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Beta-blocker drugs impede the stimulating action of adrenaline-like hormones, which are released by nerves, and are selective for the nerves in the heart and lungs. Metoprolol is more specific for blockade of heart adrenergic nerves, being a so-called beta-two blocker. It should not have a great effect on the lungs, yet such effects may logically occur as a consequence of metoprolol treatment. The pulmonary effects of metoprolol, given in two long-acting formulations, have been compared with those of another beta-two blocker, atenolol, and a nonselective beta-blocker, propranolol. These tests, evaluated in 15 healthy subjects, were intended to give an indication of the selectivity for heart effects of each agent. Artificially induced bronchodilation was least affected by metoprolol OROS, the slowest release formulation, and even more so by metoprolol SR (slow release) and atenolol, and most by propranolol, which was expected to have the greatest pulmonary effects. Thus, the two drugs anticipated to be most cardioselective, metoprolol and atenolol, did possess that attribute, with minimal pulmonary side effects. (Consumer Summary produced by Reliance Medical Information, Inc.)

The effect of calculation stress on hemodynamic parameters and plasma adrenalin and noradrenalin was studied in two groups of 6 male subjects, before and during β-Blockade. One group received propranolol 15 mg i. v. and the other received mepindolol sulphate 0,5 mg i. v. There was an increase in heart rate, cardiac output and blood pressure during mental stress. A significant increase in plasma adrenalin but not in noradrenalin occurred at the same time. The stress-induced rise in HR but not that in blood pressure could be prevented by β-receptor blockade with proprandolol and mepindolol sulfate. The peripheral resistance (PR) and diastolic blood pressure in stress were even higher after propranolol than in the control study. Propranolol had no effect on the increased adrenalin concentration during stress, but it was prevented by mepindolol sulfate. There was no correlation between the increase in HR and that in adrenalin during stress, but the HR in stress and the HR reaction to infused isoproterenol were highly correlated. [ABSTRACT FROM AUTHOR]

This study investigated the effects of isamoltane on the changes induced by cumulative doses of inhaled albuterol (salbutamol) on bronchomotor tone, skeletal muscle, circulatory system, and metabolism after single (day 1) and multiple dosing (day 7) in 15 healthy subjects. The volunteers were given placebo, 4 mg isamoltane, 10 mg isamoltane, or 20 mg propranolol over a 7-day period in a randomized, double-blind, crossover design. The greatest attenuation in albuterol-induced beta-adrenergic receptor responses occurred with propranolol. The median provocative dose of albuterol causing a 50% increase in specific airway conductance was 337 and 315 micrograms (day 1 and day 7, respectively) for placebo, 336 and 322 micrograms for 4 mg isamoltane, 344 and 389 micrograms for 10 mg isamoltane, and 667 and 652 micrograms for propranolol. The provocative dose of albuterol producing a 35% increase in tremor was 464 and 539 micrograms (day 1 and day 7, respectively) for placebo, 1122 and 1270 micrograms for 4 mg isamoltane, 1612 and > 1612 micrograms for 10 mg isamoltane, and > 1612 and > 1612 micrograms for propranolol. On day 5 of each period an exercise test was performed. Propranolol reduced exercise heart rate by 11% (compared with placebo), 10 mg isamoltane reduced heart rate by 5%, and 4 mg isamoltane reduced heart rate by 1%. In conclusion, low-dose isamoltane caused measurable systemic effects on both beta 2- and beta 1-adrenergic receptors, and the dose-dependent blockade on beta 2-receptors of skeletal muscle was more clear than the attenuation of exercise heart rate.

The airway and tremor response and cardiovascular and hypokalemic effects of single doses of inhalative fenoterol dry powder capsules (0.4 mg) were compared with the fenoterol metered dose inhaler (0.4 mg) and colforsin (forskolin) dry powder capsules (10.0 mg), a direct activator of the adenylate cyclase system, in 16 patients with asthma. Subjects (FEV1 < or = 60% predicted) were investigated in a randomized, double-masked, placebo-controlled, four-period, crossover trial for a 120 minute period. All active drugs caused a significant increase in specific airway conductance (p < 0.05); the order of potency (mean +/- SEM maximum increase from baseline) was fenoterol metered dose inhaler (0.51 +/- 0.06 sec-1 x kPa-1), fenoterol dry powder capsules (0.49 +/- 0.07), and colforsin dry powder capsules (0.30 +/- 0.03). A marked increase in finger tremor amplitude resulted after fenoterol metered dose inhaler only (62.93% +/- 10.21%; p < 0.05) in contrast to fenoterol dry powder capsules (15.84% +/- 4.35%; p < 0.05) and colforsin dry powder capsules (12.87% +/- 10.44%; p > 0.05). A decrease in plasma potassium was found after fenoterol (metered dose inhaler > dry powder capsules; p < 0.05). In conclusion, fenoterol dry powder capsules caused less tremor response and hypokalemic effects than the metered dose inhaler, although the bronchodilator capacity was similar. Colforsin dry powder capsules resulted in a measurable bronchodilatation in patients with asthma.

1. Butylamino-phenoxy-propanol-acetate (BPPA) is a new topical oculoselective beta-adrenoceptor blocker for the reduction of intraocular pressure (IOP) in man. Its potency on the airways of normal subjects was identical with that of placebo. A study was carried out to determine the potential of BPPA to cause bronchoconstriction in mild asthmatics (FEV1 greater than or equal to 60% predicted) with normal IOP. 2. Twelve nonsmoking outpatients who bronchoconstricted to 0.25 or 0.50% of timolol eye drops (fall in FEV1 23.33 +/- 1.20% (mean +/- s.e. mean), range 16-30) were investigated in this double-masked, randomized, 3-period, crossover study. On three different occasions six incremental concentrations of BPPA (range: 0.1-2%; maximum cumulative concentration 4%), timolol (0.1-1%; 2%), and placebo were administered bilaterally until bronchoconstriction (decrease in FEV1 greater than or equal to 20% and in specific airway conductance (sGaw) greater than or equal to 35% simultaneously) or the maximum cumulative concentration was reached. 3. Airway response was measured as change in FEV1 and sGaw and dose-response curves to timolol, BPPA and placebo were performed. IOP was measured 3 h after the highest concentration of each study day. 4. Timolol caused dose-dependent falls in FEV1 and sGaw as well as clinical symptoms of respiratory distress in all subjects. The median cumulative concentrations of timolol required to decrease FEV1 by 20% and sGaw by 35% were 0.98% and 1.53%. Neither placebo (P greater than 0.05) nor BPPA (P greater than 0.05) caused a significant change in sGaw. A fall in FEV1 by 20% not accompanied by a simultaneous fall in sGaw by 35% was found in four subjects following BPPA and in five subjects following placebo.(ABSTRACT TRUNCATED AT 250 WORDS)

Systemic beta-blockade after single doses of ophthalmic beta-blockers (one drop in each eye) was investigated in healthy volunteers in two randomized, double-blind, crossover, placebo-controlled studies. beta-Blockade was evaluated by displacement of the bronchodilator (specific airway conductance), positive chronotropic (heart rate), and tremorogenic (finger tremor amplitude) dose-response curve for inhaled isoproterenol. In study 1, 0.5% betaxolol, 0.6% metipranolol, and 0.5% timolol were tested in 16 subjects. Compared with placebo, all beta-blockers resulted in a significant systemic beta-blockade (p greater than 0.05); the increasing order of potency was betaxolol, metipranolol, and timolol. In study 2, 2% butylamino-phenoxy-propanol-acetate (BPPA; a noncardioselective but topically oculoselective drug) and 1% timolol were investigated in 12 subjects. Placebo and BPPA showed no differences (p greater than 0.05), whereas timolol resulted in a significant beta-blockade (p less than 0.05). Topical oculoselectivity is an important aspect of drug safety of beta-blocking eyedrops. Measure of tremor is appropriate to evaluate beta 2-blockade.

The effect of single oral doses of the antiallergic agent azelastine hydrochloride (1.1, 2.2 and 4.4 mg) was compared to placebo on airway response to histamine challenge in 12 asymptomatic extrinsic asthmatics with proven bronchial hyperresponsiveness to inhaled histamine in a randomized double-blind crossover trial. All doses of azelastine resulted in a significant protection compared to placebo. The effects of 2.2 and 4.4 mg were equivalent and superior compared to 1.1 mg. A naturally small but statistically significant bronchodilator effect was observed 4 h after the two higher doses of azelastine. Tiredness was reported by two patients, the symptom occurred following each placebo and the active drug.

The bio-availability of Novodigal (beta-acetyldigoxine) alone and applied together with Alucol (aluminum hydroxide, magnesium hydroxide) was studied in six healthy probands. Bio-availability parameters were calculated from the areas under the plasma concentration curves and from the comparison of the blood levels after absorption during steady state. There was no significant difference between the bio-availability of beta-acetyldigoxine alone and that of the combination with Alucol. Thus, beta-acetyldigoxine combined with antacids of the aluminum hydroxide and magnesium hydroxide type can be applied in the same dosage as usual since no decrease of effect has to be apprehended.

The hemodynamic effects of diltiazem were investigated in six volunteers at rest, supine and erect, under psychologic stress and orthostatic conditions. Plasma concentrations were also estimated. Under all conditions diltiazem showed a vasodilating property that was more pronounced on the arterial resistance vessels than on the pulmonary vessels. The first plasma concentrations were detected 15 min after drug intake, and the highest values were seen at the end of the study in the 3rd h.

The bronchodilator effect of intravenously administered drugs was tested by whole bodyplethysmography in 24 patients with chronic obstructive airway disease over a period of 60 min. Subsequent to this, another bronchodilator was applied by a metered dose inhaler. Aminophylline (0,24 g i.v.) was followed by a decrease of airway resistance to a maximum of 73,04% of the base line value after 30 min. and to 76,33% after 60 min; inhalation of fenoterol (0,4 mg) caused a further decrease to 47,33% after 20 min. Diprophylline (0,28 gi.v.) produced only a slight decrease to a maximum of 95,75% after 20 min. and to 99,54% after 60 min.; fenoterol (0,4mg) reduced airway resistance to 55,29%. Hexoprenaline (0,005 mg i.v.) was followed by a decrease to a maximum of 74,71% after 5 min. and to 92,83% after 60 min.; ipratropiumbromide (0,08 mg) caused a further decrease to 54,92%. A considerable increase of heart rate, from 89,25/min. to 106,15/min. occurred only after hexoprenaline. For intravenous bronchodilator therapy we prefer aminophylline. Optimal bronchodilation however, was seen only after further application of fenoterol or ipratropiumbromide by a metered dose inhaler.

IK-6, a combination of the sympathomimetic fenoterol (low dose) and the anticholinergic ipratropium bromide (normal dose), was tested single-blind and cross-over in outpatients with intrinsic asthma and in healthy volunteers. In 12 patients IK-6 resulted in a good acute bronchodilatation, the onset was as quick as following fenoterol and the maximum was as good as following ipratropium bromide. In another 12 patients the protective effect against an acetylcholine-induced bronchoconstriction was better after IK-6 than after ipratropium bromide and much better than after salbutamol. In these patients IK-6 caused no unwanted side effects. In 10 healthy volunteers the effect on heart rate was tested after inhalation of 20 puffs of bronchodilators applied by metered dose inhaler. The anticholinergics (ipratropium bromide, oxitropium bromide, dibenzothiepine-derivative) caused no effect. Following fenoterol a marked increase in heart rate could be observed, whereas the combination IK-6 caused only a slight increase.

Twenty patients with bronchoconstriction induced by inhaled acetylcholine were treated with Sch 1000 and Berotec comparatively. From the mean value diagrams a faster, stronger and more constant decrease of bronchial resistance due to Berotec inhalation can be recognized. The effect, however, is called in question by contrasting diagrams of single cases.

Unlabelled: The hemodynamic effect of mepindolol-sulfate, a new non-cardioselective beta-receptor blocking agent, was compared with the hemodynamic effect of propranolol at rest and during exercise in five patients with coronary artery disease during an eight week double blind cross-over study., Results: 1. The beta-receptor blocking effect of mepindolol-sulfate is 25 times higher than that of propranolol. 2. No hemodynamic difference between mepindolol-sulfate and propranolol was seen at rest. 3. The increase of blood pressure during exercise was less pronounced during mepindolol-sulfate-medication compared to propranolol. 4. Propranolol seems to achieve a more pronounced negative inotropic effect than mepindolol-sulfate.

The acute bronchodilator effect of the beta 2-adrenoceptor agonist terbutaline was tested single-blind cross-over in out-patients with chronic obstructive airways disease (intrinsic asthma). In 7 series comparisons were made with other marketed bronchodilators. Airways resistance was measured by whole body plethysmography. In another 3 series the effect on heart rate of terbutaline and other adrenocepter agonists was tested in healthy volunteers. Terbutaline and the adrenoceptor agonists clenbuterol, epinephrine, fenoterol, hexoprenaline, isoprenaline, metaproterenol, reproterol and salbutamol, the vagolytics atropine, ipratropium bromide and AA 22-263, the xanthinederivative theophylline ethylenediamine and one combined substance drug were used.

Unlabelled: The effect of exercise upon hemodynamic variables was investigated in seven patients with coronary artery disease during an eight-week double blind cross-over study with placebo and with mepindolol-sulfate, a new beta-receptor blocking agent., Results: 1. The first hemodynamic sign of myocardial ischemia during exercise was an increase of pulmonary capillary pressure in parallel with ST-segment depression in the Ecg. 2. Angina was accompanied by a fall of the stroke volume and an increase of the peripheral resistance. 3. During beta-receptor blockade with mepindolol-sulfate angina was compensated, the unfavourable hemodynamic effects seen during placebo did not occur. 4. No signs of congestive heart failure were found during mepindolol-sulfate-therapy. 5. Mepindolol-sulfate showed a pronounced blood-pressure lowering effect.

The study was conducted in six healthy male volunteers aged between 20 and 30 years. Cardiac output was determined by means of the Swan-Ganz-thermodilution-method. A control-study was carried out, during which an isoproterenolinfusion with increasing doses was given. Fifty minutes after i.v. injection of a beta-receptor-blocker the hemodynamic parameters were measured again under increasing doses of isoproterenol until the block was overcome. This study procedure was performed twice in each subject at an interval of at least 14 days. For the one study 15 mg propranolol i.v. and for the other 0,5 mg mepindolol i.v., a new beta-receptor-blocker, were injected. After i.v. injection of propranolol the dose-response-relationship-curve for the heart-rate (HR) and stroke volume (SV) describes a definite shift to the right. After mepindolol the dose-effect curve for the heart rate describes a definite shift to the right, as seen with propranolol. In contrast, only a very slight shift can be seen in respect of the SV increase, i.e. the SV and HR curves dissociate under mepindolol. The results of our study indicate, that a distinction can be made with respect to the so-called beta 1-receptors between those mediating a specific effect on the heart-rate and those mediating a mainly positive inotropic effect.

NAB 365, a new beta2-adrenergic bronchodilator was tested in oral doses of 0,01, 0,02, 0,03, and 0,04 mg. An acute trial was carried out in outpatients, suffering from chronic obstructive airways disease. with doses of 0,02 and 0,04 mg NAB 365 a quick, dose related and statistically significant bronchodilation without remarkable side effects was found.

The selectivity of the beta-adrenoceptor blockade produced by single oral doses of cetamolol, atenolol, and nadolol was compared in normal male subjects. Study 1 established the dose at which each drug provides equivalent beta-1 blockade. Beta-1 blockade was estimated using the degree of inhibition of the increased heart rate (HR) response to graded exercise. Cetamolol (30 mg), atenolol (100 mg), and nadolol (80 mg) all attenuated the HR response to a comparable extent. This result established that the dose ratio of cetamolol:atenolol:nadolol of 1.00:3.33:2.67 provides equipotent beta-1 blockade. This ratio of doses was used in Studies 2 and 3 to evaluate the antagonism of beta-2-mediated responses to titrated doses of intravenous isoproterenol (ISO) by low and high doses of each drug. Beta-2 blockade was assessed using the attenuation of ISO-induced reductions in diastolic blood pressure (DBP) in Study 2 and ISO-induced increases in specific airway conductance (sGAW) in Study 3. For within drug comparisons, antagonism of the HR increase induced by ISO (a response mediated by both beta-1 and beta-2 receptors) was also examined. Treatments included cetamolol (15 and 60 mg), atenolol (50 and 200 mg), and nadolol (40 and 160 mg in Study 2; 40 mg only in Study 3). All drugs tested suppressed the HR, DBP, and sGAW responses to ISO, and this blockade was dose dependent. Cetamolol and nadolol produced approximately equipotent beta-1 blockade, whereas cetamolol at both doses produced a less potent beta-2 blockade. Atenolol antagonized ISO effects on all parameters less than either cetamolol or nadolol. Quantitative cardioselectivity indices revealed that cetamolol 60 mg was the most cardioselective and nadolol 40 mg the least. Data from the three studies demonstrate that cetamolol is cardioselective relative to nadolol and that, in contrast to atenolol, cardioselectivity appears to increase at the higher dose.