Identification of Alprenolol Hydrochloride as an Anti-prion Compound Using Surface Plasmon Resonance Imaging.

Prion diseases are transmissible neurodegenerative disorders of humans and animals, which are characterized by the aggregation of abnormal prion protein (PrPSc) in the central nervous system. Although several small compounds that bind to normal PrP (PrPC) have been shown to inhibit structural conversion of the protein, an effective therapy for human prion disease remains to be established. In this study, we screened 1200 existing drugs approved by the US Food and Drug Administration (FDA) for anti-prion activity using surface plasmon resonance imaging (SPRi). Of these drugs, 31 showed strong binding activity to recombinant human PrP, and three of these reduced the accumulation of PrPSc in prion-infected cells. One of the active compounds, alprenolol hydrochloride, which is used clinically as a ß-adrenergic blocker for hypertension, also reduced the accumulation of PrPSc in the brains of prion-infected mice at the middle stage of the disease when the drug was administered orally with their daily water from the day after infection. Docking simulation analysis suggested that alprenolol hydrochloride fitted into the hotspot within mouse PrPC, which is known as the most fragile structure within the protein. These findings provide evidence that SPRi is useful in identifying effective drug candidates for neurodegenerative diseases caused by abnormal protein aggregation, such as prion diseases.

Comparative efficacy of ß-blockers on mortality and cardiovascular outcomes in patients with hypertension: a systematic review and network meta-analysis.

The differential efficacy of lipophilic and hydrophilic ß-blockers on clinical outcomes has not been investigated. We sought to compare the effects of lipophilic and hydrophilic ß-blockers on mortality and cardiovascular outcomes by conducting a comprehensive systematic review and network meta-analysis. MEDLINE/PubMed, EMBASE, and the Cochrane Database were searched for all dates to January 5, 2015, for randomized trials with comparisons between all ß-blockers or between ß-blockers and other antihypertensive agents. Mortality and cardiovascular outcomes were also reported. Characteristics of each study and associated clinical outcomes were extracted, including all-cause mortality, coronary heart disease, stroke, and cardiovascular death. Thirteen trials with 90,935 participants were included, focusing on lipophilic ß-blockers (metoprolol, propranolol, and oxprenolol) and a hydrophilic ß-blocker (atenolol). In this review, lipophilic ß-blockers showed a significant reduction for the risk of cardiovascular mortality (odds ratio [OR] 0.72, 95% confidence interval [CI; 0.54-0.97]) compared with hydrophilic ß-blocker, and lipophilic ß-blockers showed decreased trend for the risk of all-cause mortality (OR 0.86, 95% CI [0.72-1.03]) and coronary heart disease (OR 0.88, 95% CI [0.64-1.23]). When the risk of stroke was evaluated using age stratification, lipophilic ß-blockers showed a significant reduction in the risk of stroke (OR 0.63, 95% CI [0.41-0.99]) compared with hydrophilic ß-blocker in patients aged <65 years.

Molecular dynamics simulations of Oxprenolol and Propranolol in a DPPC lipid bilayer.

Extensive microscopic molecular dynamics simulations have been performed to study the effects of tow ß-blocker drugs (Propranolol, Oxprenolol) on fully hydrated dipalmitoylphosphatidylcholine (DPPC) in the fluid phase at 323K. Simulation of 4 systems containing varying concentrations of drugs was carried out. For the purpose of comparison, a fully hydrated DPPC bilayer without drugs was also studied at the same level of simulation technique which has been done on 4 other systems. The length of each simulation was 100ns. The effects of concentrations of both drugs were analyzed on lipid bilayer properties, such as electrostatic potential, order parameter, diffusion coefficients, and hydrogen bond formation, etc. Penetration of water in the bilayer system was also investigated using radial distribution function analysis. Efficacy of varying concentrations of both drugs has no significant effect on P-N vector. Consistent with experimental results, by increasing the concentration of Propranolol, the thickness of the bilayer was increased.

High frequency controlled capsules with integrated gas producing cells.

In the present investigations, a new high frequency remote-controlled capsule has been developed in which the mechanical energy to empty a drug reservoir is generated by a miniature gas producing cell. If the poles of the gas producing cell are connected by an electric circuit, the gas production starts. The rate of gas production can be regulated by a resistor in the electric circuit and by the duration of activation of the system. To get a remote control, we developed a small receiver which is located inside the capsule. The receiver consists of an oscillating circuit, which is in resonance with an external 24 MHz high frequency transmitter. A MOSFET transistor acts as a switch in the electric circuit to start the gas production. Release experiments with oxprenolol show that different release patterns can be obtained.

Principles for different modes of multiple-injection CZE.

This paper introduces four different modes of multiple-injection CZE (MICZE). The validity of these MICZE models was evaluated by the experimental data. Prior to the application of MICZE, the electrophoretic conditions are developed in the single-injection mode by adjusting different experimental parameters such as pH, type and concentration of buffer additives and temperature. Based on the migration time difference (Deltatmig) between the analyte and the internal standard or injection marker, one or more MICZE modes can be employed. The injection marker is added to the sample to compensate for injection-volume fluctuations. The inter-plug distance is regulated by applying an electrical field over the capillary for a short period of time between each injection. After the final injection, the separation is completed by electrophoresis for a time period corresponding to that in the single-injection mode.

Quantitative determination of salbutamol in tablets by multiple-injection capillary zone electrophoresis.

A multiple-injection capillary zone electrophoresis (MICZE) method has been developed for the assay of salbutamol in Ventoline Depot tablets (GlaxoSmithKline). In the developed method, seven sample sets, each consisting of three samples, were sequentially injected into the capillary and analyzed within a single run. This enabled a total of twenty-one sequential injections, i.e., six standards and fifteen samples, containing salbutamol and the injection marker oxprenolol. The injected sample plugs were separated by plugs of background electrolyte, through application of a short-term voltage (30kV) over the capillary for different time periods, i.e., t(PE1) and t(PE2). The samples in each set were isolated from each other by partial electrophoresis for 2.35min (t(PE1)), while the sample sets were separated for 10.50min (t(PE2)). After the final injection, all the applied samples were subjected to electrophoresis for a time period corresponding to that in conventional single-injection CZE. The method was validated regarding linearity, accuracy, precision and robustness before it was applied to the determination of salbutamol in 15 tablets of Ventoline Depot with a labeled content of 8mg salbutamol. The average salbutamol content was determined to 7.8mg (+/-0.3mg) from simultaneous analyses of the 15 different tablets.

Study on chiral resolution of three beta-blockers by affinity electrokinetic chromatography.

The chiral resolution of three beta-blockers including propranolol, pindolol and oxprenolol, was studied by affinity electrokinetic chromatography. The effect of various chiral selectors and some key parameters including buffer pH, buffer concentration, capillary temperature and applied voltage were carefully studied, respectively. At optimum condition, based on the signal-to-noise ratio of 3, the detection limits for the simple resolution and chiral resolution were found to be 1.0x10(-5) and 4.0 x 10(-5)M, respectively. In addition, the interactions of these beta-blockers with bovine serum albumin (BSA) were studied and the binding constant (K(a)) between BSA and each of beta-blockers were calculated. Based on linear correlation coefficient, it can be concluded that the binding ratio of pindolol (oxprenolol) combining with BSA is 1:1, and that the binding number of propranolol interacting with BSA deviates one.

Chiral separation of oxprenolol by affinity electrokinetic chromatography-partial filling technique using human serum albumin as chiral selector.

The intrinsic characteristics of capillary electrophoresis have made this technique a powerful tool in the chiral separation field. The present paper deals with the enantiomeric separation of oxprenolol enantiomers by affinity electrokinetic chromatography-partial filling technique using human serum albumin (HSA) as chiral selector. Several experimental conditions and variables affecting the separation such as pH, HSA concentration and plug length, background electrolyte concentration, temperature and voltage were studied. Baseline separation of oxprenolol enantiomers was obtained in less than 8 min under the following selected conditions: electrophoretic buffer composed of 50 mM Tris-(hydroximethyl)-aminomethane (Tris) at pH 8.5; 190 microM HSA solution applied at 50 mbar for 225 s as chiral selector; oxprenolol samples contained 190 microM HSA solution injected hydrodynamically at 30 mbar for 2s and the electrophoretic runs performed at 30 degrees C applying 15 kV voltage. The proposed methodology was applied for the analysis of two pharmaceutical preparations. Resolution, accuracy, reproducibility, speed and cost of the proposed method make it suitable for quality control of the enantiomeric composition of oxprenolol in drugs. The results show that a different affinity between oxprenolol enantiomers and HSA exists and can contribute to the pharmacokinetic differentiation of these enantiomers.

[Medium sized rings from alprenolol and oxprenolol]. / Mittlere Ringe aus Alprenolol und Oxprenolol.

The N-allyl derivatives 2 formed from the beta-blockers 1, were acetylated to give the esters 5. The 1,5-benzoxazacycloundecine 6a and the 1,10,5-benzodioxazacyclododecine 7a were isolated by ring closing metathesis (RCM) of 5a and 5b, respectively, using Grubbs catalyst in the presence of titanium tetraisopropanolate. Alkaline hydrolysis yielded the alcohols 6b and 7b.

Complexation of the antihypertensive drug oxprenolol with copper(II).

The complexation between copper(II) and the antihypertensive drug oxprenolol (HOxp) was studied both in methanol and slightly alkaline aqueous media at Cu:HOxp molar ratio from 1:1 to 1:10. Copper(lI) forms two types of complexes-a mononuclear violet one, CuOxp2, with bidentately bound ligands and a green dimeric one, Cu2Oxp2Cl2, in which the two Cu(II) centres are linked by the ligand through oxygen bridges. The crystal structure of the Cu2Oxp2Cl2 complex consists of two crystallographically non-equivalent centrosymmetric copper dimers. Each copper atom is four-coordinated in a distorted square-planar environment. The Cu2O2 structural core is characterized by a Cu1-O1-Cu1' angle of 104.15(13)degrees (Cu2-O2-Cu2' 104.30(13) degrees) and a relatively short Cu1-Cu1' separation of 3.026(1) A (Cu2-Cu2'-3.023(1) A). Magnetic susceptibility and EPR measurements indicate an antiferromagnetic coupling of the copper(II) centers.

A study of the relationship between the structure of homologous series of oxprenolol at various pH values.

Stability of series of O-acyl esters of oxprenolol prepared as potential pro-drugs, is investigated over the pH range 0.4-10 at 37 degrees C. Maximum stability of all esters occurred at pH 3-4. The most stable derivative was found to be pivaloyl ester. The relationship between Charton Steric parameters (v) and the catalytic rate constant of hydrolysis is investigated.

Enzymatic hydrolysis of O-acyl esters of oxprenolol.

The stability of each O-acyl derivative was investigated in a solution of hydrochloric acid, artificial gastric juice, phosphate buffer at pH 7.4 and in artificial intestinal juice. A study of the relationship between the structure and enzymatic hydrolysis of the homologous series of oxprenolol esters was made.

Physico-chemical properties and hydrolysis of oxprenolol octanoyl and benzoyl esters.

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.

Separation of enantiomers on HPLC chiral stationary phases based on human plasma alpha1-acid glycoprotein: effect of sugar moiety on chiral recognition ability.

HPLC chiral stationary phases based on human plasma alpha1-acid glycoprotein (AGP) and partially deglycosylated AGP (pd-AGP) were prepared to investigate the effects of sugar moiety of AGP on chiral discrimination of various solutes. Removal of a sugar moiety of AGP by treatment with N-glycosidase was confirmed by high-performance capillary electrophoresis, reversed-phase HPLC and matrix-assisted laser desorption-time of flight (MALDI-TOF) mass spectrometry. The average molecular weights of AGP and pd-AGP were estimated to be ca. 33,000 and 30,600, respectively, by MALDI-TOF mass spectrometry. Next, AGP and pd-AGP were bound to aminopropyl-silica gels activated with N,N '-disuccinimidylcarbonate. The retentivity+ and enantioselectivity of the neutral, acidic and basic solutes tested on the pd-AGP column were significantly or not significantly larger in most solutes than those on the AGP column. This is ascribable to that by cleavage of a sugar chain(s) by N-glycosidase, pd-AGP could become more hydrophobic than AGP, and/ or that a solute could be easily accessible to the specific and/or non-specific binding sites of pd-AGP. It is interesting that warfarin enantiomers are not resolved on the pd-AGP column, but resolved on the AGP column. A sugar chain(s) of AGP cleaved by N-glycosidase might be involved in the enantioselective binding of warfarin enantiomers.

Unexpected difference in enantioselective retention on cellulase (CHB I) silica stationary phase caused by exchange of potassium for sodium ion in the mobile phase.

An increase in both retention and enantioselectivity for some beta-blocking agents was observed when exchanging potassium to sodium ion in the buffer used as mobile phase. A large effect of ionic strength on retention was observed, while the enantioselectivity was constant.

Evaluation of the immobilized artificial membrane phosphatidylcholine. Drug discovery column for high-performance liquid chromatographic screening of drug-membrane interactions.

Chromatographic retention factors (k') of a series of eight beta-adrenoceptor antagonist compounds (beta-adrenolytic drugs) were determined employing an immobilized artificial membrane column (IAM.PC.DD). The influence of mobile phase pH, ionic strength, and organic modifier composition was studied in order to examine column performance. After the IAM.PC.DD columns were exposed to approximately 7000 column volumes of a 0.01 M PBS mobile phase, five out of six columns tested showed significant peak broadening and decreased k' values indicative of premature column failure. The data suggested that the immobilized phospholipids stationary phase was removed by the 0.01 M PBS mobile phase. The beta-adrenolytic drug's log k'IAM values obtained with an IAM.PC.DD column were compared to an esterIAM.PC.MG column for predicting drug membrane interactions. For the linear regression analysis between log k'IAM and the logarithm of the n-octanol-water partition coefficients (rIAM.PC.DD = 0.8710 vs. rIAM.PC.MG = 0.9538), the C18 HPLC retention factors (rIAM.PC.DD = 0.8408 vs. rIAM.PC.MG = 0.9380), the liposome partition coefficients (rIAM.PC.DD = 0.8887 vs. rIAM.PC.MG = 0.9187), and various pharmacokinetic parameters, significantly better correlations were obtained with the esterIAM.PC.MG column than the IAM.PC.DD column.

A study of the relationship between the structure and physicochemical parameters of a homologous series of oxprenolol esters at various pH values and temperatures.

A number of beta-adrenergic blockers, including timolol and propranolol, are administered in eyedrops for the treatment of glaucoma, but their therapeutic value is limited by a relatively high incidence of cardiovascular and respiratory side effects. Because of poor ocular bioavailability, many ocular drugs are applied in high concentrations, which give rise to both ocular and systemic side effects. Methods to increase ocular bioavailability include (a) the development of drug delivery devices designed to release drugs at controlled rates, (b) the use of various vehicles that retard precorneal drug loss, and (c) the conversion of drugs to biologically reversible derivatives (prodrugs) with increased corneal penetration properties, from which the active drugs are released by enzymatic hydrolysis. A homologous series of aliphatic esters of oxprenolol were synthesized and investigated as potential prodrugs for ocular use. The stability of each O-acyl derivative was investigated in aqueous solutions over the pH range 2.2-9.0 at 37 degrees C. The observed rate constants (k[obs]), shelf-lives (t90), lipophilicities, and Arrhenius parameters were determined for each ester. A study of the relationship between the structure and physicochemical parameters of the homologous series of oxprenolol esters at various pH values and temperatures was made.

On-line column-switching high-performance liquid chromatography analysis of cardiovascular drugs in serum with automated sample clean-up and zone-cutting technique to perform chiral separation.

A selective and highly reproducible, multi-column HPLC method is described for the analysis of the following cardiovascular drugs: lidocaine, pindolol, metoprolol, oxprenolol, diltiazem and verapamil, in serum. Column-switching devices are employed in combination with advanced separation media technologies for the automated analysis of samples containing complex matrices. The method consists of on-line sample clean-up using a restricted access sorbent, HPLC analysis of the drugs on a microsphere non-porous silica RP-18 column, and front-cutting to perform the chiral separation of pindolol enantiomers on a second HPLC system. Simultaneous control of the two HPLC systems and data analysis is achieved from a single centralized software. The R.S.D. values of the peak areas for spiked serum are less than 1% for metoprolol and oxprenolol, 2-5% for lidocaine, diltiazem and verapamil, and 1.2 and 2.4% for the two pindolol enantiomers. Recoveries, limits of detection and linearities are provided.

Disposition of human drug preparations in the horse. V. Orally administered oxprenolol.

Urinary concentrations of the beta-antagonist oxprenolol and some of its major human metabolites were determined following oral administration of a dose of 160 mg to five fasted horses. Quantitation was performed by gas chromatography-mass spectrometry (GC-MS) in the selected ion mode (SIM) by monitoring ion m/z 466 of the heptafluorobutyric derivatives. As early as 2 h after dosage oxprenolol could be detected in hydrolysed urine and remained detectable up to 24 h. Maximum urinary concentrations and excretion rates were obtained between 2 and 12 h. After 12 h only 2.8% of the administered dose was excreted as conjugates of oxprenolol and major human metabolites including 4-OH-oxprenolol and 5-OH-oxprenolol. These metabolites were detectable up to 48 h.

Effect of the degree of substitution of cyclodextrin derivatives on chiral separations by high-performance liquid chromatography and capillary electrophoresis.

Optical isomers of some basic racemic drugs (oxprenolol, AMEBD, ephedrine) were separated by high-performance liquid chromatography (HPLC) and/or capillary electrophoresis (CE) using carboxymethyl-beta-cyclodextrin (CMBCD) with various degree of substitution (DS). The effects of the separation conditions (pH, concentration and DS of CMBCD) were studied and compared using CE and HPLC. The degree of substitution had a significant effect on the resolution of the optical isomers and the ionic strength of the separation media, hence the use of well characterized CD derivatives is crucial. Different optimum DS values for the same test samples were obtained when HPLC or CE was used.