Value Of Propranolol Research Articles

Clinical value of propranolol combined with oxaliplatin and tigio in concurrent chemoradiotherapy for locally advanced gastric cancer

Objectives:To investigate the clinical value of propranolol combined with oxaliplatin and tigio in concurrent chemoradiotherapy for locally advanced gastric cancer.Methods:A total of 74 patients with locally advanced gastric cancer admitted to the First Affiliated Hospital of Hainan Medical University from August 2018 to June 2020 were selected as the subject and divided into two groups by random number table method: Group-A and Group-B, with 37 cases in each group. Patients in Group-A were treated with oxaliplatin injection and oral administration of tigio combined with concurrent radiotherapy, while patients in Group-B were given propranolol on the basis of treatment in Group-A. The clinical efficacy and incidence of adverse reactions in the two groups were observed.Results:The response rate (RR) of Group-B was higher than that of Group-A, but with no statistically significant difference (P>0.05). No statistical difference was observed in the incidence of gastrointestinal reaction, bone marrow suppression, oral mucositis, and the incidence of grade III-IV adverse reactions in the two groups (P>0.05). There were no serious adverse reactions related to propranolol in Group-B, and the levels of tumor markers CEA, CA50, CA125, and CA242 in Group-B were lower than those in Group-A.Conclusion:Propranolol combined with oxaliplatin and tigio boasts satisfactory sensitization safety in radiotherapy for gastric cancer, but its sensitization effect needs to be further investigated in a multi-center study involving large sample size.

Oral Propranolol: A Useful Treatment for Infantile Hemangioma

Background: Infantile haemangioma is the commonest childhood tumor. Several lines of treatment are available. Recent reports have focused on the value of propranolol in treating rapidly proliferating haemangioma. The aim of this study was to assess oral propranolol in treatment for facial haemangioma. Patients and Methods: Fifteen patients with rapidly proliferating infantile facial haemangioma with cosmetic disfigurement were treated with oral propranolol. All patients had cardiovascular pre-treatment work-up and commenced on oral propranolol at 3 mg/kg/day. Results: A rapid decrease in hemangioma proliferation was seen in 100% of patients and significant regressions occuring in all patients. This treatment was well tolerated and had little side effects. Conclusions: Oral propranolol is a reliable and easily reproducible method for treatment of facial hemangioma.

PROPRANOLOL INDUCED CHROMOSOMAL ABERRATIONS IN CHINESE HAMSTER OVARY CELL LINE

Propranolol (PL), a non-selective beta-blocker, is a cardiovascular drug widely used to treat hypertension. The present study was concerned with assessing the cytogenetic effects of this drug on Chinese hamster ovary (CHO) cell line. MTT assay was then carried out to determine the cytotoxicity index (IC50) of the drug. The IC50 value of PL was 0.43±0.02 mM. To investigate the clastogenic effects of the drug, chromatid and chromosome breaks and polyploidy in metaphases were analyzed. CHO cells were exposed to different concentrations of the drug (0.1, 0.2, 0.3, 0.4 mM) for 24 hours. Considering that PL has liver metabolism, experiments were carried out in the presence and absence of the metabolic activation system (S9 mix). Mitomycin-C and sodium arsenite were used as positive controls. It was observed that in cells treated with different PL concentrations as 0.1, 0.2 and 0.3 mM, the frequency of chromatid and chromosome breaks as well as polyploidy increased when compared with untreated CHO cells. The addition of S9 mix significantly decreased the chromatid breaks, chromosome breaks and polyploidy compared to the treatment of PL alone. It is concluded that, PL causes chromatid and chromosome aberrations in CHO cell line and the metabolic activation system (S9 mix), playing an important role in drug cytotoxicity reduction.

Heterologous expression of CYP102A5 variant from Bacillus cereus CYPPB-1: Validation of model for predicting drug metabolism of human P450 probe substrates

CYP102A5 variant (ADL27534) from isolated Bacillus cereus CYPPB-1 was heterologously expressed in Escherichia coli Top 10 cells. Comparative sequence analysis of purified CYP102A5 variant with respect to reported CYP102A5 (AAP10153) from Bacillus cereus ATCC 14579 revealed amino acid sequence changes at positions P245S and M318I of heme domain. The binding affinities of 15 selected human P450 probe substrates towards isolated CYP102A5 were analyzed in silico using a homology model together with molecular docking techniques to predict the human drug metabolism. In vitro analysis suggested that the purified CYP102A5 metabolizes typical substrates of human CYP2C9, CYP2D6, CYP2E1, and CYP3A4, such as coumarin, propranolol, aniline, chlorzoxazone, p-nitrophenol, and nifedipine. The calculated K M values for propranolol, chloroxazone, coumarin, aniline, and 4-nitrophenol were calculated to be 0.962 ± 0.041, 1.254 ± 0.057, 2.859 ± 0.083, 2.732 ± 0.106, and 2.528 ± 0.11mM, respectively. Importantly, taking a ChemScore cutoff value of -31kJ/mol, substrate binding at active site and in vitro activity as the distinguishing lines between "substrates" and "nonsubstrates" revealed one false-positive and one false-negative results out of the 15 compounds examined. This is the first report on validation of CYP102A family homology model for in silico prediction of human drug metabolism.

Construction of adrenergic receptor subtype affinity chromatographic models for detection of ligand–receptor interactions

Adrenergic receptors (ARs) are members of the super family of G protein-coupled receptors (GPCRs). A large number of small molecular drugs performed their actions on ARs. In this study, two subtypes of ARs affinity chromatographic models have been constructed for investigating the interactions between small molecular compounds and the α- and β-AR subtypes. The α-ARs were obtained from HEK 293 cells stably transfected human α-ARs on the membrane and the β-ARs were obtained from lung tissues of rabbits. ARs were purified and immobilized on the surface of macro-pore silica gel by covalent bonds. Then the gel was packed into a stainless steel column (4.6 × 50 mm). Binding abilities between small molecules and immobilized ARs were determined by on-line chromatographic technologies. Preliminary on-line binding studies employing frontal chromatographic techniques were conducted with the known α-AR agonist (norepinephrine, NE) and β-AR antagonist (propranolo). Calculated association constants (Ka) and binding sites (mLtot) values for NE on immobilized α-AR were 0.9 × 104 L mol−1 and 5.5 × 10−7 mol L−1, and on immobilized β-AR were 0.2 × 104 L mol−1 and 3.3 × 10−7 mol L−1, respectively. Ka and mLtot values for propranolol on immobilized α-AR were 1.1 × 103 L mol−1 and 1.0 × 10−7 mol L−1, and on immobilized β-AR were 2.5 × 104 L mol−1 and 5.0 × 10−7 mol L−1, respectively. Above association values were obviously different, but the changes of their laws were comparatively unanimous: there was stronger binding between small molecular compounds and their immobilized target ARs. The conclusions indicated that the immobilized ARs stationary phases can be used to assess the binding affinities of compounds and screen possible active compounds qualitatively. In addition, this study represented an example of using immobilized subtype ARs in a chromatographic system.

Adrenoceptive receptors in the duodenum, aorta and atria of the rabbit.

Abstract pA10 values for the α-receptor blocking drug phentolamine against adrenaline, noradrenaline and phenylephrine were determined in rabbit aorta and duodenum, and for the β-receptor blocking drug propranolol, against adrenaline, noradrenaline and isoprenaline in rabbit atria and duodenum. The values for phentolamine against different amines were found to be similar, varying by less than half a log unit, between or within the tissues, as were the values for propranolol. These data provide quantitative evidence that α-receptors in the aorta and duodenum are similar, as are the β-receptors in the atria and duodenum, even though both types of receptor serve divergent functions in different tissues.

Absorption and transportation characteristic of alkaloids from Herba Ephedrae in model of Caco-2 cells monolayer

To study the absorption and transportation characteristic of 1-ephedrine (LEP), d-pseudoephedrine (DPEP), d-norpseudoephedrine (DNPE) isolated from Herba Ephedrae, which were classified the alkaloids, in human intestinal epithelium. Caco-2 (the human colon adeno carcinoma cell lines) cells monolayer was used as an intestinal epithelial cell model. The permeability of the three alkaloids from apical side (AP side) to basolateral side (BL side) or from BL side to AP side was evaluated. The concentration of the three alkaloids was measured by HPLC coupled with UV detector. Transportation parameters and apparent permeability coefficients (P(app)) were then calculated, and P(app) values were compared with the reported values for model compounds, propranolol and atenolol. The P(app) values of the three alkaloids in the bi-directional transportation were quantitative degree of 1.0 x 10(-5) cm x s(-1), which was comparable with the P(app), value of propranolol, which is a transcellular transportation marker and a well-transported compound with a P(app) > or = 1.0 x 10(-5) cm x s(-1). The absorption and transportation of the three alkaloids were positive correlation to the concentration of 10-200 mol x L(-1). LEP, DPEP and DNPE can be absorbed across intestinal epithelial cells by passive diffusion mechanism, and are well absorbed compounds.

Absorption and transport of 6 coumarins isolated from the roots of Angelica pubescens f. biserrata in human Caco-2 cell monolayer model

To study the absorption and transepithelial transport of six coumarins (umbelliferone, osthole, columbianadin, columbianetin acetate, angelol-A and angelol-B, isolated from the roots of Angelica pubescens f. biserrata) in the human Caco-2 cell monolayer model. The in vitro cultured human colon carcinoma cell line, Caco-2 cell monolayer model, was applied to study the absorption and transport of the six coumarins from apical (AP) to basolateral (BL) side and from BL to AP side. The six coumarins were measured by reversed-phase high-performance liquid chromatography (HPLC) coupled with ultraviolet absorption detector. Transport parameters and apparent permeability coefficients (P(app)) were calculated and compared with those of propranolol as a control substance of high permeability and atenolol as a control substance of poor permeability. The transport mechanism of angelol-B was assayed by using iodoacetamide as a reference standard to inhibit ATP-dependent transport and MK571 as a well-known inhibitor of MRP2. The absorption and transport of six coumarins were passive diffusion as the dominating process. The P(app) values of umbelliferone, osthole, columbianadin, columbianetin acetate, angelol-A and angelol-B from AP to BL side were (2.679+/-0.263) x 10(-5), (1.306+/-0.324) x 10(-5), (0.595+/-0.086) x 10(-6), (2.930+/-0.410) x 10(-6), (1.532+/-0.444) x 10(-5) and (1.413+/-0.243) x 10(-5) cm/s, and from BL to AP side were (3.381+/-0.410) x 10(-5), (0.898+/-0.134) x 10(-5), (0.510+/-0.183) x 10(-6), (0.222+/-0.025) x 10(-6), (1.203+/-0.280) x 10(-5) and (0.754+/-0.092) x 10(-5) cm/s, respectively. In this assay, the P(app) value of propranolol was 2.18 x 10(-5) cm/s and the P(app) value of atenolol was 2.77 x 10(-7) cm/s. Among the 6 coumarins, the P(app) values of umbelliferone, osthole, angelol-A and angelol-B from AP to BL side were identical with that of propranolol, and columbianadin and columbianetin acetate lied between propranolol and atenolol. When replaced the HBSS with EBSS, and iodoacetamide or MK-591 were used in the experiment, the P(app) of angelol-B had no statistical difference as compared with the control group. In the mean total recoveries, umbelliferone was (83.31+/-3.52)%, angelol-A was (77.39+/-7.38)%, osthole, columbianadin and angelol-B were between 50% to 65%, and columbianetin acetate was lower than 10%. The accumulation rates of osthole and columbianadin in the Caco-2 cells were (36.15+/-5.87)% and (53.90+/-4.39)%, respectively. The absorption and transport of umbelliferone, osthole, columbianadin, columbianetin acetate, angelol-A and angelol-B are passive diffusion as the dominating process in Caco-2 cell monolayer model. Umbelliferone, osthole, angelol-A and angelol-B are estimated to be highly absorbed compounds, and columbianadin and columbianetin acetate are estimated to be moderately absorbed compounds. In the Caco-2 cells, osthol and columbianadin appear to accumulate, and columbianetin acetate may be metabolized. The absorption and transport of angelol-B are not influenced by the change of pH and the presence of iodoacetamide or MK571.

Evidence for a plasma membrane-mediated permeability barrier to Tat basic domain in well-differentiated epithelial cells: lack of correlation with heparan sulfate.

Membrane permeation peptides, such as Tat basic domain, have emerged as useful membrane transduction agents with potential utility in therapeutic delivery and diagnostic imaging. While generally thought to universally permeate all cells by a nonselective process, the mechanism of membrane transduction remains poorly characterized. To examine vectorial transport properties of Tat basic domain in well-differentiated epithelial cells possessing tight junctions, L and D stereoisomers of Tat(48-57) peptide conjugates labeled with (99m)Tc were quantitatively analyzed in confluent monolayers of MDCK renal epithelial and CaCo-2 colonic carcinoma cells grown in transwell configurations. In both cell lines, vectorial transepithelial apparent permeability coefficients (P(app)) for L- and D-[(99m)Tc]Tat-peptides ranged from 30 to 70 nm/s, comparable to values for the macromolecular impermeant marker inulin in both apical-to-basolateral and basolateral-to-apical directions, but 100-fold less than the P(app) values for propranolol, a highly permeable control compound. Upon direct instillation of [(99m)Tc]Tat-peptide into the urinary bladder of living rats in vivo, no transepithelial permeation into other tissues was identified. Furthermore, MDCK and CaCo-2 cells showed a complete lack of intracellular accumulation of fluorescein conjugated Tat-peptide. However, translocation into cells was induced by treatment with plasma membrane permeabilizing agents such as digitonin and acetone/methanol, while cholesterol depletion with beta-methyl-cyclodextrin and metabolic inhibition with CCCP or 4 degrees C showed no effect. By contrast, in Hela and KB 3-1 cells, epithelial lines that do not form tight junctions in monolayer culture, baseline cytoplasmic and nucleolar accumulation was readily observed. Because all four cell lines expressed heparan sulfate proteoglycans, putative receptors for Tat basic peptides, we found no correlation between heparan sulfate and the permeation barrier observed in MDCK and CaCo-2 cells. The unanticipated presence of a permeation barrier to Tat-peptides in well-differentiated epithelial cells suggests the existence of cell-specific mechanisms for mediated translocation of these permeation peptides.

Relaxant responses by optical isomers of ephedrine and methylephedrine in guinea pig tracheal smooth muscle.

The effects of optical isomers of ephedrine and methylephedrine on the guinea pig tracheal smooth muscle were studied. l-Ephedrine markedly caused a graded relaxation of the guinea pig trachea where the tone had been raised spontaneously. A rightward shift of the l-ephedrine concentration-response curve was observed for propranolol and butoxamine, and the pA2 values for propranolol and butoxamine were 8.55 and 6.38, respectively. d-Methylephedrine markedly caused a graded relaxation of the guinea pig trachea contracted with histamine. Propranolol and bupranolol did not affect the relaxant response to d-methylephedrine. d-Methylephedrine competitively antagonized the contractile responses to histamine, and the pA2 value for d-methylephedrine was 5.12. These results suggest that l-ephedrine-induced relaxation of the guinea pig trachea is mediated through beta 2-adrenoceptors, whereas d-methylephedrine relaxes the guinea pig trachea by blocking histamine receptors.

Enhancement by Fatty Acids of the Rectal Absorption of Propranolol: In Vitro Evaluation in the Rat.

The effects of a series of fatty acids on the rectal absorption of propranolol (PL) were examined in vitro, using macrogol 1500 base and rat rectal tissue. Lauric acid, at a fatty acid: PL molar ratio of 1:1, produced the largest increase in permeation rate (Js), penetration coefficient and partition coefficient of PL. PL flux was increased 2.5-fold in the presence of lauric acid compared to that without the fatty acid. However, the Js value of PL was decreased at increased molar ratios (e.g., 3:1) of lauric acid. The permeation rate of lauric acid across the rectal membrane was much larger than that of PL. Furthermore, the apparent partition coefficient of PL in an n-octanol/buffer system was significantly increased at a 1:1 molar ratio to lauric acid compared with that of PL alone. These results suggest that a complex-mediated mechanism facilitates PL transport, thereby partially contributing to the enhancement of PL rectal absorption. A similar mechanism is applicable to percutaneous drug absorption, as reported previously. Thus, a portion of PL, after first forming a complex with fatty acids, may rapidly permeate across rectal membranes.

Quantitative pharmacological characterization of beta-receptors and two types of alpha-receptors mediating sympathomimetic smooth muscle response in the human Fallopian tube at various cyclic stages.

The dissociation constants for adrenoceptor-antagonist complexes (KB) were determined in vitro in circular and longitudinal smooth musculature from the ampullary and isthmic regions of the human Fallopian tube. High extracellular potassium concentrations were used to eliminate the spontaneous contractile activity. Neuronal and extraneuronal amine uptake mechanisms were blocked. The parallel shift of the log dose-response curves was secured in Arunlakshana-Schild plots. KB for the beta-receptor, mediating sympathomimetic relaxation, were determined during alpha-receptor blockade: the values for propranolol were the same (approximately 10(-6) M) in all preparations and at all cyclic stages, as determined from plasma estradiol and progesterone levels. KB for the complex between the alpha-receptor (mediating contraction) and phentolamine were determined during beta-receptor blockade. The values were the same in all types of smooth musculature, but varied with cyclic stage: they were around 7 x 10(-8) M when plasma estradiol and progesterone were both minimum, and around 2 x 10(-7) M when these steroid levels were moderate to high, suggesting that the properties of the contractile receptors of the human Fallopian tube are modified during the menstrual cycle.

The use of guinea pig K +-depolarized tracheal chain preparations in β-adrenoceptor studies

Guinea pig tracheal chain preparations were K +-depolarized using Krebs solution in which all the Na + was replaced by an equivalent amount of K +. This caused a sustained contraction of the preparations. Reproducible concentration-response (relaxation) curves to isoprenaline could be obtained provided that the preparations were repolarized by washing in normal Krebs solution between curves. pA 2 values for propranolol (8.30) and butoxamine (5.89) were in good agreement with values obtained on other types of tracheal preparation. The maximum relaxation to salbutamol was less than that to isoprenaline and the maxima to both drugs were less than the maximum relaxation of the tissue (to papaverine). It is suggested that K +-depolarized tracheal preparations have no β-adrenoceptor reserve and may, therefore, be useful in studies designed to compare the efficacies of β-adrenoceptor agonists.

Use of beta-adrenergic receptor blocking drugs in psychiatry.

On the evidence surveyed it is difficult to reach clear-cut conclusions about the value of propranolol or other β-blocking drugs in psychiatry. Studies on anxiety for the most part have been of relatively short duration and, although some workers have claimed benefits for propranolol administration, more recent and better controlled trials have failed to demonstrate advantages over placebo treatment. The possibility remains that control of the autonomic symptoms associated with anxiety to some degree diminishes the patient’s distress in the face of an unpleasant affect. Hence there may be merit in the opinion that the autonomic symptoms appear to act as signals which are interpreted as warnings of impending danger. Such activation in its turn results in the psychological experience of anxiety. Hence, in this group of patients at least, control of the autonomie 1 See subject index in each issue for further indexing terms. symptoms should minimise the extent to which anxiety, as a psychological disturbance, is felt. In other forms of psychiatric disorder, the evidence is less convincing. There is no reason to believe that patients with chronic psychoses will benefit and the effects of propranolol in the treatment of alcoholism appear to be short-lived, although longer trials are clearly warranted. The finding that the drug appears to block the actions of opiates is of considerable interest and one can but hope that more extensive testing of propranolol with narcotic-dependent patients will be carried out. In healthy subjects, propranolol appears to be a relatively safe drug, but its use for the control of hypertension and cardiac symptoms in patients who have experienced former depressive illnesses should probably be strictly limited. Transitory hallucinosis and toxic confusional states have been recorded. They appear to be dose-related and subside when the drug is withdrawn. There appears to be a use for propranolol in the treatment of. lithium-induced tremor and overdosage with tricyclic antidepressants.

The action of practolol and propranolol on the rabbit isolated atrium

The mechanism of β-receptor antagonism by propranolol and practolol was investigated on rabbit isolated atrium preparations. Both drugs produced a parallel shift in the log. dose-response curve of isoprenaline without a decrease in the maximal response, suggesting that the antagonism was competitive. The pA 2 values for propranolol and practolol were 8.36±0.07 and 6.58±0.04 respectively. These results are discussed.