(−)-Timolol is a more potent antagonist of the positive inotropic effects of (−)-adrenaline than of those of (−)-noradrenaline in human atrium

1 The affinity of (−)-timolol for β₁- and β₂-adrenoceptors was determined on isolated atrial preparations from patients undergoing open heart surgery. The times for onset and offset of antagonism of the positive inotropic effects of (−)-adrenaline and (−)-noradrenaline by (−)-timolol were measured.
2 The antagonism of the positive inotropic effects of (−)-adrenaline and (−)-noradrenaline by (−)-timolol (0.1–100 nm) was simple competitive in human atrium tissue. The slope of Schild-plots was not significantly different from 1.0 [0.93±0.09 for (−)-adrenaline, 0.97±0.09 for (−)-noradrenaline].
3 The inotropic effects of (−)-adrenaline were antagonized significantly more by each concentration of (−)-timolol than those of (−)-noradrenaline. K _B-values (-log m) were 10.10±0.09 against (−)-adrenaline and 9.43±0.07 against (−)-noradrenaline ( P <0.001).
4 Blocking kinetics of (−)-timolol for the β-adrenoceptor were relatively slow. Half-times for the onset of blockade by 10 times K _B of (−)-timolol were approximately 30  min for both (−)-adrenaline and (−)-noradrenaline; offset times were similar.
5 It is concluded that (−)-timolol has a higher affinity for the β₂-adrenoceptor than for the β₁-adrenoceptor in human atrium. This property may be beneficial clinically in protecting against the β₂-adrenoceptor hypersensitivity induced by cardiac β₁-adrenoceptor blockade, but also explain why severe asthma can occur after administration of very low intra-ocular doses of the drug.     

Non-catechol phenylethanolamines: agonistic and antagonistic actions on β-adrenoreceptors in isolated tissues from the guinea-pig

SUMMARY 1. Agonistic and antagonistic activities on β-adrenoreceptors have been assessed for orciprenaline, terbutaline, soterenol and MJ7999–1 using isolated guinea-pig atrial (β₁-receptor) and tracheal (β₂-receptor) preparations.
2. As agonists MJ7999–1 is more selective for β₂-receptors than soterenol because of its increased activity in trachea, whereas terbutaline is more selective for β₂-receptors than orciprenaline because of its decreased activity in atrial preparations.
3. Antagonistic activity was assessed from shifts in concentration-effect curves to (-)-isoprenaline.
4. MJ7999–1 and soterenol possess competitive β-receptor blocking actions in atrial (pA₂≈6.5) and tracheal (pA₂≈6.0) preparations.
5. Orciprenaline and terbutaline are relatively selective competitive β-receptor antagonists, being more potent in atrial (pA₂≈6.3) than in tracheal (pA₂∼4.9) preparations. In atria non-competitive antagonistic actions are apparent with these two drugs.
6. In rat vas deferens preparations only (-)-isoprenaline and soterenol display agonistic actions on α-receptors. None of the compounds possesses α-receptor antagonistic activity.     

The rat lipolytic β-adrenoceptor: Studies using novel β-adrenoceptor agonists

EC₅₀ and relative intrinsic activity values were obtained for isoprenaline, fenoterol, salbutamol, prenalterol and three new β-adrenoceptor agonist, BRL 2841, BRL 35113 and BRL 35135 on rat white adipocyte lipolysis, rat atrial rate and tension, rat uterus tension and guinea-pig tracheal tension. Fenoterol and salbutamol were selective for tracheal and uterine responses, prenalterol was selective for atrial responses, but BRL 28410, BRL 35113 and BRL 35135 were selective for the adipocyte lipolytic response. pA₂ values for propratolol, ICI 118,551 and sotalol were obtained on adipocytes, atria and trachea. pA₂ values for propranolol and sotalol were much lower on adipocytes than on atria or trachea. The pA₂ value for practolol was lower on adipocytes than on atria and the pA₂ value for ICI 118,551 was lower on adipocytes than on trachea. Both agonist and antagonist studies therefore suggest that the rat adipocyte lipolytic receptor does not fit into the current β₁/β₂-adrenoceptor classification.     

Benazepril, an angiotensin converting enzyme inhibitor: drug interaction with salbutamol and bronchial response to histamine in normal subjects

Aims To investigate the effect of the angiotensin converting enzyme inhibitor, benazepril, on pulmonary function.
Methods We investigated the influence of benazepril, on lung function and the interaction with inhaled salbutamol (0.1 to 6.6  mg) and histamine (0.03 to 30.69  g  l⁻¹ ) in normal subjects. Benazepril 20  mg, salbutamol 8  mg, propranolol 160  mg, and placebo were given orally once daily over 10 days.
Results On day 8, there was no difference in the area under the salbutamol dose-response curves between benazepril, placebo and oral salbutamol ( P >0.05), propranolol shifted the curves to the right ( P <0.05). On day 10, histamine challenge resulted in following P D ₃₅sGaw values (geometric mean and 95% CI): with placebo 1.02 (0.95–1.09)  g  l⁻¹ , benazepril 1.04 (0.99–1.08), salbutamol 1.19 (1.13–1.25), propranolol 0.57 (0.50–0.65).
Conclusions Benazepril had no influence on baseline lung function, caused no interaction with inhaled salbutamol and the bronchial response to histamine was similar to placebo. However, our findings in normal subjects cannot be extrapolated automatically to asthmatics.     

H2-receptor antagonists and antacids have an aggravating effect on Helicobacter pylori gastritis in duodenal ulcer patients

Background : Antacids, such as aluminium–magnesium hydroxide (AlMg(OH)₃), or H₂-receptor antagonists, such as ranitidine, are common drugs used for treating peptic ulcer disease and acid-related symptoms.
Methods : In a prospective double-blind controlled study, 174 patients were randomized to a 4-week course of treatment with either AlMg(OH)₃ (acid-binding capacity: 280 mval/day) or ranitidine 300 mg for active Helicobacter pylori -associated duodenal ulcers (as determined by histology and the urease test). Before and after treatment, two biopsy specimens each were obtained from the antrum and corpus, and the grade and activity of gastritis, as well as H. pylori density, were determined using a score ranging from 0 = none to 4 = severe.
Results : Pre- and post-treatment histology were available for 138 patients (AlMg(OH)₃: 67, ranitidine: 71). Treatment with AlMg(OH)₃ significantly increased the activity of corpus gastritis (Wilcoxon signed-rank: P  = 0.0014), while ranitidine treatment significantly increased both the grade and activity of corpus gastritis ( P  = 0.0002 and P  = 0.0001 respectively). In the antrum, both regimens provoked a significant increase in the frequency of intestinal metaplasia, but this may be a consequence of sampling error.
Conclusions : Ranitidine and AlMg(OH)₃ have an aggravating effect on H. pylori gastritis in duodenal ulcer patients. This should be considered a side-effect of the respective drugs and is more pronounced with ranitidine.     

Diazepam–omeprazole inhibition interaction: an in vitro investigation using human liver microsomes

1 The metabolism of diazepam to its primary metabolites 3-hydroxydiazepam (3HDZ) and nordiazepam (NDZ) was evaluated in human liver microsomes. The 3HDZ pathway was the major route of metabolism representing 90% of total metabolism with a V _max /K _m ratio of 0.50–7.26  μl  min⁻¹  mg ⁻¹ protein.
2 Inhibition of the two metabolic pathways of diazepam by omeprazole was investigated. The NDZ pathway was not affected by omeprazole whilst a K _i of 201±89  μm was obtained for the 3HDZ pathway ( K _m /K _i ratio of 3.0±0.9).
3 Inhibitory effects of omeprazole sulphone on the 3HDZ and NDZ pathways were also investigated. Omeprazole sulphone inhibited both pathways with similar K_is of 121±45 and 188±73  μm respectively ( K _m /K _i ratios of 5.2±2.3 and 3.3±1.5 respectively).
4 These in vitro data provide direct evidence for cytochrome P450 inhibition as the mechanism for the well documented diazepam-omeprazole clinical interaction and indicate that omeprazole sulphone, as well as the parent drug, contribute to the inhibition effect.     

Nitric oxide: an important role in the maintenance of systemic and pulmonary vascular tone in man

Aims The aim of this study was to examine whether nitric oxide (NO) has an important role in maintaining basal vascular tone in normal man by examining the effects of nitric oxide inhibition using N ^G-monomethyl-l-arginine (l-NMMA) on systemic and pulmonary haemodynamics.
Methods Ten normal male volunteers 26±1.6 years were studied on two separate occasions in a double-blind, placebo controlled crossover study. They were randomised to receive either a continuous infusion of l-NMMA (4  mg  kg⁻¹  h⁻¹ ) with a front loaded bolus (4  mg  kg⁻¹ ) or volume matched placebo. Pulsed wave Doppler echocardiography was used to measure cardiac output (CO), mean pulmonary artery pressure (MPAP) and hence systemic vascular resistance (SVR) and total pulmonary vascular resistance (TPR). Measurements were made prior to infusion ( t ₀ ) and after 4, 8, and 12  min ( t ₁, t ₂ and t ₃ ).
Results Infusion of l-NMMA significantly increased mean arterial blood pressure (MAP), SVR and TPR and significantly reduced heart rate (HR), stroke volume (SV) and CO compared to placebo. These effects were observed at t ₁ and persisted during the entire infusion period.
Conclusions These results are consistent with a role for basal nitric oxide generation in the maintenance of basal systemic and pulmonary vascular tone in normal man.     

Metabolic interactions of selected antimalarial and non-antimalarial drugs with the major pathway (3-hydroxylation) of quinine in human liver microsomes

Aims Nine antimalarial (plus two metabolites of proguanil) and twelve non-antimalarial drugs were tested for their possible interaction with CYP3A4-catalysed 3-hydroxylation of quinine by human liver microsomes in vitro .
Methods 3-Hydroxyquinine was assayed in the incubation mixture by an h.p.l.c. method using fluorometric detection. The respective I C ₅₀ values were estimated for the twenty-one drugs and two metabolites of proguanil tested herein.
Results Thirteen drugs exhibited an inhibitory effect on the 3-hydroxylation of quinine. According to the respective mean I C ₅₀ values, the inhibitory rank order of the drugs was: ketoconazole>troleandomycin (TAO, with preincubation)> doxycycline>omeprazole>primaquine>tetracycline=TAO (without preincubation)>nifedipine>erythromycin>verapamil>cimetidine>diltiazem>oleandomycin>hydralazine. Other drugs or metabolites showed little or no inhibition of quinine metabolism (mean I C ₅₀>200 or 500  &mgr;m ). Among the antimalarial drugs, doxycycline showed relatively potent inhibition of quinine 3-hydroxylation with a mean I C ₅₀ value of 17  &mgr;m, followed by primaquine and tetracycline, with mean I C ₅₀ values of 20 and 29  &mgr;m, respectively.
Conclusions When the plasma/serum concentrations possibly attained after their usual therapeutic doses were taken into account, tetracycline, doxycycline, omeprazole, ketoconazole, nifedipine, TAO and erythromycin are likely to be inhibitors of quinine metabolism in patients when the drugs are co-administrated with quinine.     

Review article: β3-adrenoceptor agonists—future anti-inflammatory drugs for the gastrointestinal tract?

The β₃-adrenoceptor is now a recognized sub-type of β-adrenoceptor and is the principle adrenoceptor responsible for lipolysis in rat adipocytes. The receptor is also found in the gastrointestinal tract where β₃-adrenoceptor agonists are both spasmolytic and potent inhibitors of experimental non-steroidal anti-inflammatory drug (NSAID)-induced gastric and small intestinal ulcers. There is evidence to suggest that the underlying mechanism of protection involves enhancement of mucosal blood flow, possibly as a result of relaxation of vascular and non-vascular smooth muscle.
This review examines some possible therapeutic applications for β₃-adrenoceptor agonists in ulcero-inflammatory disorders of the gastrointestinal tract where an altered blood flow state is a component of the underlying pathogenic process.     

Differential inhibition of cytochrome P450 isoforms by the protease inhibitors, ritonavir, saquinavir and indinavir

Aims To compare the inhibitory potential of the HIV protease inhibitors saquinavir, ritonavir and indinavir against CYP1A2, CYP2C9, CYP2E1 and CYP3A4 catalysed metabolic reactions in human liver microsomes in vitro .
Methods Microsomes from six human livers were utilized in this study. The probe substrates were phenacetin (CYP1A2), tolbutamide (CYP2C9), chlorzoxazone (CYP2E1) and testosterone (CYP3A4). Metabolites were analysed by high performance liquid chromatography. I C ₅₀ (concentration of inhibitor giving 50% decrease in enzyme activity) and, where appropriate, K _i values were calculated.
Results Ritonavir was a very potent inhibitor of CYP3A4 mediated testosterone 6β-hydroxylation (mean K _i=0.019±0.004  μm, mean±s.d.; n =6) and also inhibited tolbutamide hydroxylation (I C ₅₀=4.2±1.3  μm, mean±s.d.; n =6). Inhibition of phenacetin O -deethylation and chlorzoxazone 6-hydroxylation was negligible. Indinavir was an order-of-magnitude less potent in inhibiting CYP3A4 ( K _i=0.17±0.01  μm ) and did not produce appreciable inhibition of the CYP1A2, CYP2C9 or CYP2E1 catalysed reactions. Saquinavir was the least potent CYP3A4 inhibitor ( K _i =2.99±0.87  μm ) and produced some inhibition of CYP2C9 (approximately 50% at 50  μm ).
Conclusions The HIV protease inhibitors have differential effects on CYP isozymes. There is obvious potential for clinically significant drug interactions particularly with ritonavir. Pharmacokinetic drug interaction studies are crucial to gain an overall understanding of the beneficial and potentially harmful effects of this important group of drugs.     

Effect of intravenous magnesium sulphate on airway calibre and airway reactivity to histamine in asthmatic subjects

In a randomized, double-blind, placebo controlled cross-over study we have investigated the effect of intravenous magnesium on airway calibre and airway reactivity to histamine in 20 subjects with mild to moderate asthma. After baseline measurements of forced expiratory volume in one second (FEV₁), subjects received 100 ml normal saline with or without 2 g of magnesium sulphate by infusion over 20 min. Measurements of FEV₁ were repeated at 5 min intervals throughout the infusion, and the provocative dose of histamine required to drop the FEV₁ by 20% from baseline ( PD ₂₀FEV₁) was determined at 20 min. The area under the curve (AUC) in litre minutes for change from baseline in FEV₁ between 0 and 20 min was significantly higher on the magnesium study day (mean difference in AUC (95% CI) 1.71 (0.02-3.4), P = 0.049). The increase in FEV₁ from baseline with magnesium relative to saline was maximal at 20 min (mean difference (95% CI) 0.13 (0.02-0.23) 1, P = 0.01). Log P D ₂₀FEV₁ to histamine was not significantly different after magnesium and saline (mean difference in log P D ₂₀FEV₁ (95% CI) 0.04 (-0.19 to 0.27), P = 0.7). We conclude that intravenous magnesium is a weak bronchodilator but does not alter airway reactivity at this dose in stable asthmatic subjects.     

[13C]-pantoprazole breath test to predict CYP2C19 phenotype and efficacy of a proton pump inhibitor, lansoprazole

Background  ¹³CO₂ is produced on metabolism of ¹³C-labelled-pantoprazole ([¹³C]-pantoprazole) by CYP2C19.
Aim  To investigate whether the [¹³C]-pantoprazole breath test can predict CYP2C19 status and efficacy of proton pump inhibitors (PPIs) in Japanese.
Methods  We classified 110 healthy volunteers as rapid metabolizers (RM), intermediate metabolizers (IM) or poor metabolizers (PM) of CYP2C19 by genotyping. Breath samples were collected at 10-min intervals for 60 min after dosing with 100 mg [¹³C]-pantoprazole. Changes in the carbon isotope ratios (¹³CO₂/¹²CO₂) in carbon dioxide in breath samples were measured and expressed as a delta-over-baseline (DOB) ratio (‰). Of the 110 subjects, twenty-two randomly selected subjects underwent intragastric pH monitoring on day 7 of dosing with 30 mg of lansoprazole.
Results  The DOB values of RMs were the highest and those of PMs the lowest of the three groups. Statistically significant differences were observed in the area-under-the-curve ( AUC )_20–60 min of DOB among the three groups. The mean 24-h intragastric pHs attained by lansoprazole 30 mg for 7 days were inversely correlated with the AUC _20–60 min of DOB.
Conclusions  [¹³C]-pantoprazole breath test can easily estimate the individual activity of CYP2C19 and predict the efficacy of a PPI (i.e. lansoprazole). This test would be useful for individualized medicine with a PPI.     

A possible role for mono(ADP-ribosyl)transferase in the signalling pathway mediating neutrophil chemotaxis

1 Mono(ADP-ribosyl)transferase activity has been identified on the external surface of human polymorphonuclear neutrophil leucocytes (PMNs). The enzyme is released from the plasma membrane by phosphoinositide-specific phospholipase C, suggesting a glycosylphosphatidylinositol (GPI) linkage of the enzyme to the plasma membrane. Partial sequence of cDNA encoding the enzyme suggests that it is identical to the GPI-linked mono(ADP-ribosyl)transferase identified previously on human skeletal muscle.
2 A panel of inhibitors of mono(ADP-ribosyl)transferase (including vitamins K₁ and K₃, novobiocin and nicotinamide) showed a rank order of inhibitory potency similar to that described for other mono(ADP-ribosyl)transferases. Furthermore, the mono(ADP-ribosyl)ation of agmatine was inhibited also by diethylamino(benzylidineamino)guanidine (DEA-BAG), another substrate of the enzyme related structurally to arginine.
3 There was a close linear correlation between the I C ₅₀ values for inhibition of mono(ADP-ribosyl)ation of agmatine by DEA-BAG or the enzyme inhibitors and their I C ₅₀ values for inhibition of receptor-dependent polymerization of cytoskeletal actin and chemotaxis.
4 These results suggest a role for mono(ADP-ribosyl)transferase in the transduction pathway involved in receptor-dependent re-alignment of the cytoskeleton during neutrophil chemotaxis.     

Pharmacodynamics of oxypurinol after administration of allopurinol to healthy subjects

1   Eight healthy subjects received 50, 100, 300, 600 and 900  mg allopurinol daily for 1 week each, in random order with 1 week separating each treatment period. The pre-dose plasma concentration of oxypurinol, the extent of inhibition of xanthine oxidase, plasma urate concentration and urine urate excretion rate were assessed on the last 2 days of each treatment week.
2   The ratio of 1-methyluric acid (1MU) over 1-methylxanthine (1MX) in the urine, following a dose of 50  mg 1MX infused intravenously over 20  min, was used to measure the inhibition of xanthine oxidase.
3   The steady-state plasma concentration of oxypurinol increased linearly with increasing dose of allopurinol between 50  mg to 600  mg day⁻¹, with a weak indication of saturation at the higher 900  mg day⁻¹ dose rate.
4   The relationships between plasma oxypurinol concentration and xanthine oxidase inhibition (1MU/1MX ratio), plasma urate concentration and urine urate excretion rate were fitted to an inhibition sigmoid E_max model and the C ₅₀ values for oxypurinol were 26.38±4.87, (mean±s.d.) 36.58±8.36 and 24.61±9.08  μm, respectively.
5   1MU/1MX ratio appeared to be a reliable index of xanthine oxidase activity in vivo as the C ₅₀ for oxypurinol observed for 1MU/1MX ratio, plasma urate concentration and urine urate excretion rate were similar.
6   The concentration of oxypurinol required for inhibition of xanthine oxidase, as indicated by C ₅₀, was lower than those often observed in clinical practice.     

The airway effects of stopping regular oral theophylline in patients with asthma

Aims We investigated whether the deterioration in asthma control reported following cessation of theophylline was due to tolerance to theophylline.
Methods Eighteen subjects with mild stable asthma were given oral theophylline 10  mg  kg⁻¹ day⁻¹ or placebo for 2 weeks in a double-blind crossover study. FEV₁ and PD₂₀ histamine were measured before and 8  h after the first dose of treatment and 8, 32 and 56  h after the final dose. PD₂₀ AMP was measured before treatment and 9  h after the final dose.
Results Six patients did not tolerate theophylline. In the other 12 subjects there were no differences between treatments in daily PEF, symptom scores, rescue bronchodilator use, PD₂₀ histamine or FEV₁ up to 8  h post treatment. Following withdrawal of theophylline there were significantly lower values for mean FEV₁ (mean difference 0.15  l, 95% CI 0.03, 026) and PD₂₀ AMP compared to placebo but no difference in other end points.
Conclusions The small rebound deterioration in lung function following regular treatment with therapeutic doses of oral theophylline is consistent with the development of tolerance.     

Attenuation by ACE inhibitor drugs of α-adrenoceptor sensitivity in human vessels: possible differences related to drug lipophilicity

Aims We investigated the effect of angiotensin converting enzyme inhibitors (ACEIs) on postsynaptic adrenoceptor sensitivity and compared the effect of the lipophilic ACEI, quinapril, and that of hydrophilic agent, enalapril in human vessels.
Methods α-adrenoceptor sensitivity was evaluated using the dorsal hand vein compliance technique. The dose–response curves of vasoconstriction to phenylephrine and prostaglandin F_2α were obtained in healthy male volunteers.
Results The ACEIs shifted the dose–response curve of phenylephrine to the right and raised the median effective dose (E D ₅₀; 189.3 (57.6  ng  min⁻¹ ) of phenylephrine. Following quinapril administration, E D ₅₀ increased to 481.1 (101.8  ng  min⁻¹ compared with 266.8 (55.8  ng  min⁻¹ after enalapril (95% CI for differences; 31.1–397.5  ng  min⁻¹ ). Quinapril administration had no effect on the dose–response curve of PGF_2α .
Conclusions ACE inhibition attenuates α-adrenoceptor sensitivity in human vessels. The effect of quinapril, a lipophilic ACEI, was greater than that of enalapril, a hydrophilic ACEI. Lipophilic ACEIs may be more potent in vasodilating effect than hydrophilic ACEIs. Angiotensin II concentration in tissue rather than that in plasma may contribute to the α-adrenoceptor sensitivity of the vessels.     

YF476 is a new potent and selective gastrin/cholecystokinin-B receptor antagonist in vitro and in vivo

Background : We newly synthesized YF476 ((R)-1-[2,3-dihydro-2-oxo-1-pivaloylmethyl-5-(2'-pyridyl)-1H-1,4-benzodiazepin-3-yl]-3-(3-methylamino-phenyl)urea) as a gastrin/cholecystokinin-B (CCK-B) receptor antagonist. We investigated the pharmacological profile of YF476 in vitro and in vivo .
Methods : We examined the binding properties of YF476 to the rat brain, cloned canine and cloned human gastrin/CCK-B receptors, and the effect of YF476 on secretagogue-induced gastric acid secretion in rats and Heidenhain pouch dogs.
Results : YF476 replaced the specific binding of [¹²⁵I]CCK-8 to the rat brain, cloned canine and cloned human gastrin/CCK-B receptors, with K _i values of 0.068, 0.62 and 0.19 n M , respectively. The affinity of YF476 for rat brain gastrin/CCK-B receptor was 4100-fold higher than that for rat pancreatic CCK-A receptor. In anaesthetized rats, intravenous YF476 inhibited pentagastrin-induced acid secretion with an ED ₅₀ value of 0.0086 μmol/kg, but did not affect histamine- and bethanechol-induced acid secretion at a dose of 10 μmol/kg. In Heidenhain pouch dogs, intravenous and oral YF476 inhibited pentagastrin-stimulated gastric acid secretion in a dose-dependent manner with ED ₅₀ values of 0.018 and 0.020 μmol/kg, respectively, but did not affect histamine-induced acid secretion.
Conclusion : These results suggest that YF476 is an extremely potent and highly selective gastrin/CCK-B receptor antagonist, and that the gastrin/CCK-B receptor is not involved in histamine- or bethanechol-induced gastric acid secretion in dogs or rats.     

Pharmacodynamics of a new selective beta2-adrenergic bronchodilator 3-(4-methoxybenzylamino)-4-hydroxy-alpha-(tert. butylaminomethyl)-benzyl-alcohol, HCl (QH25)

The bronchodilator effect of QH25 (3-(4-methoxybenzylamino)-4-hydroxy-alpha-(tert. butylaminomethyl)benzylalcohol, HCl) a new beta2-adrenergic bronchodilator has been investigated in conscious guinea pigs and in anaesthetized guinea pigs and cats and compared to that of salbutamol and isoprenaline. In anaesthetized guinea pigs QH25 and isoprenaline were equipotent after intravenous administration, whereas salbutamol was four times less active. The same difference between QH25 and salbutamol was observed after intraduodenal administration. After oral administration in conscious guinea pigs QH25 was eight and five times more potent than salbutamol and isoprenaline respectively, whereas no difference was observed when the agents were administered as aerosols. The bronchodilator action of QH25 was apprxomately three times that of salbutamol in egg-albumine sensitized guinea pigs after oral administration. In anaesthetized cats the bronchodilator potency of QH25 was three times that of salbutamol and the same or slightly higher than that of isoprenaline. A half-life of 4 hours for the bronchodilator action in guinea pigs was determined for both QH25 and salbutamol after oral administration. The effect of QH25 and salbutamol on cardiovascular parameters i.e. chrono- and inotropic action and blood pressure decreasing effect in guinea pigs, cats and dogs was essentially the same whereas isoprenaline was from 5 to 30 times more potent. The potential tremorogenic action of QH25 estimated on the cat soleus muscle was eight times less than that of isoprenaline and the same or slightly less than that of salbutamol. From the experimental data it is concluded that QH25 has the same potency as isoprenaline as a bronchodilator agent but is more potent than salbutamol. Taking into account that isoprenaline is considerably more active on cardiovascular parameters and on the cat soleus muscle than QH25 which has the same or less effect than salbutamol on these parameters the data suggest that QH25 is a more selective bronchodilator agent than both isoprenaline and salbutamol.     

Pharmacodynamics of a New Selective Beta2-adrenergic Bronchodilator 3-(4-methoxybenzylamino)-4-hydroxy-α- (tert. butylaminomethyl)-benzyl-alcohol,HCl (QH25)

Abstract The bronchodilator effect of QH25 (3-(4-methoxybenzylamino)-4-hydroxy-α-(tert. butylaminomethyl)benzylalcohol, HCl) a new beta₂-adrenergic bronchodilator has been investigated in conscious guinea pigs and in anaesthetized guinea pigs and cats and compared to that of salbutamol and isoprenaline. In anaesthetized guinea pigs QH25 and isoprenaline were equipotent after intravenous administration, whereas salbutamol was four times less active. The same difference between QH25 and salbutamol was observed after intraduodenal administration. After oral administration in conscious guinea pigs QH25 was eight and five times more potent than salbutamol and isoprenaline respectively, whereas no difference was observed when the agents were administered as aerosols. The bronchodilator action of QH25 was approximately three times that of salbutamol in egg-albumine sensitized guinea pigs after oral administration. In anaesthetized cats the bronchodilator potency of QH25 was three times that of salbutamol and the same or slightly higher than that of isoprenaline. A half-life of 4 hours for the bronchodilator action in guinea pigs was determined for both QH25 and salbutamol after oral administration. The effect of QH25 and salbutamol on cardiovascular parameters i. e. chrono- and inotropic action and blood pressure decreasing effect in guinea pigs, cats and dogs was essentially the same whereas isoprenaline was from 5 to 30 times more potent. The potential tremorogenic action of QH25 estimated on the cat soleus muscle was eight times less than that of isoprenaline and the same or slightly less than that of salbutamol. From the experimental data it is concluded that QH25 has the same potency as isoprenaline as a bronchodilator agent but is more potent than salbutamol. Taking into account that isoprenaline is considerably more active on cardiovascular parameters and on the cat soleus muscle than QH25 which has the same or less effect than salbutamol on these parameters the data suggest that QH25 is a more selective bronchodilator agent than both isoprenaline and salbutamol.     

Effects of age on cardiovascular responses to adrenaline in man

Aims Whereas the effects of ageing on β-receptor mediated responses have been extensively studied in vitro and in vivo using the β-adrenoceptor agonist isoprenaline, little is known regarding ageing induced changes in responses to endogenous catecholamines. In the present study, we assessed age-related changes in cardiac responses to the endogenous β-adrenoceptor agonist adrenaline and the influence of age-related changes in arterial baroreflex function on these responses.
Methods Adrenaline alone was infused in 14 young subjects, age 30±2 years (eight males, six females), and 18 older subjects (six males, 12 females), age 60±2 years, and together with ganglionic blockade (trimetaphan) in seven young and 11 older subjects. Adrenaline was infused at 3–4 incremental rates, each rate for 8  min. Cardiac function was assessed by echocardiography.
Results Adrenaline alone, at infusion rates 20–160  ng  kg⁻¹  min⁻¹ caused similar increases in heart rate in the two groups. In contrast, adrenaline caused larger increases in stroke volume, ejection fraction, cardiac index and systolic blood pressure and larger decreases in end-systolic wall stress and diastolic blood pressure in the young compared with older subjects. Older females exhibited the smallest increases in stroke volume index and ejection fraction. With concomitant ganglionic blockade, all above cardiovascular responses to adrenaline were similar in the young and older group. Plasma adrenaline increased similarly in the two groups.
Conclusions We conclude that ganglionic blockade does not unmask an age-related decrease in cardiovascular responses to adrenaline (in contrast to isoprenaline). A concomitant ageing induced decrease in neuronal uptake (which applies to adrenaline, but not isoprenaline) may explain such a differential effect..