bluuebunny/crossref_metadata_2025_split huggingface dataset:
Stereospecific determination of the in vitro dissolution of modified release formulations of (±)‐verapamil
Authors: Carr Robert A. , Pasutto Franco M. , Longstreth James A. , Foster Robert T. 
Published: January 2005

AbstractThe determination of the in vitro dissolution profiles of three different modified‐release formulations of (±)‐verapamil were determined and compared to a reference (Calan SR). The determination of (±)‐verapamil utilized a microwave‐facilitated derivatization reaction with an enantiomerically pure reagent followed by measurement of drug by reversed‐phase high‐performance liquid chromatography (HPLC). The dissolution profile of each of the four modified‐release formulations was followed for the first hour in simulated gastric fluid (pH 1.2) and then in simulated intestinal fluid (pH 7.5) for up to a total of 12 h. The resulting dissolution profiles of each modified‐release formulation suggested that only one of the three test formulations had a similar dissolution to the Calan SR reference. Interestingly, the (S:R)‐enantiomer ratios of two of the test products were significantly different from unity, and the third test product was also significantly different from unity if 4 out of 5 outliers were omitted. It is suggested that dissolution testing of modified‐release formulations containing chiral active ingredients must be stereospecific in order to discern whether a drug‐excipient interaction occurs. Additionally, it may be suggested that dissolution techniques relying more upon diffusion of medium through the tablet matrix, rather than erosion of the tablet, may accentuate enantiomeric differences in release rates. © 1993 Wiley‐Liss, Inc.
Chromatographic resolution of chiral intermediates in β‐adrenergic blocker synthesis on chiral stationary phases
Authors: Ader Ulrich , Muschalek Volker , Schneider Manfred P. 
Published: January 2005

AbstractThe enantiomeric purities of optically active intermediates for β‐adrenergic blocking agents prepared via enzyme‐assisted processes can be determined rapidly and with high accuracy using HPLC on commercially available columns with chiral supports [Chiralcel OD, OB; Chiralpak OT(+)]. The dependence of the resolution parameters on the substitution pattern of both hydroxy compounds and their esters is reported. © 1993 Wiley‐Liss, Inc.
Use of isotopically chiral [4′‐13C]famciclovir and 13C NMR to identify the chiral monoacetylated intermediates in the conversion of famciclovir to penciclovir by human intestinal wall extract
Authors: Hodge R. Anthony Vere , Darlison Sarah J. , Readshaw Simon A. 
Published: January 2005

AbstractFamciclovir is the oral form of the potent antiherpesvirus agent, penciclovir. Hydrolysis of one of the acetyl ester groups of famciclovir creates a chiral centre leading to the possible formation of (R)‐ and (S)‐enantiomers. During its conversion to penciclovir, famciclovir forms two chiral metabolites, namely monoacetyl‐6‐deoxy‐penciclovir and monoacetyl‐penciclovir. The absolute configuration and stereospecificity of the monoacetyl metabolites of famciclovir, produced in human intestinal wall extract, were determined using isotopically chiral famciclovir and 13C NMR spectroscopy of the isolated metabolites. 13C NMR showed that the esterase(s), in human intestinal wall extract, hydrolysed the acetyl group preferentially from the pro‐(S)‐acetoxymethyl group of famciclovir. The specificity of esterase action in forming monoacetyl‐6‐deoxy‐penciclovir and monoacetyl‐penciclovir was about 77 and 72%, respectively. © 1993 Wiley‐Liss, Inc.
Diagnosis and monitoring of disseminated candidiasis based on serum/urine D/L‐arabinitol ratios
Authors: Roboz John 
Published: January 2005

AbstractDisseminated candidiasis, a devastating disease with high morbidity and mortality in immunosuppressed patients, is difficult to diagnose because of the protean nature of symptoms and the lack of rapid and reliable laboratory diagnostic procedures. The subject of this review is the status of gas chromatographic–mass spectrometric techniques for the determination of D‐arabitinol, a unique metabolite of pathogenic Candida species, in serum and urine. The enantiomers are separated by chiral chromatography followed by specific and sensitive detection using chemical ionization and selected ion monitoring. Using D/L‐arabinitol ratios, instead of individual concentrations, eliminates the need for knowing the volume of samples and for calibration curves. A new filter paper technique requires only an unmeasured drop of whole blood (venous or finger/heel puncture) or urine; paper spots are mailable. Parallel determinations of D/L‐arabinitol ratios in serum and urine in normal subjects and cancer patients with both normal and increased D/L‐arabitinol ratios revealed constant (1.2–1.3 range) ratios of serum D/L‐arabitinol/urine D/L‐arabinitol for all populations studied. Analyzing two body fluids taken at the same time increases reliability by reducing false positives. © 1994 Wiley‐Liss, Inc.
(1′R,2′S,5′R)‐Menthyl‐(5R)‐acetoxy‐1,3‐oxathiolan‐(2R)‐carboxylate: Synthesis and isomeric purity determination by HPLC
Authors: Siddiqui M. Arshad , Jin Haolun , Evans Colleen A. , Dimarco Marika P. , Tse H. L. Allan , Mansour Tarek S. 
Published: January 2005

AbstractChemoselective reduction of one isomer of the 1‐menthylester of 1,3‐oxathiolan‐5‐one‐2‐carboxylic acid produces a mixture of four lactol diastereomers from which the title compound was isolated after acylation. The isomeric purity and absolute stereochemistry were determined by spectroscopic methods, chiral HPLC techniques, and conversion to (−)‐2′‐deoxy‐3′‐thiacytidine (Lamivudine, 3TCTM). © 1994 Wiley‐Liss, Inc.
Single dose pharmacokinetics of (S)‐atenolol administered orally as a single enantiomer formulation and as a racemic mixture (tenormin™)
Authors: Clementi William A. , Garvey Thomas Q. , Clifton G. Dennis , McCoy Randall A. , Brandt Steven , Schwartz Sheldon 
Published: January 2005

AbstractThe purpose of this study was to describe the pharmacokinetics of and heart rate and blood pressure responses to (S)‐atenolol (SATN) and (R)‐atenolol (RATN) after oral administration of (S)‐atenolol and (R,S)‐atenolol (Tenormin™) in man. Eight male subjects were given single oral doses of 50 mg of SATN as a single enantiomer formulation (SEF) and 100 mg of Tenormin™ (TMN) using a randomized, double‐blind, 2‐period, complete crossover study design. Subjects performed exercise tolerance tests (Bruce Protocol) before and 2, 4, 6, 8, 12, and 24 h after drug administration. Plasma samples were obtained 2 min before and 30 min, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 16, and 24 h after dosing. Urine was collected for the first 48 h after dosing. Plasma and urine samples were analyzed for SATN and RATN by an enantioselective HPLC method. SEF and Tenormin™ attenuated exercise‐induced increases in heart rate and systolic blood pressure. Mean changes in exercise heart rates 4 h after dosing were −38 ± 3 bpm and −37 ± 3 bpm for SEF and TMN, respectively, P = 0.792. Mean changes in exercise systolic blood pressure were −42 ± 12 mm Hg and −55 ± 14 mm Hg for SEF and TMN, respectively, P = 0.484. Mean area under the plasma level time curve (AUC0–24) and mean Cmax for SATN for SEF were significantly lower than for SATN after TMN. Mean SATN AUCs0–24 were 1867 ± 261 and 2543 ± 223 ng · h/ml (P = 0.005) and mean Cmaxs were 225 ± 29 and 333 ± 30 ng/ml, for SEF and TMN, respectively (P = 0.011). Mean Tmax for SATN occurred significantly earlier after SEF than after TMN (2.9 ± 0.3 and 3.3 ± 0.3 h, P = 0.028). The amount of SATN excreted in urine was significantly lower after SEF than after TMN (18.7 ± 2.7 and 24.2 ± 2.0 mg, P = 0.017). AUC, Cmax, and amount excreted in urine (Au) were significantly higher for RATN than SATN after TMN. Mean AUCs, Cmaxs, and Aus for RATN compared to SATN were 2806 ± 239 vs 2543 ± 223 ng ± h/ml (P < 0.0001), 360 ± 31 vs 333 ± 30 ng/ml (P < 0.0001), and 25 ± 2.1 vs 24 ± 2 mg (P = 0.004), respectively. SEF and TMN are equieffective in attenuating exercise‐induced increases in heart rate and systolic blood pressure. The SEF has lower bioavailability compared to TMN and RATN plasma levels are higher than SATN after TMN administration. © 1994 Wiley‐Liss, Inc.
Optical resolution by preferential crystallization of 4‐methylpiperidinium hydrogen (RS)‐phenylsuccinate
Authors: Shiraiwa Tadashi , Ohki Yasunobu , Sado Yujin , Miyazaki Hideya , Kurokawa Hidemoto 
Published: January 2005

AbstractGibbs energy of racemate formation, binary melting point diagram, and ternary solubility diagram suggested that 4‐piperidinium hydrogen (RS)‐phenylsuccinate [(RS)‐4‐MP salt] exists in a conglomerate. Appropriate conditions were explored on the basis of free energy of critical nucleation in a supersaturated solution to resolve efficiently (RS)‐4‐MP salt by preferential crystallization. Successive preferential crystallization of (RS)‐4‐MP salt in ethanol at 20°C gave (R)‐ and (S)‐4‐MP salts of 90–94% optical purities. Optically pure (R)‐ and (S)‐phenylsuccinic acids were obtained by recrystallization of the (R)‐ and (S)‐4‐MP salts, followed by treatment of the salts purified with hydrochloric acid. © 1994 Wiley‐Liss, Inc.
Investigation of enantioselective ligand–protein binding and displacement interactions using capillary electrophoresis
Authors: Lloyd David K. , Li Song , Ryan Patricia 
Published: January 2005

AbstractWhen a protein such as human serum albumin is added to the separation buffer in capillary electrophoresis, the mobility of solutes which bind to that protein may be altered. The change in mobility of the solute is a function both of the strength of the binding interaction, and the difference in mobility between the free solute and protein additive. By adding other ligands which themselves bind to the protein, the strength of the solute–protein binding may be modified, leading to a measurable change in the mobility of the solute. These effects are particularly striking for chiral compounds, where enantioselectivity may be completely lost on addition of a competitive ligand. Capillary electrophoresis with human serum ablumin as a buffer additive was used to separate the enantiomers of benzoin and three phenothiazine derivatives. A comparison of the binding of (S)‐benzoin to human serum albumin as determined by capillary electrophoresis and by ultrafiltration was made. A variety of other ligands were then added to the buffer along with the protein, and the effects on mobility and enantioselectivity were studied. The displacers included (R)‐ and (S)‐oxazepam hemisuccinate, (R)‐ and (S)‐warfarin, nitrazepam, phenylbutazone, and octanoic acid. From the results obtained, it seems that capillary electrophoresis may be a useful, rapid method to screen for drug–drug interactions. There are some advantages of using this technique to study protein–ligand interactions: Only very small amounts of ligand are needed (useful when dealing with metabolites); for chiral compounds, if protein binding is stereoselective, then the method is also stereoselective, so single enantiomers are not needed; finally, measurements are obtained in solution, without the need for immobilization of the protein. A disadvantage is that the ligand and protein must have significantly different electrophoretic mobilities. © 1994 Wiley‐Liss, Inc.
Assignment of absolute configuration and optical purity determination of (R)‐ and (S)‐econazole nitrate by enantioselective HPLC: Method development and application
Authors: Lämmerhofer Michael , Lindner Wolfgang 
Published: January 2005

AbstractA method is described for the synthesis and optical purity determination of (−)‐(R)‐ and (+)‐(S)‐econazole via the optically pure intermediates, (R)‐ and (S)‐imidazolylethanol, which are available by chromatographic resolution or by fractional crystallization of diastereomeric O,O′‐disubstituted (R*;R*)‐ or (S*;S*)‐tartaric acid monoesters of the parent imidazolylethanol racemate. Furthermore, this method allows the chromatographic assignment of the absolute configuration of the chiral center of the imidazolylethanol enantiomers and consequently of econazole enantiomers. In addition, a direct liquid chromatographic enantioseparation method for the determination of the optical purity of (R)‐ and (S)‐econazole and other chiral imidazoles on a protein type CSP (OVM) is described and applied to confirm chromatographically the absolute configuration evaluations. © 1994 Wiley‐Liss, Inc.
Effect of cytochrome P‐450 1A induction on enantioselective metabolism and pharmacokinetics of an aryltrifluoromethyl sulfide in the rat
Authors: Benoît Etienne , Buronfosse Thierry , Delatour Paul 
Published: January 2005

AbstractThe pharmacokinetics of the antiparasitic drug toltrazuril (1‐methyl‐3‐[3‐methyl‐4‐[4‐[trifluoromethyl]thio]phenoxy]phenyl‐1,3,5‐ triazine‐2,4,6(1H,3H,5H)‐trione) were studied in the rat following pretreatment with 3‐methylcholanthrene, an inducer of rat liver cytochrome P‐450 1A. The induction markedly modified the pharmacokinetics of the compound, leading to a decrease in the AUC value for toltrazuril sulfoxide. The results were explained on the basis of previous results from our laboratory relating to the product enantioselectivity of the formation of the sulfoxide and the substrate enantioselectivity of the subsequent formation of the sulfone. © 1994 Wiley‐Liss, Inc.
Influence of endotoxin on the stereoselective pharmacokinetics of oxprenolol, propranolol, and verapamil in the rat
Authors: Laethem Martine E. , Belpaire Frans M. , Wijnant Pascal , Rosseel Marie‐Thérèse , Bogaert Marc G. 
Published: January 2005

AbstractThe influence of endotoxin‐induced inflammation on the enantioselective pharmacokinetics of propranolol, oxprenolol, and verapamil, which bind to α1‐acid glycoprotein, was studied in the rat. The racemic mixtures were given orally. In the control animals, for propranolol and oxprenolol, the plasma concentrations of the (R)‐enantiomer were higher than those of the (S)‐enantiomer, while for verapamil the reverse was true. Protein binding and intrinsic clearance are the main factors responsible for this enantioselectivity. After endotoxin treatment, for the three drugs tested the plasma concentrations and the plasma binding of both enantiomers were significantly increased. This effect was more pronounced for (R)‐propranolol, (R)‐oxprenolol, and (S)‐verapamil than for their respective antipodes. The enantioselective effect of endotoxin on the plasma concentrations of the drugs studied seems mainly due to the enantioselective increase in binding to α1‐acid glycoprotein. © 1994 Wiley‐Liss, Inc.
The chemical and thermal stability of the acetamido group of (R)‐ and (S)‐atenolol: Synthetic and chromatographic studies
Authors: Kleidernigg Oliver P. , Maier Norbert M. , Uray Georg , Lindner Wolfgang 
Published: January 2005

AbstractThe chemical stability of the acetamido moiety of the β‐blocker atenolol toward possible dehydration causing a nitrile formation during an acid‐catalyzed chiral derivatization procedure with O,O′‐(R,R)‐diacylated tartaric acid anhydrides was elucidated. All the necessary reference compounds including the oxazolidine‐2‐one derivatives of the respective aminopropanols were synthesized, their structures confirmed by various spectroscopic methods, and chromatographically compared using HPLC and GC‐MS. In the course of this work it was shown that the acetamido moiety of atenolol is quite stable toward dehydrating agents but shows a significant thermolability, e.g., in the injection system of a GC, which leads to the dehydrated form of atenolol namely, “nitriloatenolol.” © 1994 Wiley‐Liss, Inc.
Effects of catechol ring fluorination on cardiovascular and renal activities of fenoldopam enantiomers
Authors: Kinter Lewis B. , Mann William A. , Weinstock Joseph , Ruffolo Robert R. 
Published: January 2005

AbstractSK&F 87516 is a potent DA1 receptor agonist with demonstrated renal vasodilator activity. SK&F 87516 is the 6‐fluoro analog of another DA1 agonist/renal vasodilator agent, fenoldopam. SK&F 87516 is a racemic mixture of two enantiomers, SK&F(R)‐87516 and SK&F(S)‐87516, and like fenoldopam, the (R)‐enantiomer is responsible for the biological activities of the racemate. SK&F(R)‐87516 is diuretic in spontaneously hypertensive rats and in dogs, whereas its enantiomer, SK&F(S)‐87516 is inactive. SK&F(R)‐87516 increases glomerular filtration rate, an effect which may account, in part, for its diuretic activity. Unlike fenoldopam, SK&F(R)‐87516 is not associated with acute hypotensive activity, tachycardia, or stimulation of the renin‐angiotensin‐aldosterone system. The activity differences between SK&F(R)‐87516 and fenoldopam are not related to differences in DA1 agonist potency. The activity differences may be due to the differing effects of fluorine and chlorine on the electron distribution in the catechol ring, resulting in an enhanced effect of SK&F(R)‐87516 at α2‐adrenoceptors. © 1994 Wiley‐Liss, Inc.
Chiral pharmacokinetics of rac‐flurbiprofen and pharmacodynamics of anabolic bone response in the normal rat
Authors: Wechter William J. , Bigornia Annette E. , Murray E. David , Jee Webster S. S. 
Published: January 2005

AbstractThe route of administration of the NSAID, flurbiprofen (sq vs. po) resulted in positive and negative results respectively with regard to enhanced cancellous and cortical bone accumulation in the immature rat. This pharmacokinetic study was an effort to understand the pharmacodynamic difference between the two routes of administration observed when the same dose range of drug, given as single daily doses, had been employed in both studies. Conventional chiral pharmacokinetics were evaluated in young rats. A significant difference was observed in the Tmax of the active (S)‐enantiomer by both administration routes (sq 4 h and po 1 h). The bioavailability, as evaluated by AUCs favored the sq route as expected. The plasma concentrations over 18 h, at steady state, for one po dose group (0.5 mg/kg/day) fell well within the therapeutic window described by the 0.1 and 0.5 mg/kg sq doses which had demonstrated anabolic bone activity. Oral dosing had exhibited no significant bone activity. We conclude that the pharmacodynamic difference between routes of administration cannot be simply explained on a pahrmacokinetic basis. Consequently, experiments detailing the pharmacodynamics and pharmacokinetics of single and multiple dose administration of aryl‐propionic acids in normal and osteopenic states need further pharmacologic study. © 1994 Wiley‐Liss, Inc.
Evaluation of the macrocyclic antibiotic vancomycin as a chiral selector for capillary electrophoresis
Authors: Armstrong Daniel W. , Rundlett Kimber L. , Chen Jing‐Ran 
Published: January 2005

AbstractVancomycin is one of a family of related macrocyclic glycopeptide antibiotics that were discovered by scientists at the Eli Lilly Company in the 1950s. It has been used to treat severe staphylococcal infections, particularly when bacterial resistance to other antibiotics has developed. Vancomycin is a naturally occurring chiral compound and has a number of stereogenic centers. Furthermore, it contains a variety of functionalities that are known to be useful for enantioselective interactions (e.g., hydrogen bonding groups, hydrophobic pockets, aromatic groups, amide linkages, etc.). The physicochemical properties of vancomycin, including its stability in solution, are discussed as they pertain to capillary electrophoresis. Over 100 racemates were resolved including many nonsteroidal antiinflammatory drugs, antineoplastic compounds and N‐derivatized amino acids. Many of these compounds had very high resolution factors. Optimization and the effect of different experimental parameters on the enantioselective separations are discussed. © 1994 Wiley‐Liss, Inc.
Enantioselective syntheses and calcium channel modulating effects of (+)‐ and (−)‐3‐isopropyl 5‐(4‐methylphenethyl) 1,4‐dihydro‐2,6‐dimethyl‐4‐(2‐pyridyl)‐3,5‐pyridinedicarboxylates
Authors: Iqbal Nadeem , Vo Dean , McEwen Carol‐Anne , Wolowyk Michael W. , Knaus Edward E. 
Published: January 2005

AbstractThe (+)‐ and (−)‐enantiomers of 3‐isopropyl 5‐(4‐methylphenethyl) 1,4‐dihydro‐2,6‐dimethyl‐4‐(2‐pyridyl)‐3,5‐pyridinedicarboxylate were synthesized using an efficient highly enantioselective (ee ≥ 96%) variant of the Hantzsch dihydropyridine synthesis. The key step in this procedure involved the asymmetric Michael addition of a metalated chiral aminocrotonate, derived from D‐valine or L‐valine, respectively, to the Knoevenagel acceptor (Z)‐2‐isopropoxycarbonyl‐1‐(2‐pyridyl)‐but‐1‐en‐3‐one. Both enantiomers exhibited a dual cardioselective partial calcium channel agonist (positive inotropic)/smooth muscle selective calcium channel antagonist effect. The relative in vitro smooth muscle calcium channel antagonist activities of the (−):(+) enantiomers was 26:1. In contrast, the (+)‐enantiomer exhibited a greater in vitro positive inotropic effect on guinea pig left atrium where the contractile force was maximally increased by 14.8% at a concentration of 1.63 × 10−8 M. © 1994 Wiley‐Liss, Inc.
Chiral copper(I)—thiolate clusters in metallothionein and glutathione
Authors: Presta Anthony , Stillman Martin J. 
Published: January 2005

AbstractMetallothionein (MT) is a ubiquitous mammalian protein comprising 61 or 62 nonaromatic amino acids of which 20 are cysteine residues. The high sulfhydryl content imparts to this protein a unique and remarkable ability to bind multiple metal ions in structurally significant metal–thiolate clusters. MT can bind seven divalent metal ions per protein molecule in two domains with exclusive tetrahedral metal coordination. The domain stoichiometries for the M7S20 structure are M4(Scys)11 (α domain) and M3(Scys)9 (β domain). Up to 12 Cu(I) ions can displace the 7 Zn2+ ions bound per molecule in Zn7–MT. The incoming Cu(I) ions adopt a trigonal planar geometry with domain stoichiometries for the Cu12S20 structure of Cu6(Scys)11 and Cu6(Scys)9 for the α and β domains, respectively. The circular dichroism (CD) spectra recorded as Cu+ is added to Zn7–MT to form Cu12–MT directly report structural changes that take place in the metal binding region. The spectrum arises under charge transfer transitions between the cysteine S and the Cu(I); because the Cu(I)–thiolate cluster units are located within the chiral binding site, intensities in the CD spectrum are directly related to changes in the binding site. The CD technique clearly indicates stoichiometries of several Cu(I)–MT species. Model Cu(I)–thiolate complexes, using the tripeptide glutathione as the sulfhydryl source, were examined by CD spectroscopy to obtain transition energies and the Cu(I)–thiolate coordination geometries which correspond to these bands. Possible structures for the Cu(I)–thiolate clusters in the α and β domains of Cu12–MT are proposed. © 1994 Wiley‐Liss, Inc.