bluuebunny/crossref_metadata_2025 huggingface dataset:
Direct resolution of ergot alkaloid enantiomers on a novel chiral silica‐based stationary phase
Authors: Flieger Miroslav , Sinibaldi Massimo , Cvak Ladislav , Castellani Loredana
Published: January 2005

A new covalently‐bonded, silica‐based stationary phase, using as the chiral selector the 1‐(3‐aminopropyl) derivative of (+)‐(5R,8S,10R)‐terguride, has been developed to resolve optically active isomers by HPLC. Good resolution of structurally related racemic ergot alkaloids were obtained using water‐methanol mixtures as the eluent. Analysis of the influence of the type and concentration of the organic modifier, and the pH of the buffer in the mobile phase allowed the enantioseparation of these compounds to be optimized. Determination of the optical purity of a lisuride‐containig drug is reported. © 1994 Wiley‐Liss, Inc.
Semipreparative enantiomeric separation of a series of putative melatonin receptor agents using tri‐acetylcellulose as chiral stationary phase
Authors: Jansen Johanna M. , Copinga Swier , Gruppen Gert , Isaksson Roland , Witte Dirk T. , Grol Cor J.
Published: January 2005

In order to obtain milligram amounts of the enantiomers of a series of compounds to be tested for binding to the melatonin binding site, a system for semipreparative enantiomeric separation was set up using tri‐acetylcellulose as the chiral stationary phase. Interactions of this class of compounds with tri‐acetylcellulose were examined on an analytical scale with a series of 20 compounds. Apparently, both steric and electrostatic interactions determine retention behavior on tri‐acetylcellulose. Semipreparative separations were carried out for a subset of seven compounds. The purity of the first eluting enantiomer usually was around 99%, whereas the purity of the second eluting enantiomer was slightly less. The system described is easy to use and has the major advantage that a series of compounds can be separated with one technique. The purities obtained are sufficient for a first screen of their affinity. © 1994 Wiley‐Liss, Inc.
Investigations into the chirality of the metabolic sulfoxidation of cimetidine
Authors: Kuzel Ryta A. , Bhasin Satvinder K. , Oldham Harriet G. , Damani Lyaquatali A. , Murphy Jo , Camilleri Patrick , Hutt Andrew J.
Published: January 2005

The individual enantiomers of cimetidine sulfoxide were resolved by preparative chromatography using a Chiralcel OC stationary phase and were characterized by the determination of optical rotation and circular dichroism spectra. Cimetidine sulfoxide was isolated from the urine of two healthy male volunteers following oral administration of cimetidine (400 mg). Urine was collected every 2 h for 12 h postdosing, after which time HPLC analysis indicated negligible recovery of the drug as the sulfoxide. Some 7% of the dose was recovered as cimetidine sulfoxide over this period. The enantiomeric composition of cimetidine sulfoxide was determined by sequential achiral—chiral chromatography using the OC phase. Over the collection period the enantiomeric ratio was found to be constant in all samples at (+/−) of 71 ± 2.5:29 ± 2.5. The enantiomeric composition of cimetidine sulfoxide was also determined in rat urine (24 h) following the administration of cimetidine (30 mg/kg po) to male Wistar rats (n = 7). The enantiomeric ratio in this case was found to be (+/−) 57 ± 2.3:43 ± 2.3. These preliminary data indicate that sulfoxidation of cimetidine is stereoselective with respect to the (+)‐enantiomer and that species variation in enantiomeric composition occurs. © 1994 Wiley‐Liss, Inc.
Enantioselective esterification of 2‐methylbutyric acid catalyzed via lipase immobilized in microemulsion‐based organogels
Authors: Uemasu Isamu , Hinze Willie L.
Published: January 2005

Chromobacterium viscosum lipase (c.v. lipase) was immobilized in microemulsion‐based órganogels and successfully utilized for the enantioselective esterification of (+/−)‐2‐methylbutynic acid to preferentially form ethyl‐(+)‐2‐methylbutyrate. The reaction time course and enantioselectivity obtained with the organogel—lipase system was compared and contrasted to that achieved in a reversed micellar solution system that contained lipase solubilized in its inner water core as well as that in which powdered lipases were directly dispersed in an organic solvent. The unique properties and potential benefits of the organogel system are discussed. © 1994 Wiley‐Liss, Inc.
Substituent effects in the enantioselective reduction of acetophenones with nabh4 in the presence of β‐cyclodextrin
Authors: Deratani André , Renard Estelle
Published: January 2005

The effect of substituent groups on asymmetric induction by β‐cyclodextrin (β‐CD) was investigated in the reduction of a series of o‐, m‐, and p‐substituted acetophenones (X = H, Br, Cl, CH3, NO2, OCH3) with aqueous NaBH4. The inclusion of the ketones studied in β‐CD led to water‐insoluble compounds so that the reaction proceeded in the solid state. The substitutions resulted generally in higher enantioselectivities than that obtained for acetophenone indicating stronger host—guest interactions. Acetophenone and its m‐ and p‐derivatives gave preponderantly the (−)‐alcohol while the prevailing enantiomer was the (+)‐alcohol in the case of the o‐derivatives. The enantioface selectivity was found to be mainly governed by steric demands imposed by the size and the shape of the β‐CD cavity in the case of the o‐substituted acetophenones and by hydrophobic interactions in the case of the m‐derivatives. A more complicated situation arose from the asymmetic reduction of p‐derivatives where a combination of these factors with hydrogen bonding of the carbonyl group to the hydroxyls of β‐CD are responsible for the enantioselectivity. © 1994 Wiley‐Liss, Inc.
Circular dichroism studies of the self‐association of amphotericin B
Authors: Brittain Harry G.
Published: January 2005

Circular dichroism (CD) spectroscopy has been used to evaluate the ability of 21 different solvents to influence the aggregation state of amphotericin B. Using the relative donor/acceptor tendencies known for each solvent system, it was possible to deduce information as to the factors which goven the self‐association of amphotericin B. It was concluded that in the absence of strong solvent interaction, amphotericin B prefers to self‐associate into oligomeric species. This intrinsic driving force can be overcome through the use of solvents which function as strong electron pair donors, probably forming specific solvent—solute species. © 1994 Wiley‐Liss, Inc.
Stereospecific determination, chiral inversion in vitro and pharmacokinetics in humans of the enantiomers of thalidomide
Authors: Eriksson Tommy , Bjöurkman Sven , Roth Bodil , Fyge Årsa , Höuglund Peter
Published: January 2005

The purposes of this work were (1) to develop a high performance liquid chromatographic (HPLC) assay for the enantiomers of thalidomide in blood, (2) to study their inversion and degradation in human blood, and (3) to study the pharmacokinetics of (+)‐(R)‐ and (−)‐(S)‐thalidomide after oral administration of the separate enantiomers or of the racemate to healthy male volunteers. The enantiomers of thalidomide were determined by direct resolution on a tribenzoyl cellulose column. Mean rate constants of chiral inversion of (+)‐(R)‐thalidomide and (−)‐(S)‐thalidomide in blood at 37°C were 0.30 and 0.31 h−1, respectively. Rate constants of degradation were 0.17 and 0.18 h−1. There was rapid interconversion in vivo in humans, the (+)‐(R)‐enantiomer predominating at equilibrium. The pharmacokinetics of (+)‐(R)‐ and (−)‐(S)‐thalidomide could be characterized by means of two one‐compartment models connected by rate constants for chiral inversion. Mean rate constants for in vivo inversion were 0.17 h−1 (R to S) and 0.12 h−1 (S to R) and for elimination 0.079 h−1 (R) and 0.24 h−1 (S), i.e., a considerably faster rate of elimination of the (−)‐(S)‐enantiomer. Putative differences in therapeutic or adverse effects between (+)‐(R)‐ and (−)‐(S)‐thalidomide would to a large extent be abolished by rapid interconversion in vivo. © 1995 Wiley‐Liss, Inc.
Macromolecular ionophores. 1. Chiral recognition properties of poly[(1→6)‐2,5‐anhydro‐D‐glucitol] toward racemic amino acid ester
Authors: Kakuchi Toyoji , Satoh Toshifumi , Umeda Satoshi , Mata Junji , Yokota Kazuaki
Published: January 2005

The chiral recognition property of poly[(1→6)‐2,5‐anhydro‐3,4‐di‐O‐alkyl‐D‐glucitol] (1) toward racemic RCH (CO2CH3)NH3+ · PF6− (2 · HPF6) has been studied using a transport system involving an aqueous source and receiving phases separated by a chloroform phase containing 1. Transport rates for aromatic guests 2a (R = Ph) and 2b (R = CH2Ph) were faster than those for aliphatic guests, 2c (R = CH(CH3)2) and 2d (R = CH2CH(CH3)2), using the polymer substituted with methyl groups (1a). The enantiomeric excess (e.e.) was 10.9% for 2a as a maximum value and decreased in the order of 2a > 2c > 2b = 2d. When the transport of 2a · HPF6 was carried out using the polymers with 3,4‐di‐O‐methyl (1a), ethyl (1b), allyl (1c), and pentyl (1d) groups, the e.e. was 22.0% for 1d as a maximum value and increased in the order of 1a < 1b < 1c < 1d. The formation of a complex between 1a and 2a · HPF6 was confirmed by 1H and 13C NMR spectral measurements. © 1995 Wiley‐Liss, Inc.
Resolution and determination of enantiomeric purity of the enantiomers of felodipine using chiral‐AGP® as stationary phase
Authors: Karlsson Anders , Pettersson Karin , Hernqvist Kerstin
Published: January 2005

A direct chiral chromatographic reversed phase method for the determination of the enantiomers of felodipine is described. The influence of charged and uncharged modifiers as well as the effect of the mobile phase pH on the enantiomeric resolution is discussed. A high mobile phase pH and the addition of 2‐propanol as organic modifier gave the highest separation factor (α = 1.3). The high mobile phase pH (pH = 7.6) is outside the recommended pH limit of silica based columns but was necessary to achieve baseline resolution of (R)‐ and (S)‐felodipine. Improvement of column efficiency by increasing column temperature was utilized for optimization of the enantiomeric resolution (Rs = 1.7). The enantiomers of felodipine and three related compounds were separated within 15 min. The enantiomeric purity of (R)‐ and (S)‐felodipine in injections and (R)‐felodipine in bulk substance was higher than 99.5% and no racemization was observed after storage at accelerated conditions. A poor Chiral‐AGP® column used for a long period was restored using a simple wash step together with repacking the top of the chromatographic column. © 1995 Wiley‐Liss, Inc.
Resolution by chiral hplc of the stable free radical perchlorotriphenylmethyl: Thermodynamic and chiroptical properties
Authors: Irurre José , Santamaría Jesüs , González‐rego M. Concepción
Published: January 2005

The perchlorotriphenylmethyl radical (PTM) shows enantiomerism due to restricted internal rotations. Several chiral stationary phases have been tested in different conditions for the resolution of PTM by HPLC. Only poly(triphenylmethyl methacrylate) provided sufficient resolution for carrying out a micropreparative scale separation. Racemization of (+)‐ and (−)‐PTM was monitored polarimetrically as a function of time. The process was found to follow strict first‐order kinetics. The value of ΔG#303.8 = 23.6 Kcal · mol−1 agrees with that determined previously by HPLC with the stopped flux technique (Crespo, Doctoral Thesis, CETS Institut Químic de Sarrià, 1991). Following the helicity rules in the circular dichroism spectrum, (+)‐PTM can be assumed to have (P) configuration and (−)‐PTM (M) configuration. © 1995 Wiley‐Liss, Inc.
Myocardial uptake kinetics of tocainide enantiomers in the isolated perfused rabbit heart
Authors: Christensen Ellen Bech , Hansen Steen Honoré , Rasmussen Søren Nørgaard
Published: January 2005

The extent of myocardial accumulation of tocainide, administered as single enantiomers and as well as racemate, was determined in the isolated, spontaneous beating rabbit heart. The heart was retrogradely perfused at a constant rate and fractions of the perfusate were collected during and after infusion. Kinetic parameters for myocardial accumulation and disposition of tocainide were indirectly determined from drug concentration/time course in the outflow perfusate. No stereoselectivity in myocardial accumulation was observed. A two compartment model with mean half‐lives for distribution and elimination of 0.60 and 3.78 min, respectively, was fitted to the accumulation and disposition data. At steady‐state, tocainide enantiomers were accumulated about three times in the myocardium relative to the perfusion liquid. © 1995 Wiley‐Liss, Inc.
Preparative scale enantioseparation of 1‐cyclohexyl‐1‐phenylethyl hydroperoxide and 1,2,3,4‐tetrahydro‐1‐naphthyl hydroperoxide on a modified cellulose stationary phase
Authors: Wagner Jürgen , Hamann Hans‐Jürgen , Döpke Werner , Kunath Annamarie , Höft Eugen
Published: January 2005

The analytical and preparative scale optical resolution of 1‐cyclohexyl‐1‐phenylethyl hydroperoxide and 1,2,3,4‐tetrahydro‐1‐napthyl hydroperoxide has been achieved by chiral HPLC on a cellulose tris(3,5‐dimethylphenyl carbamate) stationary phase coated on silica gel. The method has been used to obtain several hundred milligrams of highly enriched enantiomers (%ee >98) which were characterized by [α]D and circular dichroism spectra, respectively. Configurational assignments were achieved for 1,2,3,4‐tetrahydro‐1‐naphthyl hydroperoxide enantiomers. © 1995 Wiley‐Liss, Inc.
A new class of network‐polymeric chiral stationary phases
Authors: Allenmark Stig G. , Andersson Shalini , Möller Per , Sanchez Domingo
Published: January 2005

A strategy based on the use of homo bi‐ and multifunctional building blocks for the synthesis of a new class of network‐polymeric chiral stationary phases has been evaluated. The key steps comprise acylation of N,N′‐diallyl‐L‐tartardiamide (DATD) and reaction with a multifunctional hydrosilane, yielding a network polymer incorporating the bifunctional C2‐symmetric chiral selector. Covalent bonding to a functionalized silica takes place during the latter process. Many of these chiral sorbents show interesting enantioselective properties toward a wide variety of racemic solutes under normal‐phase (hexane‐based) conditions. The retention is mainly caused by the hydrogen‐bonding ability of the analyte, which is regulated by mobile phase additives like alcohol or ether cosolvents. The most interesting chiral stationary phases, in terms of broad enantioselectivity, were obtained from O,O′‐diaryol‐DATD‐derivatives, particularly those containing the 3,5‐dimethylbenzoyl and the 4‐(tert‐butyl)benzoyl moieties. Since high column efficiencies can be obtained with these chiral sorbents, an α‐value of ca. 1.2 is usually sufficient to produce baseline separation. A large number of neutral as well as acidic or basic drug racemates are resolved without derivatization. © 1995 Wiley‐Liss, Inc.
Stereochemical aspects of the hydration of trans‐anethole epoxide in the rat
Authors: Ishida Takashi , Bounds Stephen V. J. , Caldwell John
Published: January 2005

Racemic trans‐anethole epoxide [1‐(4′‐methoxyphenyl)‐propane‐1,2‐oxide] was incubated with water, buffers, and rat liver microsomes and cytosol and the stereochemistry of the diols produced was determined by HPLC as their dicamphanyl esters. The diol metabolites were isolated by HPLC from the urine of rats administered [1′‐14C] trans‐anethole and their stereochemistry determined after derivatization to their camphanyl esters. The stereochemical course of the metabolism of trans‐anethole by rat liver microsomes and cytosol is discussed. © 1995 Wiley‐Liss, Inc.
Stereoselective and species‐dependent kinetics of reboxetine in mouse and rat
Authors: Benedetti Margherita Strolin , Frigerio Enrico , Tocchetti Paola , Brianceschi Giannantonio , Castelli Maria Grazia , Pellizzoni Cinzia , Dostert Philippe
Published: January 2005

Reboxetine, (RS)‐2‐[(RS)‐α‐(2‐ethoxyphenoxy)benzyl]morpholine methanesulphonate, is a racemic compound and consists of a mixture of the (R,R)‐ and (S,S)‐enantiomers. In this study, brain and plasma levels of both enantiomers were determined in mice and rats after oral administration of reboxetine at doses (1.1 mg/kg, mouse; 20 mg/kg, rat) twice the respective ED50 values in the antireserpine test. Plasma and brain concentrations of each enantiomer were measured up to 6 h postdosing using an HPLC method with fluorimetric detection after derivatization with a chiral agent (FLEC). In mice and rats, brain and plasma levels of the (R,R)‐enantiomer were always higher than those of the (S,S)‐enantiomer. After normalization for dose, the mean AUC0‐tz values of both the (R,R)‐ and (S,S)‐enantiomers in mouse brain were about 23 and 32 times higher than in rat brain, respectively. In plasma, the corrected mean AUC0‐tz values were about 5 (R,R) and 10 (S,S) times higher in mice than in rats. These results provide evidence for the higher bioavailability and/or lower clearance of both enantiomers in mice than in rats, and for a higher penetration of both enantiomers into mouse brain compared to rat brain. © 1995 Wiley‐Liss, Inc.
Does solute stereochemistry influence percutaneous penetration?
Authors: Heard Charles M. , Brain Keith R.
Published: January 2005

The stratum corneum, the rate‐limiting barrier to percutaneous penetration, is made up of several components, principally keratin and ceramides. These are potential sources of chiral discrimination that could result in differential diffusion rates, dependent upon the stereochemistry of the solute. Although binding to keratin can occur it is not a stereoselective process [percent binding to solubilised epidermal keratin: (R)‐propranolol 7.9 ± 1.7, (S)‐propranolol 8.3 ± 2.0]. On the other hand, studies with ceramide monolayers produced qualitative evidence of dose‐dependent stereoselective interaction when the pure diastereomers of ephedrine were present in the aqueous subphase which suggested that differences in diffusion rates might occur in skin. However, the differences in permeation rates in vitro for these diastereomers through human skin were not statistically different [(+)‐(1S, 2R)‐ephedrine 119.1 ± 2.6 μg/cm2, (‐)‐(1R,2S)‐ephedrine 107.0 ± 3.9 μg/cm2, 12 h]. Time averaging, involving contributions from binding to all lipid headgroups present in the intercellular channels, may obscure specific differential interactions. Further, any stereospecific interaction may be subtle and readily overwhelmed if diffusant concentration is greater than the capacity of the skin to differentiate between stereoisomers. Evidence for intrinsic stereoselectivity in skin permeation has therefore yet to be obtained. © 1995 Wiley‐Liss, Inc.
Stereoselectivity of the carbonyl reduction of dolasetron in rats, dogs, and humans
Authors: Dow James , Berg Christiane
Published: January 2005

The initial step in the metabolism of dolasetron or MDL 73, 147EF [(2α,6α,8α,9aβ)‐octahydro‐3‐oxo‐2,6‐methano‐2H‐quinolizin‐8‐yl 1H‐indol‐3‐carboxylate, monomethanesulfonate] is the reduction of the prochiral carbonyl group to give a chiral secondary alcohol “reduced dolasetron.” An HPLC method, using a chiral column to separate reduced dolasetron enantiomers, has been developed and used to measure enantiomers in urine of rats, dogs, and humans after dolasetron administration. In all cases, the reduction was enantioselective for the (+)‐(R)‐enantiomer, although the dog showed lower stereoselectivity, especially after iv administration. An approximate enantiomeric ratio (+/−) of 90:10 was found in rat and human urine. The contribution of further metabolism to this enantiomeric ratio was considered small as preliminary studies showed that oxidation of the enantiomeric alcohols by human liver microsomes demonstrated only minor stereoselectivity. Further evidence for the role of stereoselective reduction in man was obtained from in vitro studies, where dolasetron was incubated with human whole blood. The enantiomeric composition of reduced dolasetron formed in human whole blood was the same as that found in human urine after administration of dolasetron. Enantioselectivity was not due to differences in the absorption, distribution, metabolism, or excretion of enantiomers, as iv or oral administration of rac‐reduced dolasetron to rats and dogs lead to the recovery, in urine, of essentially the same enantiomeric composition as the dose administered. It is fortuitous that the (+)‐(R)‐enantiomer is predominantly formed by carbonyl reductase, as it is the more active compound. © 1995 Wiley‐Liss, Inc.
Development of chiral drugs in Japan: An update on regulatory and industrial opinion
Authors: Shindo Hideyo , Caldwell John
Published: January 2005

The purpose of this commentary is to provide information on the present status of the racemate/enantiomer debate in Japan and current industrial and regulatory attitudes to chiral drugs in Japan. It provides an update of our previous paper (Shindo and Caldwell, Chirality 3:91–93, 1991), and the interested reader is referred to this for background information. © 1995 Wiley‐Liss, Inc.
A conformational analysis of mono and dialkyl ethers of 2,2′‐dihydroxy‐1,1′‐binaphthalene by circular dichroism spectroscopy and cholesteric induction in nematic liquid crystals
Authors: Rosini Carlo , Rosati Ivana , Spada Gian Piero
Published: January 2005

The coupling of the analysis of the absorption and circular dichroism (CD) spectra with that of the cholesteric mesophases induced in nematic liquid crystals indicated some interesting conformational features of bridged and nonbridged mono‐ and dialkylethers of optically active 2,2′‐dihydroxy‐1,1′‐binaphthalene. Bridged derivatives are characterized by relatively small dihedral angles. Simple monoalkyl ethers are characterized by larger dihedral angles but they all assume an s‐cis conformation, owing to the existence of intramolecular hydrogen bonds. Nonbridged dialkylethers prefer even larger dihedral angles and, depending on the bulkiness of the alkyl groups, the s‐trans conformation can be found. Interestingly, the conformation of dialkylethers is strongly dependent on the structure of the liquid crystal solvent, because the intramolecular hydrogen bond is not possible there. © 1995 Wiley‐Liss, Inc.
A new method for enantiomer enrichment: Distillation to separate the free and complexed enantiomers after partial salt formation
Authors: Kozma Dávid , Madarász Zoltán , Ács Mária , Fogassy Elemér
Published: January 2005

A new method is described for the enrichment of enantiomeric mixtures having an enantiomeric ratio other than 1:1. The method is based on partial salt formation of the enantiomeric mixture with an achiral substance followed by the distillation of the free enantiomer. The distillate has a different enantiomeric composition than the starting mixture. The method was performed on enantiomeric mixtures of α‐phenylethylamine using four different dicarboxilic acids. © 1995 Wiley‐Liss, Inc.
Circular dichroism of ketoprofen complexed to serum albumins: Conformational selection by the protein: A novel optical purity determination technique
Authors: Zandomeneghi Maurizio
Published: January 2005

Complexation of 2‐(3′‐benzoylphenyl)propionic acid (ketoprofen), 1, to bovine serum albumin (BSA) results in an intense negative circular dichroism in the ketonic n → π* band of the benzoylphenyl moiety. This high CD contrasts with the weak CD of 1‐enantiomers dissolved in common solvents. Furthermore, a number of chiral and achiral molecules containing the benzophenone moiety are easily complexed to BSA: all these complexes show an intense CD at the same transition. To account for the observed CD intensities of the above molecules, it appears that BSA complexation markedly shifts the equilibrium between strongly asymmetric, antipodic conformers. Dissymmetry of these conformers is connected to the instability of a structure with phenyl rings coplanar to the carbonyl chromophore, as also indicated by molecular mechanics calculations. The magnification of the Cotton effects of the 1‐antipodes, due to the protein, can be used to measure the optical purity of 1‐samples with excellent precision. In contrast with BSA, human SA is unable to recognize the chirality of 1‐antipodes; oleic acid cocomplexation modifies this fact as well as other features of the binding. © 1995 Wiley‐Liss, Inc.
Determination of the enantiomeric purity of dihydroxy‐ and dimethoxy‐2‐aminotetralins by high‐performance capillary electrophoresis with cyclodextrins as chiral selector
Authors: Castelnovo Pierfrancesco , Albanesi Carlo
Published: January 2005

A chiral separation of 5,6‐ and 6,7‐dihydroxy‐2‐aminotetralin and of the corresponding dimethoxy analogues can be achieved by high‐performance capillary electrophoresis using cyclodextrins as chiral selector. The selectivity of a number of native and derivatized cyclodextrins was screened and hydroxylalkyl‐β‐cyclodextrins turned out to be the most effective. Optimization of hydroxyethylcyclodextrin and hydroxypropylcyclodextrin concentration for each compound led to baseline separation (resolution factors from 1.7 to 2.3) resulting in a detection limit of 0.1% for the enantiomer present as impurity. Modifiers of the electroendosmotic flow, such as hydroxypropylcellulose and hexadecyltrimethylammoniun bromide, must be added to the background electrolyte to obtain such results. © 1995 Wiley‐Liss, Inc.
Accuracy in the chromatographic determination of extreme enantiomeric ratios: A critical reflection
Authors: Meyer Veronika R.
Published: January 2005

The chromatographic quantitation of very low amounts of an enantiomer in the presence of its antipode can be an extraordinary challenge. If resolution of the peaks is not complete even at extreme mass ratios an integrator will yield inaccurate results due to geometric effects. A given resolution can be adequate for peaks of similar size but result in severe overlap if one of the signals is markedly smaller. If tailing occurs, which is more the rule than the exception, the problem is especially severe for last eluted small peaks. Additional obstacles are detector nonlinearity and other sources of unsatisfactory calibration curves, overloading phenomena, and the possible lack of standards of highest optical purity. These problems have been studied by computer simulations and the liquid chromatographic separation of (R,S)‐phenylethyl naphthoic acid amide on a chiral stationary phase. © 1995 Wiley‐Liss, Inc.
Synthesis of optically active diols using an efficient polymer bound cinchona alkaloid derivative
Authors: Petri Antonella , Pini Dario , Rapaccini Silvia , Salvadori Piero
Published: January 2005

A new insoluble polymer containing a Cinchona alkaloid derivative has been synthesized and used as chiral ligand in the heterogeneous enantioselective dihydroxylation of olefins. It is shown that the enantioselectivity of the optically active diols obtained from both aliphatic and aromatic substrates is always comparable to that observed in the homogeneous phase under the same reaction conditions. A method for evaluating the enantiomeric excesses of the optically active products is also described. © 1995 Wiley‐Liss, Inc.
Pharmacokinetics and pharmacodynamics of ketoprofen enantiomers in calves
Authors: Landoni Maria Fabiana , Lees Peter
Published: January 2005

The pharmacokinetics (PK) and pharmacodynamics (PD) of (S)‐ and (R)‐ ketoprofen (KTP) enantiomers were studied in calves after intravenous administration of each enantiomer at a dose of 1.5 mg/kg. Pharmacodynamic properties were evaluated using a model of acute inflammation, comprising subcutaneously implanted tissue cages stimulated by intracaveal injection of carrageenan.

Chiral inversion of (R)‐KTP to the (S)‐antipode occurred. The R:S ratio in plasma was 33:15 min after administration, decreasing to 1:1 at 8 h. The calculated extent of inversion was 31 ± 7%. The R:S ratio in inflammatory exudate was of the order 3:1 at all the sampling times and the ratio in transudate was approximately 2:1 for 6 h, declining to 1:1 at 30 h. Only (S)‐KTP was detected in biological fluids after administration of this enantiomer. Elimination half‐life was longer for the (S) (2.19 h) than the (R)‐enantiomer (1.30 h) and volume of distribution was also somewhat higher for the (S)‐enantiomer. Body clearance values were 0.119 1/kg/h for (S)‐KTP and 0.151 1/kg/h for the (R)‐antipode. For (R)‐KTP effects obtained were considered as a hybrid, since they potentially reflect the actions of both enantiomers. Concentrations of LTB4and the cytokines interleukin‐1, interleukin‐6, and tumor necrosis factor alpha, in exudate were not significantly affected by either (R)‐ or (S)‐KTP treatments. Inhibition of ex vivo thromboxane B2(TxB2) synthesis, exudate prostaglandin E2(PGE2) synthesis, β‐glucuronidase release (β‐glu), and bradykinin‐induced skin swelling was significant in both treated groups. PK/PD modelling was applied to the (S)‐KTP treatment only. EC50values for inhibition of serum TxB2, exudate PGE2and β‐glu and BK‐induced swelling were 0.047, 0.042, 0.101, and 0.038 μg/ml, respectively. It is concluded that the low EC50values for inhibition of TxB2and PGE2by (S)‐KTP are likely to explain the effects produced by (R)‐KTP administration, since concentrations of (S)‐KTP in exudate of these calves following chiral inversion were at least 5 times higher than the EC50at all sampling times. The data for β‐glu and bradykinin‐induced swelling inhibition indicate possible inhibitory actions of (R)‐KTP as well as (S)‐KTP. © 1995 Wiley‐Liss, Inc.
Validation of a nomogram for predicting disease‐specific survival after an R0 resection for gastric carcinoma
Authors: Peeters Koen C. M. J. , Kattan Michael W. , Hartgrink Henk H. , Kranenbarg Elma Klein , Karpeh Martin S. , Brennan Murray F. , van de Velde Cornelis J. H.
Published: January 2005

BACKGROUND

A statistical model for predicting disease‐specific survival in patients with gastric carcinoma, based on a single U.S. institution experience, was tested for validity in a sample of patients treated at different institutions.

METHODS

The authors analysed 459 patients from the Dutch Gastric Cancer trial that compared limited (D1) with extended (D2) lymph node dissection. The discrimination ability of the nomogram with respect to 5 and 9‐year disease‐specific survival probabilities was superior to that of the American Joint Committee on Cancer (AJCC) staging system.

RESULTS

There was considerable heterogeneity of risk within many of the AJCC stages. Calibration plots suggested that predicted probabilities from the nomogram corresponded closely to actual disease‐specific survival. The gastric carcinoma nomogram performed well when applied to patients treated in a large number of institutions.

CONCLUSIONS

The nomogram provided predictions that discriminated better than the AJCC staging system, regardless of the extent of lymph node dissection. Patient counseling and adjuvant therapy decision‐making should benefit from use of the nomogram. Cancer 2005. © 2005 American Cancer Society.
Breast conservation after neoadjuvant chemotherapy
Authors: Chen Allen M. , Meric‐Bernstam Funda , Hunt Kelly K. , Thames Howard D. , Outlaw Elesyia D. , Strom Eric A. , McNeese Marsha D. , Kuerer Henry M. , Ross Merrick I. , Singletary S. Eva , Ames Fredrick C. , Feig Barry W. , Sahin Aysegul A. , Perkins George H. , Babiera Gildy , Hortobagyi Gabriel N. , Buchholz Thomas A.
Published: January 2005

BACKGROUND

The appropriate selection criteria for breast‐conserving therapy (BCT) after neoadjuvant chemotherapy are poorly defined. The purpose of the current report was to develop a prognostic index to help refine selection criteria and to serve as a general framework for clinical decision‐making for patients treated by this multimodality approach.

METHODS

From a group of 340 patients treated with BCT after neoadjuvant chemotherapy, the authors previously determined 4 statistically significant predictors of ipsilateral breast tumor recurrence (IBTR) and locoregional recurrence (LRR): clinical N2 or N3 disease, residual pathologic tumor size > than 2 cm, a multifocal pattern of residual disease, and lymphovascular space invasion in the specimen. The M. D. Anderson Prognostic Index (MDAPI) was developed by assigning scores of 0 (favorable) or 1 (unfavorable) for each of these 4 variables and using the total to give an overall MDAPI score of 0–4.

RESULTS

The MDAPI stratified the 340 patients into 3 subsets with statistically different levels of risk for IBTR and LRR after neoadjuvant chemotherapy and BCT. Actuarial 5‐year IBTR‐free survival rates were 97%, 88%, and 82% for patients in the low (MDAPI overall score 0 or 1, n = 276), intermediate (MDAPI score 2, n = 43), and high (MDAPI score 3 or 4, n = 12) risk groups, respectively (P < 0.001). Corresponding actuarial 5‐year LRR‐free survival rates were 94%, 83%, and 58%, respectively (P < 0.001).

CONCLUSIONS

Patients with an MDAPI score of 0 or 1, which made up 81% of the study population, had very low rates of IBTR and LRR. The MDAPI enabled the identification of a small group (4%) of patients who are at high risk for IBTR and LRR and who may benefit from alternative locoregional treatment strategies. Cancer 2005. © 2005 American Cancer Society.
Should patients with advanced, incurable cancers ever be sent home with total parenteral nutrition?
Authors: Hoda Daanish , Jatoi Aminah , Burnes Jan , Loprinzi Charles , Kelly Darlene
Published: January 2005

BACKGROUND

Home total parenteral nutrition (TPN) can be lifesaving and life sustaining for some patients. However, in patients with advanced, incurable cancer, its role is controversial. A retrospective study was conducted to explore whether home TPN was associated with long‐term survival (≥ 1 year) in patients with metastatic disease and to identify predictive factors to enable its judicious use.

METHODS

The records of all adult patients with incurable cancer were identified between 1979 and 1999. Records were reviewed in depth for survival from TPN initiation to death and for a variety of demographic and clinical factors.

RESULTS

Fifty‐two patients were identified. Their median age was 56 years (range, 18–83 years), and 30 (58%) were women. Malignant diagnoses included carcinoid/islet cell tumor (n = 10), ovarian carcinoma (n = 6), amyloidosis/multiple myeloma (n = 6), colorectal carcinoma (n = 5), sarcoma (n = 5), pancreatic carcinoma (n = 4), gastric carcinoma (n = 3), lymphoma (n = 2), pseudomyxoma peritonei (n = 2), and other (n = 9). TPN was initiated for the following reasons (indications are not mutually exclusive): alimentary tract obstruction (n = 20), short bowel syndrome/malabsorption (n = 16), fistula (n = 11), dysmotility (n = 3), nausea/emesis (n = 2), anorexia (n = 2), and mucositis (n = 1). The median time from initiation of TPN to death was 5 months (range, 1–154 months). Sixteen patients survived ≥ 1 year. TPN‐related complications included 18 catheter infections (1 per 2.8 catheter‐years), 4 thromboses, 3 pneumothoraces, and 2 episodes of TPN‐related liver disease. Tumor grade, the interval between diagnosis of metastatic disease and initiation of TPN, the presence of prominent cancer symptoms, and the administration of cancer therapy after TPN were not associated in any way with overall survival.

CONCLUSIONS

The initiation of home TPN can be associated with long‐term survival in very select patients with incurable cancer, and complication rates with its use appear acceptable. However, the judicious use of home TPN in this setting requires careful clinical assessment on a patient‐by‐patient basis. Cancer 2005. © 2005 American Cancer Society.
Successful treatment of low‐grade oligodendroglial tumors with a chemotherapy regimen of procarbazine, lomustine, and vincristine
Authors: Stege Elize M. Biemond‐ter , Kros Johan M. , de Bruin Hein G. , Enting R. H. , van Heuvel Irene , Looijenga Leendert H. J. , van der Rijt Carin D. D. , Smitt Peter A. E. Sillevis , van den Bent Martin J.
Published: January 2005

BACKGROUND

Anaplastic oligodendroglioma (OD) tumors, especially those with the combined loss of the short arm of chromosome 1 (1p) and the long arm of chromosome 19 (19q), are sensitive to chemotherapy. Only limited data are available on the role of chemotherapy in low‐grade OD. The authors retrospectively studied the outcome of the procarbazine, lomustine, and vincristine (PCV) chemotherapy regimen in a group of 16 patients with newly diagnosed OD and 5 patients with recurrent low‐grade OD.

METHODS

Two groups of patients were studied: newly diagnosed patients with large OD and mixed oligoastrocytomas (OA) and patients with recurrent OD and OA after radiotherapy who still showed nonenhancing tumors. Treatment consisted of standard PCV chemotherapy. In the newly diagnosed and responding patients, radiotherapy was withheld until the time of disease recurrence. Responses were assessed by T2‐weighted magnetic resonance image (MRI) scans. Loss of chromosome 1p and 19q was assessed using fluorescent in situ hybridization with locus‐specific probes.

RESULTS

Three of five patients with recurrent tumors responded. Thirteen of the 16 newly diagnosed patients showed evidence of response. The median time to disease progression in this group was > 24 months. Only one of these patients experienced disease progression while receiving chemotherapy. Several patients showed a signficant clinical improvement despite only a modest improvement of the tumor on the MRI scans. Even patients without loss of 1p or 19q showed satisfactory responses. No TP53 mutations were found.

CONCLUSIONS

Newly diagnosed patients with OD tumors, with or without loss of 1p/19q, responded to PCV chemotherapy. Up‐front chemotherapy may be indicated especially for patients with large tumors. MRI scans were of limited value for the assessment of response. A Phase III trial should be initiated to compare radiotherapy with chemotherapy. Cancer 2005. © 2005 American Cancer Society.
Does the number of lymph nodes examined in patients with lymph node‐negative breast carcinoma have prognostic significance?
Authors: Salama Joseph K. , Heimann Ruth , Lin Fen , Mehta Neil , Chmura Steven J. , Singh Rachana , Kao Johnny
Published: January 2005

BACKGROUND

There are conflicting data on the prognostic significance of the number of lymph nodes examined in patients with lymph node‐negative breast carcinoma. Therefore, the authors analyzed the impact of the number of tumor‐free axillary lymph nodes on disease‐free survival (DFS) in two distinct patient populations.

METHODS

Eight hundred thirty‐three consecutive patients with breast carcinoma who underwent mastectomy between 1927 and 1987 and 1094 consecutive patients with breast carcinoma who underwent with breast‐conservation therapy between 1984 and 2001 were diagnosed pathologically with negative axillary lymph node status. Patients were stratified into 4 groups according to the number of lymph nodes examined: Group 1 had 1–3 lymph nodes examined, Group 2 had 4–9 lymph nodes examined, Group 3 had 10–20 lymph nodes examined, and Group 4 had > 20 lymph nodes examined.

RESULTS

In the mastectomy cohort, with a median follow‐up of 153 months, the 10‐year DFS rate was 70%, 65%, 79%, and 81% for Groups 1–4, respectively. On multivariate analysis, pathologic tumor size (P < 0.001) and the number of lymph nodes examined (P = 0.010) were significant predictors for long‐term DFS. In the breast‐conservation cohort, with a median follow‐up of 53 months, the 5‐year DFS rate was 90%, 91%, 92%, and 95% for Groups 1–4, respectively. On multivariate analysis, the only predictors of DFS were method of detection (clinically vs. mammographically) (P = 0.003) and tumor size (P = 0.035).

CONCLUSIONS

The recovery of < 10 lymph nodes in lymph node‐negative patients who underwent mastectomy resulted in a 10–15% decreased long‐term DFS rate compared with patients who had a more extensive axillary assessment. However, the number of lymph nodes examined did not have an impact on the DFS rate in a contemporary cohort of patients who underwent breast‐conservation therapy, which included radiation. Cancer 2005. © 2005 American Cancer Society.
Cytokine polymorphisms and hepatocellular carcinoma
Authors: Chung Raymond T.
Published: January 2005

Regardless of whether monitoring practices change as a result of genotyping, the mandate that replicative hepatitis B virus disease must be treated because of the long‐term risk for necroinflammatory disease, fibrosis, cirrhosis, and hepatocellular carcinoma remains firmly in place.

See also pages 740–8.
Cost‐effectiveness of proton radiation in the treatment of childhood medulloblastoma
Authors: Lundkvist Jonas , Ekman Mattias , Ericsson Suzanne Rehn , Jönsson Bengt , Glimelius Bengt
Published: January 2005

BACKGROUND

Radiation therapy is an important component in the treatment of medulloblastoma; however, in many patients, it is associated with risk of late adverse events. Proton radiation therapy has potential to reduce the risk of adverse events compared with conventional radiation, but it is associated with a higher treatment cost. The objective of the current study was to assess the cost‐effectiveness of proton therapy compared with conventional radiation therapy in the treatment of childhood medulloblastoma.

METHODS

The consequences of radiation therapy were evaluated using a Markov simulation model. Children age 5 years with medulloblastoma were followed. The patients were at risk of several types of adverse events, including hearing loss, intelligence quotient (IQ) loss, hypothyroidism, growth hormone deficiency (GHD), osteoporosis, cardiac disease, and secondary malignancies. The patients also were at risk of death and were divided into risk groups for normal death, death due to tumor recurrence, treatment‐related cardiac death, treatment‐related subsequent tumor death, or treatment‐related other death. A review of the literature was conducted to estimate the parameters in the model.

RESULTS

The base‐case results showed that proton therapy was associated with €23,600 in cost savings and 0.68 additional quality‐adjusted life‐years per patient. The analyses showed that reductions in IQ loss and GHD contributed to the greatest part of the cost savings and were the most important parameters for cost‐effectiveness.

CONCLUSIONS

The results of the current study indicated that proton radiation therapy can be cost‐effective and cost‐saving compared with conventional radiation therapy in the treatment of children with medulloblastoma if the appropriate patients are selected for the therapy. However, there have been few long‐term follow‐up studies, and more much information on the long‐term consequences of radiation therapy is needed. Cancer 2005. © 2005 American Cancer Society.
Expression of receptor tyrosine kinases epidermal growth factor receptor and HER‐2/neu in synovial sarcoma
Authors: Thomas Dafydd G. , Giordano Thomas J. , Sanders Donita , Biermann Sybil , Sondak Vernon K. , Trent Jonathan C. , Yu Dihua , Pollock Raphael E. , Baker Laurence
Published: January 2005

BACKGROUND

Synovial sarcomas are high‐grade soft tissue neoplasms often characterized by a biphasic spindle and epithelioid cell morphology. The majority of synovial sarcomas harbor a specific chromosomal translocation in which the proximal portion of the SYT gene at chromosome 18q11 is fused to the distal portion of one of several duplicated SSX genes (most notably SSX1 and SSX2) at chromosome Xp11. SYT/SSX1 translocations are seen in nearly three times as many synovial sarcomas as SYT/SSX2 translocations. Although the SYT/SSX2 fusion is usually associated with the monophasic disease pattern, the SYT/SSX1 fusion is present in tumors with biphasic or monophasic patterns. The SYT/SSX1 fusion gene is associated with more aggressive tumor growth and poor outcome. Despite advances in the therapy of local disease, distant metastasis remains the predominant cause of death. Accordingly, there is a need for alternate therapies, such as those recently developed against the receptor tyrosine kinases, such as epidermal growth factor receptor (EGFR) and HER‐2/neu.

METHODS

Archival specimens of synovial sarcoma (n = 38) representing 30 patients were assessed for EGFR and HER‐2/neu protein expression by standard immunohistochemical techniques. To validate the immunohistochemistry results, quantitative real‐time polymerase chain reaction (Q‐PCR) assays using either fresh and/or archival material was performed. The presence of gene amplification was determined by chromogenic in‐situ hybridization.

RESULTS

EGFR and HER‐2/neu protein were detected by immunohistochemistry in 21 of 38 (55.3%) and 20 of 38 (52.6%) synovial specimens, respectively. EGFR immunoreactivity showed a granular and membranous pattern, whereas HER‐2/neu immunoreactivity demonstrated only a membrane pattern. Coexpression was observed in 13 of 38 specimens (34.2%). HER‐2/neu expression by immunohistochemistry in synovial sarcomas was restricted to tumors with the SYT/SSX1 translocations. Of 6 specimens with SSX2 translocation, none (0%) showed HER‐2/neu immunoreactivity and 1 (17%) demonstrated EGFR expression. Q‐PCR demonstrated the presence of mRNA for EGFR and HER‐2/neu in 19 of 30 specimens (63.3%) and 22 of 30 specimens (73.3%), respectively. EGFR and HER‐2/neu were expressed at low concentrations compared with the expression of glyceraldehyde 3‐phosphate dehydrogenase (GAPDH). No evidence of gene amplification was observed.

CONCLUSIONS

EGFR and HER‐2/neu are expressed in the majority of patients with SYT/SSX1 synovial sarcomas, albeit at low levels. Treatment with tyrosine kinase inhibitors may represent appropriate alternate therapy for these patients. Cancer 2005. © 2005 American Cancer Society.
Absence of V599E BRAF mutations in desmoplastic melanomas
Authors: Davison Jon M. , Rosenbaum Eli , Barrett Terry L. , Goldenberg David , Hoque Mohammad O. , Sidransky David , Westra William H.
Published: January 2005

BACKGROUND

Desmoplastic melanoma is an uncommon variant of cutaneous melanoma that mimics soft tissue sarcoma both clinically and morphologically. An activating point mutation of the BRAF oncogene has been identified in a high proportion of conventional cutaneous melanomas, but its frequency in the desmoplastic subtype is not known.

METHODS

The authors tested 12 desmoplastic melanoma specimens for the thymine (T)→adenine (A) missense mutation at nucleotide 1796 of the BRAF gene using a newly developed assay that employs a novel primer extension method. They also tested 57 vertical growth phase cutaneous nondesmoplastic melanoma specimens.

RESULTS

The 1796 T→A mutation was detected in 23 of the 57 conventional cutaneous melanoma specimens but in none of the 12 desmoplastic melanoma specimens (40% vs. 0%; P = 0.0006, Fisher exact 2‐tailed test).

CONCLUSIONS

The relative importance of BRAF mutational activation in melanocytic tumorigenesis clearly was not the same across the various subtypes of melanoma, even for melanomas of cutaneous origin that are associated with sun exposure. In contrast to conventional cutaneous melanomas, the desmoplastic variant frequently did not harbor an activating mutation of BRAF. Accordingly, patients with melanomas should not be collectively regarded as a uniform group as new therapeutic strategies are developed that target specific genetic alterations. Cancer 2005. © 2005 American Cancer Society.