Enantiocomplementary synthesis of ß-adrenergic blocker precursors via biocatalytic nitration of phenyl glycidyl ethers.

Enantiopure ß-nitroalcohols, as an important class of nitro-containing compounds, are essential building blocks in pharmaceutical and organic chemistry, particularly for the synthesis of ß-adrenergic blockers. In this study, we present the successful protein engineering of halohydrin dehalogenase HHDHamb for the enantioselective bio-nitration of various phenyl glycidyl ethers to the corresponding chiral ß-nitroalcohols, using the inexpensive, commercially available, and safer nitrite as a nitrating agent. The chiral (R)- and (S)-1-nitro-3-phenoxypropan-2-ols were synthesized by the several enantiocomplementary HHDHamb variants through the whole-cell biotransformation, which showed good catalytic efficiency (up to 43% isolated yields) and high optical purity (up to >99% ee). In addition, we also demonstrated that the bio-nitration method was able to tolerate the substrate at a high concentration of 1000 mM (150 g/L). Furthermore, representative synthesis of two optically active enantiomers of the ß-adrenergic blocker metoprolol was successfully achieved by utilizing the corresponding chiral ß-nitroalcohols as precursors.

Enantioselective binding of carvedilol to human serum albumin and alpha-1-acid glycoprotein.

Carvedilol, a highly protein-bound beta-blocker, is used in therapy as a racemic mixture of its two enantiomers that exhibit different pharmacological activity. The aim of this study was to evaluate the stereoselective nature of its binding to the two major plasma proteins: albumin and alpha-1-acid glycoprotein. The determination of the plasma protein-binding degree for carvedilol and its enantiomers was achieved using ultrafiltration for the separation of the free fraction, followed by LC-MS/MS quantification, using two different developed and validated methods in terms of stationary phase: achiral C18 type and chiral ovomucoid type. Furthermore, molecular docking methods were applied in order to investigate and to better understand the mechanism of protein-binding for S-(-)- and R-(+)-carvedilol. A difference in the binding behavior of the two enantiomers to the plasma proteins was observed when taken individually, with R-(+)-carvedilol having a higher affinity for albumin and S-(-)-carvedilol for alpha-1-acid glycoprotein. However, in the case of the racemic mixture, the binding of the S enantiomer to alpha-1-acid glycoprotein seemed to be influenced by the presence of its antipode, although no such influence was observed in the case of albumin. The results raise the question of a binding competition between the two enantiomers for alpha-1-acid glycoprotein.

UHPLC Enantiomer Resolution for the ɑ/ß-Adrenoceptor Antagonist R/S-Carvedilol and Its Major Active Metabolites on Chiralpak IB N-5.

Carvedilol (CAR), a racemic lipophilic aryloxy propanolamine, acts as a selective α1-adrenoreceptor antagonist and a nonselective ß-adrenoreceptor antagonist. CAR metabolism mainly produces three active metabolites: desmethyl carvedilol (DMC), 4'-hydroxy carvedilol (4'OHC) and 5'-hydroxy carvedilol (5'OHC). The oxidative S-(-)-metabolites contribute to the ß-antagonistic effect, yet not to the α-antagonistic effect to be observed after drug dosage. Therefore, the three ß-adrenoceptor blocking metabolites, which are structurally closely related to the parent CAR, are included into the development of a bioanalytical quantitative method for all major active species relevant with respect to adrenoceptor-blockade. Because of the given pharmacological profile, resolution of the enantiomers of carvedilol, of 4'- and 5'-hydroxy carvedilol as well as of DMC, is mandatory. The current study aims to determine the response surface for the enantiomer separation of the parent CAR as well as the major metabolites on a suitable chiral stationary phase. Design of experiment approach (DoE) was utilized in an initial screening phase followed by central-composite design for delimitation of the response surface for resolution of the four enantiomeric pairs in least run time. The impact of chromatographic variables (composition and percentage of organic modifier(s), buffer type, buffer pH, flow rate) on critical peaks resolution and adjusted retention time was evaluated, in order to select the most significant critical quality attributes. On this basis, a robust UHPLC-UV method was developed and optimized for the simultaneous, enantioselective determination of CAR along with its major active metabolites (4'OHC, 5'OHC, and DMC) on Chiralpak IBN-5. The optimized UHPLC-UV method (which includes metoprolol as the internal standard) was validated according to the ICH M10 guidelines for bioanalytical methods and proven to be linear, precise, accurate, and robust. The validated assay was applied to plasma samples from cardiovascular patients treated with rac-CAR (blood randomly drawn at different times after oral CAR intake). In order to provide more insight into the mechanism of the enantiomer separation of CAR and its metabolites on the CSP, docking experiments were performed. Molecular simulation studies suggest the chiral recognition to be mainly due to different binding poses of enantiomers of the same compound.

Analysis of ß-blockers and ß2-agonists in environmental and biological samples by magnetic solid-phase extraction combined with high-performance liquid chromatography-tandem mass spectrometry.

ß-Blockers and ß2-agonists are commonly prescribed for therapeutic treatments and are also administered to livestock, leading to their presence in both environmental and biological samples. Hence, the development of sensitive, rapid, and reliable analytical methods for the determination of ß-blockers and ß2-agonists in environmental and biological samples is important. In this study, MIL-101(Cr)-NH2 &GO-coated SiO2 /Fe3 O4 magnetic particles were prepared as sorbents for magnetic solid-phase extraction and then combined with high-performance liquid chromatography-tandem mass spectrometry for the analysis of 20 ß-blockers and eight ß2-agonists. The experimental parameters of magnetic solid-phase extraction were studied in detail, and the optimal conditions were established. Under optimal conditions, the limits of detection were in the range of 0.002-0.007 µg/L with enrichment factors of 20.2-24.9. The developed method was successfully applied for the determination of 20 ß-blockers and eight ß2-agonists in river water, human urine, and freeze-dried pork liver powder. Bisoprolol and salbutamol were detected at concentrations of 2.78 mg/L in human urine and 11.5 µg/kg in freeze-dried pork liver powder.

Unique Positive Cooperativity Between the ß-Arrestin-Biased ß-Blocker Carvedilol and a Small Molecule Positive Allosteric Modulator of the ß2-Adrenergic Receptor.

Among ß-blockers that are clinically prescribed for heart failure, carvedilol is a first-choice agent with unique pharmacological properties. Carvedilol is distinct from other ß-blockers in its ability to elicit ß-arrestin-biased agonism, which has been suggested to underlie its cardioprotective effects. Augmenting the pharmacologic properties of carvedilol thus holds the promise of developing more efficacious and/or biased ß-blockers. We recently identified compound-6 (cmpd-6), the first small molecule positive allosteric modulator of the ß2-adrenergic receptor (ß2AR). Cmpd-6 is positively cooperative with orthosteric agonists at the ß2AR and enhances agonist-mediated transducer (G-protein and ß-arrestin) signaling in an unbiased manner. Here, we report that cmpd-6, quite unexpectedly, displays strong positive cooperativity only with carvedilol among a panel of structurally diverse ß-blockers. Cmpd-6 enhances the binding affinity of carvedilol for the ß2AR and augments its ability to competitively antagonize agonist-induced cAMP generation. Cmpd-6 potentiates ß-arrestin1- but not Gs-protein-mediated high-affinity binding of carvedilol at the ß2AR and ß-arrestin-mediated cellular functions in response to carvedilol including extracellular signal-regulated kinase phosphorylation, receptor endocytosis, and trafficking into lysosomes. Importantly, an analog of cmpd-6 that selectively retains positive cooperativity with carvedilol acts as a negative modulator of agonist-stimulated ß2AR signaling. These unprecedented cooperative properties of carvedilol and cmpd-6 have implications for fundamental understanding of G-protein-coupled receptor (GPCR) allosteric modulation, as well as for the development of more effective biased beta blockers and other GPCR therapeutics. SIGNIFICANCE STATEMENT: This study reports on the small molecule-mediated allosteric modulation of the ß-arrestin-biased ß-blocker, carvedilol. The small molecule, compound-6 (cmpd-6), displays an exclusive positive cooperativity with carvedilol among other ß-blockers and enhances the binding affinity of carvedilol for the ß2-adrenergic receptor. Cooperative effects of cmpd-6 augment the ß-blockade property of carvedilol while potentiating its ß-arrestin-mediated signaling functions. These findings have potential implications in advancing G-protein-coupled receptor allostery, developing biased therapeutics and remedying cardiovascular ailments.

Design of ultra-fine carvedilol nanococrystals: Development of a safe and stable injectable formulation.

Carvedilol (CAR) is a strategic beta-blocker agent which its application has been limited by its very low water solubility. The present study describes a soluble form of drug based on nano-cocrystal (NCC) anti-solvent precipitation technique. The COSMOquick software was employed to select the optimum coformer (tartaric acid, TA) and organic solvent (acetone) relying on the enthalpy changes of cocrystallization and solubilization. Central Composite Design (CCD) considering the impact of CAR, TA, poloxamer 188 (stabilizer) concentrations, and anti-solvent/solvent ratio on CAR NCCs particle size (PS) could produce ultra-fine NCCs (about 1 nm). The lyophilization of NCCs investigating slow/fast freezing rates, various types and concentrations of cryprotectants and lyoprotectants indicated that PEG and trehalose (5 % w/vconcentration) under slow freezing rate could re-produce the initial PSs successfully. CAR NCCs indicated about 2000 fold increase in solubility compared with pure CAR. DSC and PXRD experiments proved that the formulations containing trehalose led to more crystalline and the ones comprising PEG led to more amorphous structures. Interestingly, the slow freezed PEG protected NCCs were physically stable for at least 18 months. In conclusion, the NCC technology could produce the first safe soluble form of CAR for treating hypertension urgencies easy for industrial scale-up.

Molecular determinants of pro-arrhythmia proclivity of d- and l-sotalol via a multi-scale modeling pipeline.

Drug isomers may differ in their proarrhythmia risk. An interesting example is the drug sotalol, an antiarrhythmic drug comprising d- and l- enantiomers that both block the hERG cardiac potassium channel and confer differing degrees of proarrhythmic risk. We developed a multi-scale in silico pipeline focusing on hERG channel - drug interactions and used it to probe and predict the mechanisms of pro-arrhythmia risks of the two enantiomers of sotalol. Molecular dynamics (MD) simulations predicted comparable hERG channel binding affinities for d- and l-sotalol, which were validated with electrophysiology experiments. MD derived thermodynamic and kinetic parameters were used to build multi-scale functional computational models of cardiac electrophysiology at the cell and tissue scales. Functional models were used to predict inactivated state binding affinities to recapitulate electrocardiogram (ECG) QT interval prolongation observed in clinical data. Our study demonstrates how modeling and simulation can be applied to predict drug effects from the atom to the rhythm for dl-sotalol and also increased proarrhythmia proclivity of d- vs. l-sotalol when accounting for stereospecific beta-adrenergic receptor blocking.

A preliminary metabolites identification of a novel compound with ß-adrenolytic activity.

BACKGROUND: The identification of main metabolites and assessment of renal excretion of a novel compound with ß-adrenolytic activity (2RS)-1-(1H-indol-4-yloxy)-3-((2-(2-methoxyphenoxy)ethyl)amino)propan-2-ol, briefly called (RS)-9 or 2F109, were studied in vivo in rat serum, urine, faeces, liver, intestine, lungs and kidneys, and in vitro in rat liver microsomes. METHODS: Structures of the metabolites have been developed by comparing the high-resolution product ion mass spectra of metabolites and the parent compound based on the differences in mass values of main fragments. Quantitative analysis of (RS)-9 was done using a system of liquid chromatography coupled with a triple quadrupole mass spectrometer API 2000. Identification studies of predicted metabolites were made by a high-resolution mass spectrometer LTQ XL Orbitrap Discovery and using a Roxy™ system, for online electrochemical mimicry of oxidative metabolism by cytochrome P450s connected to QTRAP 5500. RESULTS: For (RS)-9 (m/z 357.2084) phase I metabolites derived from oxidation process: hydroxyl derivatives (m/z 373.2470) and dihydroxyl derivatives (m/z 389.4318), and phase II metabolites: N-methylated compound (m/z 371.1612), O-glucuronide (m/z 533.5118), and sulfate (m/z 437.2350) were identified. CONCLUSION: (RS)-9 was extensively metabolised to several phase I and II metabolites, and renal excretion was a minor route in its elimination.

Development and Evaluation of a Physiologically Based Pharmacokinetic Drug-Disease Model of Propranolol for Suggesting Model Informed Dosing in Liver Cirrhosis Patients.

AIM: The study was aimed to understand the underlying causes for the differences in propranolol pharmacokinetics (PK) between healthy and cirrhosis populations by using a systematic whole-body physiologically based pharmacokinetic (PBPK) model-building approach for suggesting model informed propranolol dosing in liver cirrhosis patients with different stages of disease severity. METHODS: A whole-body PBPK model was developed by using population simulator PK-Sim® by using reported physicochemical and clinical data for propranolol in healthy and liver cirrhosis populations. The model evaluation was done by visual verification and comparison of PK parameters using their observed/predicted ratios (Robs/pred). RESULTS: The developed model has effectively described the disposition of propranolol after intravenous and oral application in healthy and liver cirrhosis populations. All the model predictions were comparable to the observed clinical data and the Robs/pred for all the PK parameters were within a 2-fold range. A significant increase in plasma concentration of propranolol and decrease in drug clearance was observed in progressive stages of liver cirrhosis. The developed model after evaluation with the reported clinical PK data was used for suggesting model informed propranolol dosing in different stages of liver cirrhosis based on systemic unbound drug concentration. CONCLUSION: The developed PBPK model has successfully described propranolol PK in healthy and cirrhosis populations after IV and oral administration. The evaluated PBPK propranolol-cirrhosis model can have many implications in predicting propranolol dosing in liver cirrhosis patients with different stages of disease severity.

Imprinted ß-ketoenamine-linked covalent organic frameworks as dispersive sorbents for the fluorometric determination of timolol.

Timolol accompanied the formation of fluorescent ß-ketoenamine-linked covalent organic frameworks (COFs) via the Sc(Tof)3-catalyzed condensation of derivated carbaldehyde and hydrazide in a 1,4-dioxane/mesitylene porogen to construct timolol-imprinted COFs (TICOFs). With high imprinting factors, the synthesis-optimized TICOFs were characterized by fluorescence, UV-Vis spectrometry, X-ray diffraction, N2 adsorption/desorption analyses, scanning electron microscopy, and FTIR spectrometry. The TICOF fluorescence measured at 390 nm/510 nm is dynamically quenched by timolol and was thus utilized to quantify timolol in a linear range of 25-500 nM with a LOD of 8 nM. The TICOF recovered 99.4% of 0.5% timolol maleate in a commercial eye drop (RSD = 1.1%, n = 5). In addition, TICOF was used as a dispersive sorbent to recover 95% of 2.0 nM timolol from 20 mg of TICOF in 25 mL phosphate buffer. Dilution factors of 25 and 75 were the maximum tolerated proportions of the urine and serum matrix spiked with 2.0 nM timolol to reach recoveries of 92.4% and 90.3%, respectively.

In depth investigation of the retention behavior of structurally related ß-blockers on RP-HPLC column: Quality by design and quantitative structure-property relationship complementary approaches for optimization and validation.

The persistent introduction of new ß-blockers motivates the demand for optimizing RP-HPLC well-designed analytical procedures that could be applied to this structurally related and commonly prescribed pharmacological group in order to reduce time and chemicals consumption in quality control units. Betoxolol HCl (BEX) and Carvidolol (CAR) were selected as representative examples to conduct predictive studies based on two complementary approaches, Quality by design (QBD) and Quantitative structure property relationship (QSPR). In concern QBD, a Box-Behnken design was adopted at variable chromatographic parameters to achieve the most proper conditions that might be applied for efficient analysis of the majority of group members. On the other hand, the retention time was chosen as the target property in the QSPR study that was conducted onto seven ß. blockers (the two investigated drugs in addition to five other ß. blockers) to find the best correlated molecular descriptors to the retention behavior. Both external and internal validation studies have comparable quality with training levels. Hence a simple selection algorithm of conventional features provides robust confirmatory predictive QBD and QSPR models. Derringer's desirability function as as a multi-criteria approach was applied for getting the optimum chromatographic analysis conditions. Efficient analysis of BET and CAR was achieved at column temperatures of 26.00 and 27.50 °C, respectively using acetonitrile and phosphate buffer (pH 4.55) 70:30 v/v as a mobile phase with a flow rate of 1.00 mL/min, and UV detection at 220 nm. The method was validated in accordance to ICH guidelines, and had exhibited acceptable precision, accuracy, linearity, and robustness.

Bisoprolol-based 18F-PET tracer: Synthesis and preliminary in vivo validation of ß1-blocker selectivity for ß1-adrenergic receptors in the heart.

The selectivity of a drug toward various isoforms of the target protein family is important in terms of toxicology. Typically, drug or candidate selectivity is assessed by in vitro assays, but in vivo investigations are currently lacking. Positron emission tomography (PET) allows the non-invasive determination of the in vivo distribution of a radiolabeled drug, which can provide in vivo data regarding drug selectivity. Since the discovery of propranolol, a non-selective ß-blocker inhibiting both ß1- and ß2-adrenoreceptors (ß-ARs), various selective ß1-blockers, including bisoprolol, have been developed to overcome disadvantages associated with ß2-AR inhibition. As a proof of concept, we performed an in vivo PET study to understand the selectivity and efficacy of bisoprolol as a selective ß-blocker toward ß1-AR, as the heart and peripheral smooth muscles demonstrate distinct populations of ß1- and ß2-ARs. Biodistribution of 18F-labeled bisoprolol (1, [18F]bisoprolol) showed the retention of its uptake in the heart compared with other ß-AR-rich organs at late time points post-injection. The competitive blocking assay using unlabeled bisoprolol exhibited no inhibition of [18F]bisoprolol uptake in any organ but exhibited significantly rapid loss of radioactivity between two different time points in ß1-AR-rich organs such as the heart and brain. Furthermore, the organ-to-blood ratio revealed the slow excretion and better accumulation of [18F]bisoprolol inside the heart. Collectively, the ex vivo biodistribution and blocking study presented insightful evidence to better comprehend the in vivo distribution pattern of bisoprolol as a selective inhibitor targeting ß1-ARs in the heart and provided the possibility of PET as an in vivo technique for evaluating drug selectivity.

Progress in the Enantioseparation of ß-Blockers by Chromatographic Methods.

ß-adrenergic antagonists (ß-blockers) with at least one chiral center are an exceedingly important class of drugs used mostly to treat cardiovascular diseases. At least 70 ß-blockers have been investigated in history. However, only a few ß-blockers, e.g., timolol, are clinically marketed as an optically pure enantiomer. Therefore, the separation of racemates of ß-blockers is essential both in the laboratory and industry. Many approaches have been explored to obtain the single enantiomeric ß-blocker, including high performance liquid chromatography, supercritical fluid chromatography and simulated moving bed chromatography. In this article, a review is presented on different chromatographic methods applied for the enantioseparation of ß-blockers, covering high performance liquid chromatography (HPLC), supercritical fluid chromatography (SFC) and simulated moving bed chromatography (SMB).

Bucco-Adhesive Film as a Pediatric Proper Dosage Form for Systemic Delivery of Propranolol Hydrochloride: In-vitro and in-vivo Evaluation.

OBJECTIVE: To formulate and assess bucco-adhesive films of propranolol hydrochloride for pediatric use. METHODS: Different films were formulated adopting mucin, polyvinyl alcohol, chitosan and carbopol. A drug/polymer compatibility study was conducted adopting differential scanning calorimetry and Fourier transform infrared spectroscopy. The prepared films were physically investigated for variation of weight, propranolol content, thickness, surface pH, proportion of moisture, folding endurance and mucoadhesion. In vitro drug release study and kinetic analysis of the corresponding data have been conducted. The optimized formulation was selected for a bioavailability study using albino rabbits and adopting a developed HPLC method. The pharmacokinetic parameters of the drug were calculated following administration of the optimized film and the corresponding marketed oral tablets to albino rabbits. KEY FINDING: The compatibility study revealed the absence of drug/polymer interaction. The film formulations had suitable mucoadhesive and mechanical properties. The optimized formulation exhibited reasonable drug release that followed Higuchi diffusion pattern. The calculated AUC0-8h presented an enhancement in the bioavailability of propranolol hydrochloride from the selected film formulation by 1.9 times relative to the marketed propranolol oral tablets. CONCLUSION: These findings support that propranolol hydrochloride bucco-adhesive film can be considered as a proper effective dosage form for pediatric delivery.

α1-adrenoceptor activity of ß-adrenoceptor ligands - An expected drug property with limited clinical relevance.

Many ß-adrenoceptor agonists and antagonists including several clinically used drugs have been reported to also exhibit binding to α1-adrenoceptors. Such promiscuity within the adrenoceptor family appears to occur more often than off-target effects of drugs in general. It should not be considered surprising based on the amino acid homology among the nine adrenoceptor subtypes including the counter-ions for binding the endogenous catecholamines. When ß-adrenoceptor ligands also bind to α1-adrenoceptors, they almost always act as antagonists, regardless of being agonists or antagonists at the ß-adrenoceptor. The α1-adrenoceptor affinity of ß-adrenoceptor ligands in most cases is at least one, and often more log units lower than at their cognate receptor. Consistent evidence from multiple investigators indicates that ß-adrenoceptor ligands relatively have the highest affinity for α1A- and lowest for α1B-adrenoceptors. While promiscuity among adrenoceptor subtypes causes misleading interpretation of experimental in vitro data, it is proposed based on the law of mass action that α1-adrenoceptor binding of ß-adrenoceptor ligands rarely contributes to the clinical profile of such drugs, particularly if they are agonists at the ß-adrenoceptor.

A sensitive liquid chromatography-tandem mass spectrometric method for determination of five ß-blockers after labeling with either hydrazonoyl chloride or dansyl chloride reagent.

A sensitive liquid chromatography-tandem mass spectrometry (LC-MS) method was developed for the screening of five ß-blockers (BBs), including atenolol, metoprolol, bisoprolol, propranolol, and betaxolol, in rabbit plasma. An inhouse prepared hydrazonoyl chloride compound (UOSA54) and dansyl chloride (DNS) were successfully coupled with BBs via the amino functional group and analyzed by LC-MS/MS. The excess hydrazonoyl chloride was characterized by a negligible ionization suppression at the electrospray-ionization (ESI) source, which enables the analysis of BBs at a low concentration level. The relative ESI-MS response of derivatized to underivatized BBs was enhanced 2.3 to 3.7-fold. The developed method could be applied for screening of BBs in samples by searching the most abundant MS product ions, including m/z 169 and 211, in addition to the precursor ion and the cleavage of ether moiety. The method could be applied for trace analysis and screening of BBs abuse. The use of UOSA54 was adventitious over dansylated derivatives because of minimal reaction by-products and the negligible ionization suppression effect. The extraction efficiency of BBs from rabbit plasma was improved to reach 77.5-93.9% using tert-butylamine and Chromabond® C18ec-100 mg column. The optimal reaction conditions were optimized and validated. The linear range of analyzed BBs in rabbit plasma was within the range of 0.1 to 25.0 ng/mL, while the limit of quantification (LO Q) was ranged from 0.10 to 0.25 ng/mL.

Beta-Blockers and Berberine: A Possible Dual Approach to Contrast Neuroblastoma Growth and Progression.

The use of nutraceuticals during cancer treatment is a long-lasting debate. Berberine (BBR) is an isoquinoline quaternary alkaloid extracted from a variety of medicinal plants. BBR has been shown to have therapeutic effects in different pathologies, particularly in cancer, where it affects pathways involved in tumor progression. In neuroblastoma, the most common extracranial childhood solid tumor, BBR, reduces tumor growth by regulating both stemness and differentiation features and by inducing apoptosis. At the same time, the inhibition of ß-adrenergic signaling leads to a reduction in growth and increase of differentiation of neuroblastoma. In this review, we summarize the possible beneficial effects of BBR in counteracting tumor growth and progression in various types of cancer and, in particular, in neuroblastoma. However, BBR administration, besides its numerous beneficial effects, presents a few side effects due to inhibition of MAO A enzyme in neuroblastoma cells. Therefore, herein, we proposed a novel therapeutic strategy to overcome side effects of BBR administration consisting of concomitant administration of BBR together with ß-blockers in neuroblastoma.

Hot melt-extrusion improves the properties of cyclodextrin-based poly(pseudo)rotaxanes for transdermal formulation.

This study aimed to investigate whether hot-melt extrusion (HME) processing can modify the interactions between drugs, cyclodextrins and polymers, and in turn alter the microstructure and properties of supramolecular gels. Mixtures composed of amphiphilic polymer (Soluplus), cyclodextrin (HPßCD or αCD), plasticizer (PEG400 or PEG6000) and colloidal silicon dioxide were processed by HME. Carvedilol (CAR) was added to the formulation aiming its transdermal delivery. Extrudates were characterized by HPLC, XRPD, FTIR, DSC, and solid-state NMR. Gels prepared from extrudates (HME gels) or the corresponding physical mixtures (PM gels) in PBS were analyzed regarding components ordering (NMR, SEM), rheology, and CAR diffusion rate. HME led to the loss of the crystalline lattice of CAR and αCD, without causing any drug degradation. Solid NMR indicated that HME promoted the interaction of α-CD and HPßCD with the other components. HME gels had no coarsely disperse particles in their structure and behaved as weak gels (G' ~ G″). In contrast, PM gels contained drug crystals and showed elastic behavior (G' > G″). In general, HME gels were less viscous than PM ones and led to higher drug flux, especially those prepared using HPßCD. Moreover, the association of HPßCD and PEG6000 provided faster drug flux from supramolecular gels regardless the higher gel viscosity. The results evidenced that HME processing can decisively modify the arrangement of the components in the supramolecuar gels and, consequently, their properties, notably increasing drug release rate.

An allosteric modulator binds to a conformational hub in the ß2 adrenergic receptor.

Most drugs acting on G-protein-coupled receptors target the orthosteric binding pocket where the native hormone or neurotransmitter binds. There is much interest in finding allosteric ligands for these targets because they modulate physiologic signaling and promise to be more selective than orthosteric ligands. Here we describe a newly developed allosteric modulator of the ß2-adrenergic receptor (ß2AR), AS408, that binds to the membrane-facing surface of transmembrane segments 3 and 5, as revealed by X-ray crystallography. AS408 disrupts a water-mediated polar network involving E1223.41 and the backbone carbonyls of V2065.45 and S2075.46. The AS408 binding site is adjacent to a previously identified molecular switch for ß2AR activation formed by I3.40, P5.50 and F6.44. The structure reveals how AS408 stabilizes the inactive conformation of this switch, thereby acting as a negative allosteric modulator for agonists and positive allosteric modulator for inverse agonists.

Clinical Pharmacokinetics of Propranolol Hydrochloride: A Review.

BACKGROUND: Nobel laureate Sir James Black's molecule, propranolol, still has broad potential in cardiovascular diseases, infantile haemangiomas and anxiety. A comprehensive and systematic review of the literature for the summarization of pharmacokinetic parameters would be effective to explore the new safe uses of propranolol in different scenarios, without exposing humans and using virtual-human modeling approaches. OBJECTIVE: This review encompasses physicochemical properties, pharmacokinetics and drug-drug interaction data of propranolol collected from various studies. METHODS: Clinical pharmacokinetic studies on propranolol were screened using Medline and Google Scholar databases. Eighty-three clinical trials, in which pharmacokinetic profiles and plasma time concentration were available after oral or IV administration, were included in the review. RESULTS: The study depicts that propranolol is well absorbed after oral administration. It has dose-dependent bioavailability, and a 2-fold increase in dose results in a 2.5-fold increase in the area under the curve, a 1.3-fold increase in the time to reach maximum plasma concentration and finally, 2.2 and 1.8-fold increase in maximum plasma concentration in both immediate and long-acting formulations, respectively. Propranolol is a substrate of CYP2D6, CYP1A2 and CYP2C19, retaining potential pharmacokinetic interactions with co-administered drugs. Age, gender, race and ethnicity do not alter its pharmacokinetics. However, in renal and hepatic impairment, it needs a dose adjustment. CONCLUSION: Physiochemical and pooled pharmacokinetic parameters of propranolol are beneficial to establish physiologically based pharmacokinetic modeling among the diseased population.