46 (0.83 to 2.09) mmol/l, Δ potassium −0.38 (−0.64 to −0.12) mmol/l. Thus, hypokalaemic and hyperglycaemic effects may occur with doses of salbutamol similar to those curently used for nebulizer therapy (2.5–5 mg). We postulate that during acute exacerbations of airflow obstruction these changes may be accentuated and become clinically relevant.

Materialart: Digitale Medien

URL: http://dx.doi.org/10.1007/BF00558295

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8

Digitale Medien

Single dose and steady-state pharmacokinetics of 4 mg and 8 mg oral salbutamol controlled-release in patients with bronchial asthma (1989)

Lipworth, B. J. ; Clark, R. A. ; Dhillon, D. P. ; [weitere]

Springer

European journal of clinical pharmacology 37 (1989), S. 49-52

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ISSN: 1432-1041

Schlagwort(e): salbutamol ; asthma ; controlled-release formulation ; pharmacokinetics

Quelle: Springer Online Journal Archives 1860-2000

Thema: Chemie und Pharmazie , Medizin

Notizen: Summary Fifteen patients with asthma were given salbutamol controlled-release (SCR) 4 mg or 8 mg twice daily for seven days, in a randomised double-blind cross-over design. Plasma salbutamol levels were measured after the first and fifteenth doses for a 12 h period following drug ingestion. At steady-state the geometric mean values for Cmax were 8.2 ng/ml for 4 mg, and 16.1 ng/ml for 8 mg. Median tmax values were 300 and 240 min respectively. The geometric mean AUC (0–12) were 4507 ng·min·ml−1 and 8980 ng·min/ml. Peak to trough fluctuation ratios were 0.577 and 0.572. There were no significant differences between 4 mg or 8 mg formulations, for any of the parameters measured, after appropriate corrections for dose. The concentration-time profiles at steady-state showed little fluctuation in plasma salbutamol levels over the twelve hour dosing interval. These results show that 4 mg and 8 mg formulations of SCR provide smooth plasma profiles at steady-state with a twice daily dosing regime.

Materialart: Digitale Medien

URL: http://dx.doi.org/10.1007/BF00609424

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