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Acta Poloniae Pharmaceutica 2000The kinetics of hydrolysis of octanoyl ester of oxprenolol (O-OXP) and benzoyl ester of oxprenolol (Benz-OXP) has been investigated in aqueous solution at 310 K over the...
The kinetics of hydrolysis of octanoyl ester of oxprenolol (O-OXP) and benzoyl ester of oxprenolol (Benz-OXP) has been investigated in aqueous solution at 310 K over the pH range 0.42-9.5. The decomposition was followed by UV spectral method. At the pH range 0.42 to 9.5, hydrolysis of oxprenolol esters (E-OXP) consists of hydrolysis of BH+ molecules catalyzed by hydrogen ions, spontaneous hydrolysis of BH+ molecules and hydrolysis of BH+ and B molecules catalyzed by hydroxide ions. Various buffer substances were found to exhibit general acid and base catalysis of the degradation.
Topics: Adrenergic beta-Antagonists; Chemical Phenomena; Chemistry, Physical; Colorimetry; Hydrogen-Ion Concentration; Hydrolysis; Kinetics; Magnetic Resonance Spectroscopy; Oxprenolol; Spectrophotometry, Infrared; Spectrophotometry, Ultraviolet
PubMed: 10846796
DOI: No ID Found -
CMAJ : Canadian Medical Association... Nov 1997To provide Canadian physicians with evidence-based guidelines for the pharmacologic treatment of hypertensive disorders in pregnancy. (Review)
Review
OBJECTIVE
To provide Canadian physicians with evidence-based guidelines for the pharmacologic treatment of hypertensive disorders in pregnancy.
OPTIONS
No medication, or treatment with antihypertensive or anticonvulsant drugs.
OUTCOMES
Prevention of maternal complications, and prevention of perinatal complications and death.
EVIDENCE
Pertinent articles published from 1962 to September 1996 retrieved from the Pregnancy and Childbirth Module of the Cochrane Database of Systematic Reviews and from MEDLINE; additional articles retrieved through a manual search of bibliographies; and expert opinion. Recommendations were graded according to levels of evidence.
VALUES
Maternal and fetal well-being were equally valued, with the belief that treatment side effects should be minimized.
BENEFITS, HARMS AND COSTS
Reduction in the rate of adverse perinatal outcomes, including death. Potential side effects of antihypertensive drugs include placental hypoperfusion, intrauterine growth retardation and long-term effects on the infant.
RECOMMENDATIONS
A systolic blood pressure greater than 169 mm Hg or a diastolic pressure greater than 109 mm Hg in a pregnant woman should be considered an emergency and pharmacologic treatment with hydralazine, labetalol or nifedipine started. Otherwise, the thresholds at which to start antihypertensive treatment are a systolic pressure of 140 mm Hg or a diastolic pressure of 90 mm Hg in women with gestational hypertension without proteinuria or pre-existing hypertension before 28 weeks' gestation, those with gestational hypertension and proteinuria or symptoms at any time during the pregnancy, those with pre-existing hypertension and underlying conditions or target-organ damage, and those with pre-existing hypertension and superimposed gestational hypertension. The thresholds in other circumstances are a systolic pressure of 150 mm Hg or a diastolic pressure of 95 mm Hg. For nonsevere hypertension, methyldopa is the first-line drug; labetalol, pindolol, oxprenolol and nifedipine are second-line drugs. Fetal distress attributed to placental hypoperfusion is rare, and long-term effects on the infant are unknown. Magnesium sulfate is recommended for the prevention and treatment of seizures.
VALIDATION
The guidelines are more precise but compatible with those from the US and Australia.
Topics: Antihypertensive Agents; Blood Pressure; Canada; Diastole; Evidence-Based Medicine; Female; Humans; Hypertension; Pregnancy; Pregnancy Complications, Cardiovascular; Pregnancy Outcome; Severity of Illness Index; Systole; Treatment Outcome
PubMed: 9361646
DOI: No ID Found -
The Journal of Clinical Investigation Sep 1997Interleukin 12 (IL-12) plays a central role in the immune system by skewing the immune response towards T helper 1 (Th1) type responses which are characterized by high...
Interleukin 12 (IL-12) plays a central role in the immune system by skewing the immune response towards T helper 1 (Th1) type responses which are characterized by high interferon-gamma and low IL-4 production. In this report we present evidence that beta2-agonists inhibit IL-12 production by both human monocytes in response to lipopolysaccharide (LPS) and dendritic cells stimulated via CD40. Inhibition of IL-12 production is selective, as other cytokines produced by monocytes are unaffected. IL-12 inhibition is dependent on beta2-adrenoceptor stimulation and correlates with increased levels of intracellular cAMP. In conjunction with their ability to suppress IL-12 production, when beta2-agonists are added at priming of neonatal T lymphocytes, they inhibit the development of Th1-type cells, while promoting T helper 2 (Th2) cell differentiation. Further, the in vivo administration of a therapeutic dose of salbutamol results in the selective inhibition of IL-12 production by whole blood lymphocytes stimulated in vitro with LPS. These findings provide new insight into the immunological consequences of the clinical use of beta2-agonists and may suggest new approaches for the treatment of Th1-mediated diseases.
Topics: Adrenergic beta-2 Receptor Agonists; Adrenergic beta-2 Receptor Antagonists; Adult; Albuterol; Bucladesine; Cell Differentiation; Colforsin; Cyclic AMP; Dendritic Cells; Dose-Response Relationship, Drug; Humans; Interferon-gamma; Interleukin-1; Interleukin-10; Interleukin-12; Interleukin-6; Lipopolysaccharides; Macrophages; Oxprenolol; RNA, Messenger; Th1 Cells; Th2 Cells; Tumor Necrosis Factor-alpha
PubMed: 9294119
DOI: 10.1172/JCI119674 -
Clinical and Experimental Immunology Mar 1995Elevation of intracellular cAMP levels has been shown previously to inhibit cytokine secretion by various cell types in vitro. Since salmeterol is a beta 2-agonist which...
Elevation of intracellular cAMP levels has been shown previously to inhibit cytokine secretion by various cell types in vitro. Since salmeterol is a beta 2-agonist which activates adenylate cyclase, its ability to inhibit cytokine production was evaluated. Though salmeterol, and the related drug albuterol, did not inhibit IL-1 beta production in vitro, both drugs did inhibit tumour necrosis factor-alpha (TNF-alpha) secretion by lipopolysaccharide (LPS)-activated THP-1 cells with similar IC50s of approximately 0.1 microM. This inhibition was effectively reversed by the beta 2-antagonist oxprenolol, indicating that the inhibition was mediated through the beta 2-adrenergic receptor. A strikingly different reactivity profile was seen with T cells. Salmeterol was able to inhibit the activation of both mouse and human T cells, as measured by proliferation and IL-2 secretion in response to anti-CD3 antibody, whereas albuterol was completely inactive in these assays. This T cell inhibition by salmeterol was about 10-fold less potent than that for TNF-alpha production, and was not reversed by a beta 2-antagonist, indicating that a different mechanism was involved in the effect of salmeterol on T cells. Paralleling the TNF-alpha inhibitory activity in vitro, oral dosing of salmeterol and albuterol inhibited LPS-induced increase in murine serum TNF level in vivo, with ED50s of approximately 0.1 mg/kg. This inhibition could be abrogated by dosing orally with the beta-blocker propranolol. The long-acting pharmacological profile of salmeterol was apparent in that it maintained its efficacy for 3 h, while albuterol had a much shorter duration of action. Salmeterol also had some protective effects in the galactosamine/LPS model of endotoxic shock, which is dependent upon TNF-alpha production. Though salmeterol inhibited serum TNF-alpha levels by up to 94% in this assay, it protected less than 50% of the animals from the lethal effects of the LPS/galactosamine mixture. This observation suggests that functional levels of TNF-alpha localized in tissues may not be accurately reflected by serum levels.
Topics: Adrenergic beta-Agonists; Albuterol; Animals; Cytokines; Female; Galactosamine; Lipopolysaccharides; Lymphocyte Activation; Mice; Mice, Inbred C3H; Mice, Inbred C57BL; Salmeterol Xinafoate; Shock, Septic; T-Lymphocytes; Tumor Necrosis Factor-alpha
PubMed: 7882570
DOI: 10.1111/j.1365-2249.1995.tb05573.x -
British Journal of Pharmacology Dec 19921. The outward K+ current induced by KRN2391 (K+ channel opener) in Xenopus oocytes is blocked by glibenclamide. We have investigated the effects of various classes...
1. The outward K+ current induced by KRN2391 (K+ channel opener) in Xenopus oocytes is blocked by glibenclamide. We have investigated the effects of various classes (I-IV) of antiarrhythmic drugs on this KRN2391-induced response. 2. All class I antiarrhythmic drugs (Na+ channel blockers) tested concentration-dependently suppressed KRN2391-induced responses with the rank order of potency (IC50 in microM), disopyramide (17.8) > aprindine (29.5) > propafenone (63.1) > ajmaline (145) > quinidine (151). Flecainide, SUN1165, lignocaine, mexiletine and procainamide were much less potent (IC50, 450- > 1000 microM) than quinidine. 3. The class II antiarrhythmic drugs (beta-blockers), timolol, (-)- and (+/-)- propranolol, and (+)- propranolol (a non-beta-blocker) inhibited KRN2391-induced K+ currents in a concentration-dependent manner with values for IC50 (microM) of 79, 131, 151 and 129, respectively, whilst butoxamine, oxprenolol, alprenolol, pindolol, nadolol, metoprolol and acebutolol were either weak (IC50, 300 microM-600 microM) or virtually inactive (IC50, > 1000 microM). 4. The class III antiarrhythmic drugs, amiodarone and (+)-sotalol scarcely affected KRN2391 responses. 5. All class IV drugs (Ca2+ antagonists) tested suppressed KRN2391-induced responses in a concentration-dependent manner with an IC50 of 6.3 microM for bepridil, 38 microM for prenylamine, 85 microM for verapamil and 135 microM for diltiazem. 6. In conclusion, antiarrhythmic drugs of classes I, II and IV potently blocked glibenclamide-sensitive K+ channels in Xenopus oocytes.
Topics: Adrenergic beta-Antagonists; Animals; Anti-Arrhythmia Agents; Calcium Channel Blockers; Dose-Response Relationship, Drug; Drug Interactions; Electrophysiology; Female; Glyburide; Oocytes; Potassium Channels; Pyridines; Sodium Channels; Xenopus laevis
PubMed: 1361399
DOI: 10.1111/j.1476-5381.1992.tb13407.x -
The EMBO Journal Dec 1991The gene encoding the murine beta 3-adrenergic receptor (beta 3AR) has been isolated. It translates into a polypeptide of 388 amino acid residues which shows 82% overall...
The gene encoding the murine beta 3-adrenergic receptor (beta 3AR) has been isolated. It translates into a polypeptide of 388 amino acid residues which shows 82% overall homology with the human beta 3AR. In Southern blot experiments, a probe derived from the murine beta 3AR gene hybridizes to a unique restriction fragment in the murine and human genomes. In both species, the beta 3AR gene is located on chromosome 8, in regions (8A2----8A4 in mouse, and 8p11----8p12 in man) which are conserved between mouse and man. The pharmacological profile of the mouse beta 3AR strongly resembles that of the human beta 3AR. It is characterized by a low affinity toward the radiolabelled beta-adrenergic antagonist [125I]Iodocyanopindolol and a low efficiency of other antagonists such as propranolol, ICI 118551 or CGP 20712A to inhibit cAMP production induced by isoproterenol. Another salient feature shared by the murine and the human beta 3ARs is the very potent effect of the lipolytic compound BRL 37344 on cAMP accumulation and the partial agonistic effect of the beta 1- and beta 2-adrenergic antagonists CGP 12177A, oxprenolol and pindolol. These properties are very close to those ascribed to the atypical beta AR of rodent adipocytes. In addition, Northern blot analyses indicate that the beta 3AR gene is mainly expressed in mouse brown and white adipose tissues, suggesting that the murine beta 3AR described here is the atypical beta AR involved in the control of energy expenditure in fat tissue.
Topics: 3T3 Cells; Adipose Tissue; Amino Acid Sequence; Animals; Base Sequence; Blotting, Northern; Blotting, Southern; CHO Cells; Chromosome Banding; Chromosomes, Human, Pair 8; Cloning, Molecular; Cricetinae; Cricetulus; Cyclic AMP; DNA Probes; Humans; Karyotyping; Mice; Molecular Sequence Data; RNA; Receptors, Adrenergic, beta; Sequence Homology, Nucleic Acid
PubMed: 1718744
DOI: 10.1002/j.1460-2075.1991.tb04940.x -
The Journal of Biological Chemistry Oct 1991Expression of ligand binding properties for an atypical beta-adrenergic receptor (beta-AR) subtype was studied during the adipose differentiation of murine 3T3-F442A...
Expression of ligand binding properties for an atypical beta-adrenergic receptor (beta-AR) subtype was studied during the adipose differentiation of murine 3T3-F442A cells and compared with that of the human beta 3-AR expressed in Chinese hamster ovary cells stably transfected with the human beta 3-AR gene (CHO-beta 3 cells) Emorine, L. J., Marullo, S., Briend-Sutren, M. M., Patey, G., Tate, K., Delavier-Klutchko, C., and Strosberg, A. D. (1989) Science 245, 1118-1121). 3T3-F442A adipocytes exhibited high and low affinity binding sites for (-)-4-(3-t-butylamino-2-hydroxypropoxy) [5,7-3H]benzimidazole-2-one ((-)-[3H]CGP-12177) (KD = 1.2 and 38.3 nM) and (-)-[125I]iodocyanopindolol ([125I]CYP) (KD = 47 and 1,510 pM). The high affinity sites corresponded to the classical beta 1- and beta 2-AR subtypes whereas the KD values of the low affinity sites for the radioligands were similar to those measured in CHO-beta 3 cells (KD = 28 nM and 1,890 pM for (-)-[3H]CGP12177 and [125I]CYP, respectively). These low affinity sites were undetectable in preadipocytes but represented about 90% of total beta-ARs in adipocytes. The atypical beta-AR and the human beta 3-AR add similarly low affinities (Ki = 3-5 microM) for (+/-)-(2-(3-carbamoyl-4-hydroxyphenoxy)ethylamino-3)-(4-(1-methyl- 4- trifluormethyl-2-imidazolyl)-phenoxy)-2-propanol methane sulfonate (CGP20712A) or erythro-(+/-)-1-(7-methylindan-4-yloxy)-3-isopropylaminob utan-2-ol (ICI118551), highly selective beta 1- and beta 2-AR antagonists, respectively, in agreement with the poor inhibitory effect of the compounds on (-)-isoproterenol (IPR)-stimulated adenylate cyclase activity. Atypical beta-AR and beta 3-AR had an affinity about 10-50 times higher for sodium-4-(2-[2-hydroxy-2-(3-chlorophenyl)ethylamino]propyl)phenoxyace tate sesquihydrate (BRL37344) than the beta 1-AR subtype. This correlates with the potent lipolytic effect of BRL37344 in adipocytes. The rank order of potency of agonists in functional and binding studies was BRL37344 greater than IPR less than (-)-norepinephrine greater than (-)-epinephrine both in 3T3 adipocytes and CHO-beta 3 cells. As in CHO-beta 3 cells, the classical beta 1- and beta 2-antagonists CGP12177, oxprenolol, and pindolol were partial agonists in adipocytes. Although undetectable in preadipocytes, a major mRNA species of 2.3 kilobases (kb) and a minor one of 2.8 kb were observed in adipocytes by hybridization to a human beta 3-AR specific probe.(ABSTRACT TRUNCATED AT 400 WORDS)
Topics: 3T3 Cells; Adipose Tissue; Adrenergic beta-Antagonists; Animals; Base Sequence; Binding, Competitive; Blotting, Northern; DNA; Ethanolamines; Humans; Imidazoles; Mice; Molecular Sequence Data; Oxprenolol; Pindolol; Polymerase Chain Reaction; Propanolamines; RNA, Messenger; Receptors, Adrenergic, beta
PubMed: 1682311
DOI: No ID Found -
British Journal of Clinical Pharmacology Oct 1990The in vivo inhibitory effect of five beta-adrenoceptor antagonists and levomepromazine on debrisoquine metabolism was assessed in 37 subjects. The debrisoquine...
The in vivo inhibitory effect of five beta-adrenoceptor antagonists and levomepromazine on debrisoquine metabolism was assessed in 37 subjects. The debrisoquine phenotyping test was performed before and after 7 days' treatment with oxprenolol (40 mg three times daily), propranolol (20 mg three times daily), timolol (10 mg twice daily), pindolol (5 mg twice daily), metoprolol (50 mg twice daily) or levomepromazine (10 mg daily), each of which was given to six-seven subjects. No clear change in the urinary metabolic ratio of debrisoquine/4-OH-debrisoquine (MR) was seen with any of the single beta-adrenoceptor antagonist treatments, but the MR value increased significantly when all beta-adrenoceptor blocker treatments were considered together. Debrisoquine metabolism was clearly impaired after levomepromazine 10 mg daily for 7 days; the mean MR increased from 1.24 +/- 1.6 to 4.70 +/- 5.23 (P = 0.018) and the excretion of 4-hydroxydebrisoquine decreased from 0.92 +/- 0.46 mg to 0.31 +/- 0.19 mg (P = 0.043). Thus, levomepromazine changes MRs towards those characteristic of phenotypically poor metabolizers, but beta-adrenoceptor antagonists at the doses examined have only a marginal effect.
Topics: Adrenergic beta-Antagonists; Adult; Debrisoquin; Female; Humans; Male; Methotrimeprazine
PubMed: 1981321
DOI: 10.1111/j.1365-2125.1990.tb03827.x -
British Journal of Clinical Pharmacology Oct 19881. The position in the gastrointestinal tract of an orally administered oxprenolol Oros drug delivery system labelled with technetium-99m DTPA was followed by gamma...
Relationship between the rate of appearance of oxprenolol in the systemic circulation and the location of an oxprenolol Oros 16/260 drug delivery system within the gastrointestinal tract as determined by scintigraphy.
1. The position in the gastrointestinal tract of an orally administered oxprenolol Oros drug delivery system labelled with technetium-99m DTPA was followed by gamma scintigraphy, and the corresponding plasma drug concentration-time profiles after oral and i.v. administration were used to relate pharmacokinetic and transit data. 2. Gastric emptying time (0.8 +/- 0.4 h, mean +/- s.d.), and the time to arrival in the colon (3.8 +/- 0.7 h) were reasonably consistent after administration of the Oros system to fasted subjects, as were the calculated small intestine transit times (3.0 +/- 0.7 h). As expected there were wide individual variations in colonic transit, so that recorded values for total transit ranged from 6 to 32 h (median, 24.7 h). 3. Absorption of oxprenolol occurred throughout the GI tract including the colon. Plasma drug concentration-time profiles and input functions (calculated by deconvolution) could be related to transit behaviour and in vitro release. Inflexions in the calculated rate of drug input when the Oros system was located in the colon corresponded with periods of stagnation at the hepatic and splenic flexures in two subjects and the ileocaecal junction in two others. The mechanism of these changes is unclear.
Topics: Adolescent; Adult; Biological Transport; Digestive System; Gastrointestinal Transit; Humans; Infusion Pumps; Intestinal Absorption; Male; Organometallic Compounds; Oxprenolol; Pentetic Acid; Radionuclide Imaging; Technetium Tc 99m Pentetate
PubMed: 3056482
DOI: 10.1111/j.1365-2125.1988.tb03403.x -
British Journal of Clinical Pharmacology Jun 19881. alpha 1-acid glycoprotein (AAG) concentration and molecular heterogeneity, and oxprenolol protein binding were studied in serum of 15 healthy volunteers, 14 patients...
Alpha 1-acid glycoprotein concentration and molecular heterogeneity: relationship to oxprenolol binding in serum from healthy volunteers and patients with lung carcinoma or cirrhosis.
1. alpha 1-acid glycoprotein (AAG) concentration and molecular heterogeneity, and oxprenolol protein binding were studied in serum of 15 healthy volunteers, 14 patients with lung carcinoma and 17 patients with liver cirrhosis. 2. The AAG serum concentration was increased to 180.7% in patients with lung cancer and decreased to 73.4% in cirrhotic patients as compared with controls (P less than 0.05). 3. The concanavalin A (conA) dependent heterogeneity of serum AAG was very similar in controls and patients with lung cancer: a ratio of 9/9/2 was obtained for the conA nonreactive, the conA weakly reactive and the conA strongly reactive subfraction respectively; in cirrhotic patients, the ratio shifted to 11/7/1. 4. The heterogeneity in electric charge, demonstrated by isoelectric focusing, was similar in the three groups of subjects: 70-80% of the focussed bands were found in the main three bands. 5. The binding of oxprenolol to serum proteins was increased in lung tumour patients and decreased in liver cirrhotic patients as compared with controls (P less than 0.05). There was no change in binding affinity and oxprenolol binding was significantly correlated to total AAG serum concentration and to the concentration of each of the conA dependent subtypes, in controls as well as in both patients groups.
Topics: Adult; Blood Proteins; Concanavalin A; Electrophoresis; Female; Humans; Immunoelectrophoresis; Isoelectric Focusing; Liver Cirrhosis; Lung Neoplasms; Male; Middle Aged; Orosomucoid; Oxprenolol; Protein Binding
PubMed: 3203044
DOI: 10.1111/j.1365-2125.1988.tb05260.x