-
British Journal of Pharmacology Sep 1986Atrial and ventricular chronotropic effects of the individual stereoisomers of propranolol, pindolol, metoprolol and penbutolol were studied in conscious dogs with...
Atrial and ventricular chronotropic effects of the individual stereoisomers of propranolol, pindolol, metoprolol and penbutolol were studied in conscious dogs with chronic atrio-ventricular (A-V) block. Ventricular beta-adrenoceptor blocking activity was assessed for all drugs against isoprenaline under the same experimental conditions. At low doses, the stereoisomers of propranolol and penbutolol decreased atrial rate, whereas those of pindolol and metoprolol produced an increase. At higher doses, all drugs increased atrial rate. All drugs decreased ventricular rate dose-dependently except (+)-pindolol. Relative ventricular beta-blocking potencies of the (-)-isomers of propranolol, pindolol, metoprolol and penbutolol were respectively 38, 21, greater than 43 and 31 times higher than those of their corresponding (+)-isomers. In addition, beta-blocking potencies of (-)- and (+)-pindolol were respectively 60 and 120 times higher, those of (-)- and (+)-penbutolol 7 and 8 times higher and those of (-)- and (+)-metoprolol 4 and greater than 4 times weaker than those of (-)- and (+)-propranolol. At comparable levels of ventricular beta-adrenoceptor blockade, (-)-pindolol and (-)-metoprolol were more potent in producing ventricular bradycardia than their respective (+)-isomers, whereas (-)- and (+)-propranolol and (-)- and (+)-penbutolol were equiactive. In addition, regardless of which isomer was being studied, the order of ventricular bradycardiac potencies, at comparable levels of beta-adrenoceptor blockade, was metoprolol greater than propranolol greater than penbutolol greater than pindolol. In addition, regardless of which isomer was being studied, the order of ventricular bradycardiac potencies, at comparable levels of beta-adrenoceptor blockade, was metoprolol > propranolol > penbutolol >pindolol. 5 These results show that antagonism of beta-adrenoceptors in the ventricle is at least partly responsible for the ventricular bradycardiac effect produced by these drugs, but also that some other factor, apparently distinct from the membrane stabilizing activity, is involved, suggesting the existence of some other as yet unknown pharmacological property of the beta-adrenoceptor blocking drugs, especially evident in metoprolol. Finally, these results demonstrate that the intrinsic sympathomimetic activity exhibited by some of these drugs attenuate their bradycardiac effect.
Topics: Adrenergic beta-Antagonists; Animals; Atrioventricular Node; Blood Pressure; Dogs; Electrocardiography; Female; Heart Conduction System; Heart Rate; Isoproterenol; Male; Propranolol; Stereoisomerism
PubMed: 2879587
DOI: 10.1111/j.1476-5381.1986.tb11127.x -
British Heart Journal Jul 1980
Clinical Trial Comparative Study
Left ventricular function and beta-blockade in chronic ischaemic heart failure. Double-blind, cross-over study of propranolol and penbutolol using non-invasive techniques.
Topics: Clinical Trials as Topic; Coronary Disease; Digoxin; Double-Blind Method; Heart Failure; Heart Ventricles; Humans; Male; Middle Aged; Penbutolol; Propanolamines; Propranolol
PubMed: 7000099
DOI: 10.1136/hrt.44.1.101 -
British Journal of Clinical Pharmacology 1984The degrees of interactions between the H2-receptor antagonists, cimetidine and ranitidine, and several beta-adrenoceptor blockers were investigated in healthy...
The degrees of interactions between the H2-receptor antagonists, cimetidine and ranitidine, and several beta-adrenoceptor blockers were investigated in healthy volunteers following 7 days of oral monotherapy with penbutolol, propranolol, metoprolol, pindolol and atenolol, and after co-administration with each of the H2-receptor antagonists. The kinetic parameters of unmetabolised penbutolol and penbutolol glucuronide were unaffected, whereas the levels of 4-hydroxypenbutolol and 4-hydroxypenbutolol glucuronide were significantly reduced. Furthermore, cimetidine led to a marked increase in propranolol and metoprolol plasma levels. During co-administration with cimetidine, pindolol plasma levels were only slightly raised, whereas the pharmacokinetics of atenolol were not affected. With regard to pharmacodynamics, the inhibition of exercise-induced tachycardia by each of the beta-adrenoceptor blockers was not affected by cimetidine. Ranitidine did not alter atenolol plasma levels, but did raise the peak plasma concentration of metoprolol by about 30%. It is concluded that cimetidine interactions do occur and can be predicted for substances metabolised by the cytochrome P-450 pathway.
Topics: Adrenergic beta-Antagonists; Atenolol; Cimetidine; Drug Interactions; Histamine H2 Antagonists; Humans; Kinetics; Metoprolol; Penbutolol; Pindolol; Propranolol; Ranitidine
PubMed: 6146340
DOI: 10.1111/j.1365-2125.1984.tb02428.x -
British Journal of Pharmacology Jun 19961. The effects of beta-adrenoceptor antagonists including (-)- and (+)-propranolol, (-)- and (+)-penbutolol, timolol, pindolol, atenolol, acebutolol and practolol on the...
1. The effects of beta-adrenoceptor antagonists including (-)- and (+)-propranolol, (-)- and (+)-penbutolol, timolol, pindolol, atenolol, acebutolol and practolol on the Ca(2+)-overload induced by lysophosphatidylcholine (LPC) were examined in isolated cardiomyocytes of the rat. 2. Fura-2 was used for measurement of the intracellular calcium concentration ([Ca2+]i). LPC (15 microM) produced a rapid increase in [Ca2+]i from 72 +/- 5 to 3042 +/- 431 nM which coincided with a decrease in the percentage of rod-shaped cells from 69 +/- 2 to 5 +/- 2%. 3. Preincubation with (-)-propranolol (20 microM), (+)-propranolol (50 microM), or (-)- or (+)-penbutolol (20 microM), the lipophilicity of which is higher than other beta-adrenoceptor antagonists, significantly inhibited both the increase in [Ca2+]i and the cell-shape change induced by 15 microM LPC. The inhibitory effects of the four drugs on the LPC-induced increase in [Ca2+]i and cell-shape change were concentration-dependent. The IC50S of (-)-propranolol, (+)-propranolol, (-)- and (+)-penbutolol for the increase in [Ca2+]i were 1.28, 10.50, 0.67 and 0.76 microM, respectively. 4. Pretreatment with pindolol, timolol, acebutolol, practolol, atenolol or lignocaine did not inhibit the increase in [Ca2+]i and the morphological change induced by LPC. 5. LPC markedly increased the release of creatine phosphokinase from 9 +/- 1 to 45 +/- 2% which could be significantly reduced by (-)- or (+)-propranolol but not by acebutolol or timolol. 6. The protective effects of (-)- and (+)-propranolol, (-)- and (+)-penbutolol against the Ca(2+)-overload induced by LPC were not associated with the beta-adrenoceptor antagonistic action, but probably with an unknown action which is related to the preservation of membrane integrity. Further studies are necessary to clarify the exact mechanisms of the protective action of these beta-adrenoceptor antagonists against the Ca(2+)-overload induced by LPC.
Topics: Adrenergic beta-Antagonists; Animals; Calcium; Cell Size; Chelating Agents; Creatine Kinase; Fura-2; Heart; Lysophosphatidylcholines; Male; Myocardium; Rats; Rats, Sprague-Dawley
PubMed: 8799555
DOI: 10.1111/j.1476-5381.1996.tb15479.x -
Postgraduate Medical Journal 1983The acute and long-term haemodynamic effects of pindolol, practolol, alprenolol, oxprenolol, acebutolol, penbutolol, metoprolol, atenolol, propranolol and timolol in... (Review)
Review
Haemodynamic consequences of intrinsic sympathomimetic activity in relation to changes in plasma renin activity and noradrenaline during beta-blocker therapy for hypertension.
The acute and long-term haemodynamic effects of pindolol, practolol, alprenolol, oxprenolol, acebutolol, penbutolol, metoprolol, atenolol, propranolol and timolol in patients with uncomplicated hypertension as reported in the literature were analysed. The long-term effects of these beta-adrenoceptor antagonists on plasma renin activity and the concentration of noradrenaline in plasma were also reviewed. In spite of the many pharmacological and physicochemical differences the drugs appeared to have a hypotensive effect of approximately equal magnitude. The degree of cardiodepression and the suppression of plasma renin activity as exerted by the different beta-blockers were inversely correlated with their pharmacologically defined degree of intrinsic sympathomimetic activity (ISA). The increments in vascular resistance acutely after administration of a beta-blocker are proportional to the degree of cardiodepression, suggesting that increased vasoconstrictor nerve activity mediated through the baroreflex had prevented an acute fall in arterial pressure in response to a given fall in cardiac output. After long-term therapy the inverse correlation between changes in cardiac output and changes in vascular resistance is shifted to a lower level of vascular resistance. Plasma renin activity and vascular resistance are inversely correlated during long-term beta-blocker therapy for hypertension. Consequently, the fall in vascular resistance underlying the hypotensive effect of beta-blockers cannot be explained by suppression of plasma renin activity. Thus, cardiodepression and renin suppression are not essential for the hypotensive effect of beta-adrenoceptor antagonists. The accessibility of the central nervous system to the different beta-blockers neither determines the time of onset of blood pressure reduction nor the magnitude of this effect. If it is neither the blockade of postsynaptic beta-adrenoceptors in the heart or on juxtaglomerular cells, nor the blockade of central beta-receptors that can be held responsible for the blood pressure lowering efficacy of beta-adrenoceptor antagonists, one is left with the remaining possibility that blockade of presynaptic beta-receptors underlies the vasodilator and antihypertensive action of these drugs. Changes in the concentrations of noradrenaline in plasma are compatible with this supposition, provided that changes in clearance of noradrenaline from plasma are taken into account.
Topics: Adrenergic beta-Antagonists; Blood Pressure; Cardiac Output; Heart Rate; Humans; Hypertension; Norepinephrine; Renin; Vascular Resistance
PubMed: 6139800
DOI: No ID Found -
British Journal of Clinical Pharmacology 1984There is evidence, from human and animal studies, that drug-metabolising enzymes exist in multiple forms, the individual enzymes having selective, but not specific,...
There is evidence, from human and animal studies, that drug-metabolising enzymes exist in multiple forms, the individual enzymes having selective, but not specific, substrate requirements. Consequently drug interactions may arise when two drugs bind to the same enzyme. The degree of enzyme inhibition will be partly dependent on the relative affinities of the drugs for the enzyme and on their rates of turnover. The decrease in drug clearance produced by enzyme inhibition is dependent on the fraction of the drug normally metabolised by the inhibited pathway(s). Cimetidine, a P-450 enzyme inhibitor, increases the systemic bioavailability of propranolol and labetalol, which undergo extensive metabolism, but does not affect the clearance of atenolol, which is excreted largely unchanged. In this situation, both the extent and type of biotransformation are important. Thus, cimetidine has no effect on the clearance of penbutolol, even though the drug is eliminated almost entirely by biotransformation. The major metabolite is penbutolol glucuronide, and it has been shown recently that cimetidine does not inhibit glucuronylation. Beta-adrenoceptor blockers also act as enzyme inhibitors themselves. For example, antipyrine clearance is decreased by propranolol and to a lesser extent by metoprolol, whereas atenolol has no effect. It has been suggested, therefore, that there is a relationship between the lipid-solubility of beta-adrenoceptor blockers and their ability to inhibit drug metabolism. The clearance of lipophilic beta-adrenoceptor blockers is dependent on hepatic enzyme activity, and is therefore sensitive to enzyme induction. For drugs with high hepatic clearance and subsequent high presystemic elimination, a moderate increase in the extraction ratio will produce a marked decrease in systemic bioavailability. (ABSTRACT TRUNCATED AT 250 WORDS)
Topics: Adrenergic beta-Antagonists; Animals; Drug Interactions; Enzyme Induction; Enzyme Inhibitors; Humans; Kidney; Kinetics; Liver; Mixed Function Oxygenases
PubMed: 6146338
DOI: 10.1111/j.1365-2125.1984.tb02422.x -
British Journal of Clinical Pharmacology Aug 19811 The hypotensive effect of single daily dosing with 80 mg penbutolol was compared to 100 mg hydrochlorothiazide and placebo in a double-blind cross-over controlled... (Clinical Trial)
Clinical Trial Comparative Study Randomized Controlled Trial
1 The hypotensive effect of single daily dosing with 80 mg penbutolol was compared to 100 mg hydrochlorothiazide and placebo in a double-blind cross-over controlled trial with daily home measurements in ten hypertensive patients. 2 Penbutolol, 80 mg once a day, reduced significantly the supine and standing blood pressure. 3 This hypotensive effect was more potent than hydrochlorothiazide 100 mg particularly in the evening. 4 The hypotensive effect remained for 24 h as shown by the evening (14 h after dose) and morning (24 h after dose) blood pressure readings. 5 No relevant subjective or physical side effects were recorded. There was no significant change nor individual noticeable variation in biochemical data during penbutolol treatment. However, during hydrochlorothiazide treatment, the expected electrolyte changes were observed (symptom-free hypokalemia and hyperuricemia). 6 Penbutolol serum concentration showed no cumulation after one month of treatment. 7 Sudden withdrawal of penbutolol after 1 month of therapy resulted in a slow return to baseline blood pressures over a 2-week period without rebound.
Topics: Blood Pressure; Clinical Trials as Topic; Double-Blind Method; Humans; Hydrochlorothiazide; Hypertension; Middle Aged; Penbutolol; Propanolamines; Renin; Substance Withdrawal Syndrome
PubMed: 7030372
DOI: 10.1111/j.1365-2125.1981.tb01203.x -
British Journal of Clinical Pharmacology Oct 1986Penbutolol and propranolol were administered orally in a dosage of 40 mg once daily and 80 mg twice daily, respectively to 12 patients with hypertension and impaired... (Clinical Trial)
Clinical Trial Comparative Study Randomized Controlled Trial
Penbutolol and propranolol were administered orally in a dosage of 40 mg once daily and 80 mg twice daily, respectively to 12 patients with hypertension and impaired renal function. Both drugs caused a significant decrease in mean arterial pressure and heart rate. Serum creatinine concentration increased significantly by 10% during therapy with propranolol without concomitant decrease in creatinine clearance. No such effect was seen with penbutolol. GFR measured with [125I]-iothalamate showed no significant changes with both drugs.
Topics: Blood Pressure; Clinical Trials as Topic; Creatinine; Double-Blind Method; Glomerular Filtration Rate; Humans; Hypertension; Kidney Failure, Chronic; Penbutolol; Propanolamines; Propranolol; Random Allocation
PubMed: 3533129
DOI: 10.1111/j.1365-2125.1986.tb02919.x -
British Journal of Clinical Pharmacology May 1985The effects of two beta-adrenoceptor antagonists, penbutolol (administered on separate occasions as (+/-)- and (-)-forms) and propranolol, on the kinetics of antipyrine... (Comparative Study)
Comparative Study
The effects of two beta-adrenoceptor antagonists, penbutolol (administered on separate occasions as (+/-)- and (-)-forms) and propranolol, on the kinetics of antipyrine were studied in eight normal subjects. At the same degree of beta-adrenoceptor blockade, as assessed by the lowering of exercise tachycardia, propranolol decreased antipyrine clearance by 31 +/- 11 s.d.% (P less than 0.001) whereas neither of the two penbutolol formulations had a significant effect. The volume of distribution of antipyrine was unchanged following any of the beta-adrenoceptor antagonist treatments. The lack of effect of penbutolol on oxidative drug metabolism is not consistent with in vitro data suggesting a relationship between the lipid solubility of beta-adrenoceptor antagonists and inhibition of metabolism.
Topics: Adult; Antipyrine; Half-Life; Heart Rate; Humans; Kinetics; Male; Penbutolol; Physical Exertion; Propanolamines; Propranolol; Saliva; Stereoisomerism
PubMed: 4005101
DOI: 10.1111/j.1365-2125.1985.tb02685.x -
European Review For Medical and... Dec 2012Asthma is a disease resulting from a complex interaction of multiple genetic and environmental factors. More than 200 asthma candidate genes have been identified in the...
BACKGROUND
Asthma is a disease resulting from a complex interaction of multiple genetic and environmental factors. More than 200 asthma candidate genes have been identified in the past decades by using genetic association studies, positional cloning and knockout mouse approaches.
AIM
This study was to identify differentially expressed genes and provide direction for medicine design related to pediatric allergic asthma with DNA microarray.
MATERIALS AND METHODS
The gene expression profile of pediatric allergic asthma GSE18965 was downloaded from Gene Expression Omnibus database which includes 16 samples, 7 normal and 9 pediatric allergic asthma samples. The differentially expressed genes between normal and disease samples were identified by using R language. The co-expression coefficient was calculated among the differentially expressed genes to construct co-expression networks with String Software. Software DAVID and FuncAssociate were used to analyze the functions of genes in the co-expression networks.
RESULTS
A total of 133 genes were identified as differentially expressed genes between normal and disease samples, and 8 related small medicine molecules were also obtained (penbutolol, felbinac, iodixanol, josamycin, oxolamine, 3-nitropropionic acid, scriptaid, and sanguinarine) from database CMAP. The differentially expressed genes were enriched in several biological processes, in which viral transcription and lysosome were the most significant GO term of up- or down-regulated genes.
CONCLUSIONS
Our present findings shed new light on the molecular mechanism of allergic asthma and provide three small molecular medicines (3-nitropropionic acid, scriptaid, and sanguinarine) which have the potential to use in clinic for treatment of allergic asthma in future.
Topics: Anti-Allergic Agents; Anti-Asthmatic Agents; Asthma; Case-Control Studies; Databases, Genetic; Drug Discovery; Gene Expression Profiling; Gene Expression Regulation; Gene Regulatory Networks; Humans; Hypersensitivity; Molecular Targeted Therapy; Oligonucleotide Array Sequence Analysis
PubMed: 23242723
DOI: No ID Found