Alprenolol Research Articles

Multi-residue method for enantioseparation of psychoactive substances and beta blockers by gas chromatography–mass spectrometry

Currently, consumption of illicit drugs and pharmaceuticals has increased significantly. Many of these substances are chiral and can be available as racemates or enantiomerically pure. Determination of the enantiomeric fraction (EF) in wastewater is useful for: i) distinguishing between the consumption of prescribed and illicit drugs; ii) identification of possible local of illegal synthesis; iii) illegal discharge of sewage and estimation of illicit drugs and pharmaceuticals consumption by a community (wastewater-based epidemiology). This work describes the development of an indirect method by gas chromatography–mass spectrometry (GC–MS) for enantiomeric quantification of chiral substances namely psychoactive drugs and β-blockers based on the formation of diastereomers using (R)-(−)-α-methoxy-α-(trifluoromethyl)phenylacetyl chloride ((R)-MTPA-Cl) as chiral derivatization reagent. The developed method presented linearity (R2 > 0.99) for 20 compounds, 9 diastereomer pairs and paroxetine (PAR) and sertraline (SER). Recovery ranged from 80.7 to 114.5% (RSD < 9.1%) and accuracy between 84.6 and 118% (RSD < 9.9%). The limits of detection (LOD) varied from 0.03 and 26.0 ngL−1 and limits of quantification (LOQ) from 0.15 and 104 ngL−1. Results showed the occurrence of amphetamine (AMP), illicit drugs as 3,4-methylenedioxymethamphetamine (MDMA) and methamphetamine (MAMP), alprenolol (ALP), norfluoxetine (NFLX), (SER), metoprolol (MET) and propranolol (PHO) at concentrations ranging from 21.7 ngL−1 (MDMA) to 622 ngL−1 (PHO). Measured concentrations were used to estimate the drug loads of the target chiral substances in a specific population. The EF was determined providing valuable information about the consumption and origin of the target drugs.

Quantification of alprenolol and propranolol in human plasma using a two-dimensional liquid chromatography (2D-LC)

A new two-dimensional liquid chromatography (2D-LC) method using a column switching valve, with a restricted-access media (RAM) column in the first dimension was developed and validated for the quantification of two β-blockers in human plasma. Several parameters, such as sample collection, mobile phase composition and flow rate for sample cleanup, transference and analytical separation of the β-blockers were investigated and optimized. The developed method allowed for the simultaneous pre-treatment and quantification of alprenolol (ALP) and propranolol (PRO) in human plasma in less than 25min. The method consisted in the injection of 100μL of plasma samples on the RAM alkyl-diol-silica column (Lichrospher® RP-18 ADS, 25μm) with water/acetonitrile (98:2, v/v; at a flow rate of 2.0mL/min) and then transferred (via a six-port valve) to the analytical column (Luna PFP (2), 150×4.6mm ID, 100Å, 3μm) with 0.1% (v/v) triethylamine in water acidified with trifluoroacetic acid (pH=3)/acetonitrile (74:26, v/v) at a flow rate of 0.6mL/min in a back-flush mode. The column oven temperature was optimized to 42°C and the fluorescence detector set at 280nm and 310nm (excitation and emission, respectively). The method was validated according to the European Medicines Agency’s guidelines and was linear (r2>0.999) over a dynamic range of 5.0 – 200ng/mL. Recoveries ranged from 90.2 and 107% and the lower limit of quantification was 5.0ng/mL for both compounds. Precision was expressed as a percentage of relative standard deviation and did not exceed 11%. Finally, the method was successfully applied to determine the plasma concentration of PRO in four healthy volunteers.

Identification of Radiodegradation Products of Acebutolol and Alprenolol by HPLC/MS/MS.

Two therapeutically active compounds from the group of β-blockers, acebutolol (AC) and alprenolol (AL), in solid form were subjected to ionizing radiation emitted by a beam of high energy electrons from an accelerator with a standard sterilization dose of 25 kGy and in higher doses of 50-400 kGy. The effects of irradiation were detected by chromatographic methods (TLC, HPLC) and a hyphenated method (HPLC/MS/MS). No significant changes in the physicochemical properties of both compounds studied irradiated with 25 kGy were noted, but upon irradiation with the highest dose (400 kGy) the loss of AC and AL content determined by HPLC was 2.79 and 9.12%, respectively. The product of AC decomposition and the two products of AL decomposition were separated and identified by HPLC/MS/MS. It has been established that radiodegradation of AC and AL takes place by oxidation, leading to formation of the products of radiolysis, most probably alcohol derivatives of the β-blockers studied. The additional product that appears on radiodegradation of AL is probably formed as a result of two simultaneous reactions: oxidation and CH2 group elimination.

Sensitive enantioanalysis of β-blockers via field-amplified sample injection combined with water removal in microemulsion electrokinetic chromatography.

In this study, an on-line sample preconcentration technique, field-amplified sample injection combined with water removal by electroosmotic flow (EOF) pump, was applied to realize a highly sensitive chiral analysis of β-blocker enantiomers by MEEKC. The introduction of a water plug in capillary before the electrokinetic injection provided the effective preconcentration of chiral compounds. And then the water was moving out of the column from the injection end under the effect of the EOF, which avoided dilution of the stacked β-blocker enantiomers concentration suffering from the presence of water in separation buffer. Moreover, the addition of H3 PO4 and methanol in the sample solution greatly improved the enhancement efficiency further. Under optimized conditions, more than 2700-fold enhancement in sensitivity was obtained for each enantiomer of bupranolol (BU), alprenolol (AL), and propranolol (PRO) via electrokinetic injection. LODs were 0.10, 0.10, 0.12, 0.11, 0.02, and 0.02 ng/mL for S-BU, R-BU, S-AL, R-AL, S-PRO, and R-PRO, respectively. Eventually, the proposed method was successfully applied to the determination of BU, AL, and PRO in serum samples with good recoveries ranging from 93.4 to 98.2%.

Effect of Radiation Sterilization on Alprenolol in the Solid State Studied by High-Performance Thin-Layer Chromatography

The possibility of radiation sterilization of alprenolol (AL) has been studied. Irradiation of AL in solid form with a 25 kGy beam of electrons caused only an insignificant change in color that became more intense with increasing irradiation dose. Moreover, with increasing dose a decrease in pH, the content of water, and the degree of crystallinity were observed. AL in solid form was radiated with a high-energy electron beam (9.96 MeV) at doses from 25-400 kGy and analyzed by HPTLC using the mobile phase methanol-ammonia 25% (99 + 1, v/v). Densitometric analysis was carried out directly from chromatograms at 270 nm. The applied method was validated and characterized by good precision (RSD = 3.95%); good accuracy (80% level 100.15%, 100% level 99.99%, and 120% level 104.44%); and low LOD (LOD = 0.52 microg/zone and LOQ = 1.55 microg/zone). Chromatograms recorded for samples irradiated at the doses of 25 kGy were unchanged, but at higher doses (100-400 kGy) additional peaks corresponding to the radiodegradation products appeared (Rf = 0.24 and Rf = 0.40). The decrease in the concentration of AL was proportional to the applied radiation dose, and for 400 kGy the concentration of AL was 90.23%. The calculated radiolytic yield of the radiodegradation process was G(-AL) = 7.12 x 10(-7) mol/J.

Medium Sized Rings from Alprenolol and Oxprenolol.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Restricted access media-molecularly imprinted polymer for propranolol and its application to direct injection analysis of beta-blockers in biological fluids.

A restricted access media-molecularly imprinted polymer (RAM-MIP) for propranolol (PRP) has been prepared for direct injection analysis of beta-blockers in biological fluids. First, the MIP for PRP was prepared using methacrylic acid and ethylene glycol dimethacrylate as the functional monomer and cross-linker, respectively, by a multi-step swelling and polymerization method. Next, a 1:1 mixture of glycerol monomethacrylate and glycerol dimethacrylate was used for hydrophilic surface modification, and added directly to the MIP for PRP after 4 h from the start of polymerization. Then further polymerization was carried out for 20 h. The obtained RAM-MIP for PRP showed excellent molecular recognition ability for PRP, good ones for alprenolol (ALP) and pindolol, and fair ones for other beta-blockers. The RAM-MIP was applied for direct injection analysis of ALP enantiomers in a rat plasma sample by a column-switching HPLC system using a beta-cyclodextrin phenylcarbamate-bonded silica column as the analytical column. The calibration graph, constructed from peak area versus each ALP enantiomer concentration, was linear with a correlation coefficient of > 0.999 over the concentration ranges of 12.5-250 ng ml(-1). The limit of quantitation was 12.5 ng ml(-1) with a 50 microl injection. This method could be applicable for the assay of ALP enantiomers at the therapeutic plasma levels, and have wide applicability for the assay of beta-blockers in biological fluids.

Passive Diffusion of Weak Organic Electrolytes across Caco‐2 Cell Monolayers: Uncoupling the Contributions of Hydrodynamic, Transcellular, and Paracellular Barriers

A systematic approach was used to demonstrate the quantitative interplay of pH, pKa, lipophilicity, charged and uncharged molecular species, molecular size, aqueous diffusivity, and stirring in passive transport across the aqueous boundary layer, microporous filter support, and transcellular and paracellular barriers in Caco‐2 cell monolayers. The relationship of permeability of the aqueous boundary layer and hydrodynamic stirring was elucidated from transmonolayer fluxes of testosterone. Adrenergic receptor antagonists including propranolol (PPL), alprenolol (APL), pindolol (PDL), and atenolol (ATL) represented the model series of structurally similar weak bases with pKavalues between 8.8 and 9.65. Although intrinsically lipophilic, their apparent log PC (n‐octanol/water) at pH 7.4 and 6.5 ranged from −2.6 to 1.3. Effective permeability coefficients (Pe) correlated with log PC at both pH 7.4 and 6.5 showing a single sigmoidal‐like curve: PPL > APL > PDL ≥ ATL. ThePeapproached a minimum plateau value established by the protonated ATL for the paracellular route (pore radius of 12 Å) by molecular size‐restricted diffusion within a negative electrostatic field of force. ThePeof the weak bases was delineated into component permeability coefficients of the aqueous boundary layer and porous filter support, the intrinsic permeabilities of charged and uncharged species for the transcellular and paracellular routes, and the extent to which the routes were utilized at each pH. This study emphasized a generally applicable approach to quantitatively analyze passive transport data on weak organic electrolytes and neutral molecules generated using cell culture monolayers.

Effects of pituitary adenylate-cyclase activating peptide (PACAP) on the rat adrenal secretory activity: Preliminary in-vitro studies

PACAP did not affect secretory activity of dispersed rat adrenocortical cells, but it markedly raised aldosterone (ALDO) and corticosterone (B) production by adrenal slices, containing both medullary and cortical tissues. The secretagogue effects of PACAP were suppressed by PACAP(6–38), a specific competitive antagonist. Isoprenaline (IP) enhanced ALDO, but not B secretion of adrenal slices, and l- alprenolol (AL) completely blocked IP effect. AL and corticotropin-inhibiting peptide (CIP) partially reversed ALDO response to a maximal effective concentration of PACAP; AL did not affect B response to a maximal effective concentration of PACAP, while CIP completely annulled it. Quarters of regenerated adrenocortical autotransplants, that are completely deprived of chromaffin cells, though displaying ALDO and B responses to IP and ACTH, were insensitive to PACAP. The hypothesis is advanced that adrenal medulla plays a pivotal role in the mechanism(s) underlying the adrenocortical secretagogue action of PACAP, being mineralocorticoid and glucocorticoid responses probably mediated by the release by chromaffin cells of catecholamine and ACTH or exclusively ACTH, respectively.

Involvement of arachidonic acid and its metabolites in the inhibitory effect of beta-adrenoceptor blocking drugs on blood platelets.

Propranolol (PRO), alprenolol (ALP), metipranolol (MET) and oxprenolol (OXP) inhibited arachidonic acid (AA) liberation from membrane phospholipids, malondialdehyde (MDA) formation and thromboxane B2 (TXB2) production in stimulated platelets. The inhibition was dose-dependent and with slight variations followed the rank order of potency: PRO greater than or equal to ALP greater than or equal to MET greater than or equal to OXP. Atenolol (ATE) was without any inhibitory effect. Inhibition of the arachidonic acid pathway in stimulated platelets may significantly contribute to the antiaggregatory effect of beta-adrenoceptor blocking drugs.

Improved delivery through biological membranes. LVI. Pharmacological evaluation of alprenoxime--a new potential antiglaucoma agent.

A new site-specific chemical delivery system (CDS) for alprenolol was designed and investigated as a potential novel antiglaucoma agent. The effect of this compound, alprenoxime (AO), on the intraocular pressure (IOP) of rabbits was evaluated after its uni- and bilateral administration. AO produced significant reduction of the IOP starting at 30 min and lasting for more than 6 hr after its topical administration. Both in rats and in rabbits the i.v. bolus injection of AO (6 mg/kg) led to insignificant transient bradycardia, while no activity was found after oral or topical administration. Alprenolol (ALP) in a similar dose produced a sustained and significant bradycardia for more than 30 min. When the beta-adrenergic blocking activity was assessed against isoprenaline-tachycardia, the same results were obtained, i.e., AO led to a transient brief activity, whereas ALP produced a significant long-lasting beta blockade. These results support the potent ocular hypotensive action and the weak systemic beta-adrenergic blocking and cardiovascular activity of AO: a significant improvement in the therapeutic index. This finding recommends alprenoxime as a potent site-specific antiglaucoma agent with minimal systemic side effects.

交感神経β-受容体遮断作用を有する新しいIndene誘導体の薬理作用

1) The β-blocking and direct effect on heart rate of six newly synthesized indene derivatives was studied in reserpinized rats and compared with that of propranolol (PROP), alprenolol(ALP), USVC 6524(USVC), practolol(PRACT)and YB-2. The order of potency of 1-(7-indenyloxy)-3-alkylaminopropan-2-ol derivatives(I-IV) antagonizing isoproterenol-induced tachycardia was III (tert. butyl)>YB-2 (isopropyl)>II (sec butyl)>I(isobutyl)>IV (cyclohexyl). Especially, III and YB-2 were 2.5 and 1.5 times more potent than PROP, respectively. The activity of 1-(3-methyl-7-indenyloxy)-3-isopropylaminopropan-2-ol(V)and 1-(3-methyl-4-chlor-7-indenyloxy)-3-isopropylaminopropan-2-ol(VI) was much weaker than that of YB-2. 2) In the same preparations, I-IV, VI, YB-2, and ALP showed a moderate intrinsic sympathomimetic activity (ISA), while the compound (V) exhibited a marked ISA comparable to that of PRACT 3) YB-2 and ALP in concentration of 5×10-8g/ml depressed the motility of the isolated rat uterus, while PROP and USVC were devoid of such inhibitory effect, indicating a lack of ISA in these corn : unds. 4) All indene derivatives, in concentration of 1% or less showed a local inesthetic action in the guinea pig cornea. 5) Comparison of the KB values in the left atrium and trachea isolated from guinea pigs indicated that III and ALP possessed a greater affinity for the tracheal smooth muscle than for the atrium, whereas YB-2 and PROP blocked β-receptors in both organs to the same degree.

Alprenolol in resuscitation.

Alprenolol in resuscitation.