bluuebunny/crossref_metadata_2025_split huggingface dataset:
Biases affecting the proportional reporting ratio (PRR) in spontaneous reports pharmacovigilance databases: the example of sertindole
Authors: Moore Nicholas , Hall Gillian , Sturkenboom Miriam , Mann Ron , Lagnaoui Rajaa , Begaud Bernard 
Published: May 2003

AbstractBackgroundAutomated measures of reporting disproportionality in databases of spontaneous reports of adverse drug reactions are an emerging tool to identify drug‐related alerts. Sertindole, a new atypical neuroleptic known to prolong the QT interval, was suspended in November 1998 because the proportion of reports of fatal reactions suggesting arrhythmia among all reports with sertindole was almost ten times higher than that for other atypical neuroleptics in the UK. This excess risk was not predicted in preclinical data and had not been found in premarketing trials.MethodReporting patterns over time were analysed. Prescription Event Monitoring (PEM) studies and a large retrospective cohort allowed for the comparison of actual death rates with atypical neuroleptics, and to assess which proportion of the deaths that occurred were reported.ResultsThere were indications of possible skewing of reporting related to notoriety, surveillance and market size effects. Death rates in PEM studies were essentially similar between sertindole and other neuroleptics. Cardiac deaths had been two to three times more often reported than other causes of death.ConclusionProportional reporting ratios indicate differential reporting of possible reactions, not necessarily differential occurrence. There was no indication of an actual increase of risk of all causes or cardiac deaths during sertindole treatment, but only an increased risk of its being reported. The suspension of sertindole was rescinded by Committee on Proprietary Medicinal Products (CPMP) in October 2001. Copyright © 2003 John Wiley & Sons, Ltd.
Effect of colloidal self‐assemblies on the basic hydrolysis of 2‐(4‐bromophenoxy)quinoxaline
Authors: Cuenca Angela 
Published: May 2003

AbstractIn the presence of cationic surfactants (C16H33NR3Cl; R = Me, n‐Pr, n‐Bu), the shape of rate versus surfactant concentration profiles for the basic hydrolysis of 2‐(4‐bromophenoxy)quinoxaline depends on substrate concentration. At low substrate concentration there is a single rate maximum and with a 10‐fold substrate concentration increase a double rate maximum is observed. The first rate maximum is ascribed to reaction occurring in premicellar aggregates and the second to reaction in micelles. At low substrate concentration the effect of surfactant head group size was examined. Second‐order rate constants in the micellar pseudophase increase with increasing head group size. Copyright © 2003 John Wiley & Sons, Ltd.
Rate‐limiting step and micellar catalysis of the non‐classical nitro group nucleophilic substitution by thiols in 4‐nitro‐N‐n‐butyl‐1,8‐naphthalimide
Authors: Triboni E. R. , Politi M. J. , Cuccovia I. M. , Chaimovich H. , Berci Filho P. 
Published: May 2003

AbstractNitronaphthalimides are a particularly interesting group of nitroaromatics used for staining cells in hypoxia and in photodynamic therapy. The kinetics of the aromatic nucleophilic substitution of the nitro‐group of 4‐nitro‐N‐n‐butyl‐1,8‐naphthalimide (4‐NBN) by n‐heptanethiol (RSH), thiophenol (ArSH) and 2‐hydroxy‐1‐ethanethiol (HESH) in aqueous solutions containing micelles and in water–methanol mixtures were analyzed. The substitution of the nitro group by aromatic or aliphatic thiols led to fluorescent substitution products. Hexadecyltrimethylammonium chloride micelles (CTAC) increased the rate of thiolysis of 4‐NBN by 1 × 105 (RSH) and 4 × 105 (ArSH) fold. For the reaction of ArSH with 4‐NBN the calculated second‐order rate constant in the micellar phase, k2m, is 1.4 times higher than that in the aqueous phase, k2w. For the reaction of ArSH with 4‐NBN, k2m/k2w = 0.05. Both k2w and k2m decreased with increasing pKa of the thiol, suggesting that thiolate attack is not rate limiting in either the aqueous phase or micellar pseudophase. The high micellar rate acceleration is therefore largely due to concentration of the reagents in the micellar phase and effects on the thiol acid–base equilibrium. Copyright © 2003 John Wiley & Sons, Ltd.
Theoretical studies on empirical structure–reactivity relationship: the Yukawa–Tsuno equation
Authors: Nakata Kazuhide , Fujio Mizue , Nishimoto Kichisuke , Tsuno Yuho 
Published: May 2003

AbstractThe substituent‐dependent stabilization energies (δXΔE) of a series of α,α‐R1R2 benzyl cations were determined by means of ab initio calculation at the MP2/6–31G*//RHF/6–31G* + ZPE (scaled 0.8929) level, based on the isodesmic hydride transfer reactions between ring X‐substituted and unsubstituted R1R2 benzyl cations. Substituent stabilities (δXΔE) of α,α‐dimethylbenzyl cations were determined in the same way, to define a reference set of the ab initio σ+ values. The (δXΔE) of α,α‐dimethylbenzyl cations of which the cation center is set orthogonal to the benzene π‐system were correlated linearly with σ0 (solution). Based on this correlation, a set of ab initio σ0 constants [(σ0)
ab] was determined. The ab initio resonance substituent constants $(\Delta \overline{\sigma}_{\rm R}^{+})_{ab}$ were defined as (σ+)
ab − (σ0)
ab. Employing the present ab initio set of (σ0)
ab and $(\Delta \overline{\sigma}_{\rm R}^{+})_{ab}$ constants, the ab initio Yukawa–Tsuno (Y–T) equation was applied to 18 sets of cation stabilities δXΔE associated with hydride transfer reaction systems. Successful applications of the ab initio Y–T equation confirm the theoretical validity of the empirical Y–T relationship; in practice, the Y–T equation makes it possible to divide the electronic substituent effect into the non‐resonance and resonance contributions. Copyright © 2003 John Wiley & Sons, Ltd.
Selective acylation of a sterically hindered hydroxyl group of unsymmetrical diols containing a primary hydroxyl group such as 1,5‐hexanediol in the presence of silica gel with acetyl chloride
Authors: Ogawa Haruo , Ide Yuko , Honda Ryoichi , Chihara Teiji 
Published: May 2003

AbstractThe more hindered monoacetates were selectively formed in the presence of silica gel with acetyl chloride by refluxing a suspension of unsymmetrical diols containing a primary hydroxyl group such as 1,5‐hexanediol preadsorbed on silica gel. Such regioselectivity was observed through preferential adsorption via a primary hydroxyl group of the diols. Copyright © 2003 John Wiley & Sons, Ltd.
Prediction of tautomeric preferences and pKa values for oxyluciferin and its constituent heterocycles
Authors: Dahlke Erin E. , Cramer Christopher J. 
Published: May 2003

AbstractWell converged electronic structure calculations are employed to predict the relative energies of tautomers of thiazol‐5(4H)‐one/5‐hydroxythiazole. Benchmarks established for this system are then employed to correct less complete levels of theory applied to the prediction of relative tautomer energies in substituted cases, including oxyluciferin. In the gas phase and aqueous solution, weak preferences for hydroxy and keto tautomers, respectively, are generally observed, but the magnitude is such that mixtures containing significant quantities of minor tautomers are predicted in most instances. The first pKa value for oxyluciferin is predicted to be 6.5, with phenolate tautomers dominating the anionic equilibrium. Copyright © 2003 John Wiley & Sons, Ltd.
Computational study of maleamic acid cyclodehydration
Authors: Ivanov Daniela , Constantinescu Mircea 
Published: May 2003

AbstractThe mechanism of cyclodehydration of alkyl (Bu) and aryl (Ph) substituted maleamic acids to the corresponding maleimides and isomaleimides using N,N′‐dicyclohexylcarbodiimide as dehydration agent in CH2Cl2 as the solvent was investigated by PM3/AMSOL semiempirical calculations. An addition intermediate between the dehydrating agent and the maleamic acid carboxyl group was considered to be formed at the very beginning of the reaction. Two mechanisms reported in the literature were considered, one involving initial formation of a cyclic anion intermediate and the other proposing an acyclic amide anion. Our computational results supported the latter mechanism and a new reaction step was proposed that could also explain the ratio between the maleimide and isomaleimide formation depending on the amide substituent (alkyl or aryl type). The computational data are in good agreement with reported experimental results. Copyright © 2003 John Wiley & Sons, Ltd.
Enhanced gauge symmetry from ‘toric’ G2 cones
Authors: Anguelova L. , Lazaroiu C.I. 
Published: May 2003

AbstractWe discuss the construction of M‐theory compactifications on ‘toric’ G2 cones, a class of models which generalize those recently considered by Acharya and Witten. We explain our criteria for identifying the gauge group content of such theories and briefly discuss the associated metrics.
Time asymmetric quantum theory – I. Modifying an axiom of quantum physics
Authors: Bohm A.R. , Loewe M. , Van de Ven B. 
Published: May 2003

AbstractA slight modification of one axiom of quantum theory changes a reversible theory into a time asymmetric theory. Whereas the standard Hilbert space axiom does not distinguish mathematically between the space of states (in‐states of scattering theory) and the space of observables (out‐“states” of scattering theory) the new axiom associates states and observables to two different Hardy subspaces which are dense in the same Hilbert space and analytic in the lower and upper complex energy plane, respectively. As a consequence of this new axiom the dynamical equations (Schrödinger or Heisenberg) integrate to a semigroup evolution. Extending this new Hardy space axiom to a relativistic theory provides a relativistic theory of resonance scattering and decay with Born probablilities that fulfill Einstein causality and the exponential decay law.
Time asymmetric quantum theory – II. Relativistic resonances from S‐matrix poles
Authors: Bohm A. , Kaldass H. , Wickramasekara S. 
Published: May 2003

AbstractRelativistic resonances and decaying states are described by representations of Poincaré transformations, similar to Wigner's definition of stable particles. To associate decaying state vectors to resonance poles of the S‐matrix, the conventional Hilbert space assumption (or asymptotic completeness) is replaced by a new hypothesis that associates different dense Hardy subspaces to the in‐ and out‐scattering states. Then one can separate the scattering amplitude into a background amplitude and one or several “relativistic Breit‐Wigner” amplitudes, which represent the resonances per se. These Breit‐Wigner amplitudes have a precisely defined lineshape and are associated to exponentially decaying Gamow vectors which furnish the irreducible representation spaces of causal Poincaré transformations into the forward light cone.
Time asymmetric quantum theory – III. Decaying states and the causal Poincaré semigroup
Authors: Bohm A. , Kaldass H. , Wickramasekara S. 
Published: May 2003

AbstractThese Gamow kets span an irreducible representation space for Poincaré transformations which, similar to the Wigner representations for stable particles, are characterized by spin (angular momentum of the partial wave amplitude) and complex mass (position of the resonance pole). The Poincaré transformations of the Gamow kets, as well as of the Lippmann‐Schwinger plane wave scattering states, form only a semigroup of Poincaré transformations into the forward light cone. Their transformation properties are derived. From these one obtains an unambiguous definition of resonance mass and width for relativistic resonances. The physical interpretation of these transformations for the Born probabilities and the problem of causality in relativistic quantum physics is discussed.
Minimizing respondent attrition in longitudinal research: Practical implications from a cohort study of adolescent drinking☆
Authors: Boys Annabel , Marsden John , Stillwell Garry , Hatchings Kevin , Griffiths Paul , Farrell Michael 
Published: May 2003

ABSTRACTThe methods used to maximize retention in a longitudinal study of adolescent drinking are discussed. Data were collected at three time points: at recruitment to the study, after nine months and at 18 months. Strategies to minimize attrition included the collection of detailed contact information, incentives for participation, postcard and telephone reminders and telephone interviews. Ninety‐six percent of the original sample completed the first follow‐up questionnaire, 92% completed the second and the study lost contact with just 3% of participants. The success of the current project is notable as this type of population is notoriously difficult to retain in longitudinal studies.
Effect of a kinin B2 receptor antagonist on LPS‐ and cytokine‐induced neutrophil migration in rats
Authors: Santos Danielle R , Calixto João B , Souza Glória E P 
Published: May 2003

This study examines the involvement of kinins in neutrophil migration into rat subcutaneous air pouches triggered by lipopolysaccharide (LPS), as well as the putative roles played by kinin B1 and B2 receptors, tumour necrosis factor alpha (TNF‐α), interleukin‐1 beta (IL‐1β) and selectins in this response.
LPS (5 ng to 10 μg cavity−1) injected into the 6‐day‐old pouch induced a dose‐ and time‐dependent neutrophil migration which peaked between 4 and 6 h, and was maximal following the dose of 100 ng cavity−1 (saline: 0.46±0.1; LPS: 43±3.70 × 106 cells cavity−1 at 6 h).
Bradykinin (BK) (600 nmol) injected into the pouch of saline‐treated rats induced only modest neutrophil migration (0.73±0.16 × 106 cells cavity−1). A more robust response to BK (3.2±0.25 × 106 cells cavity−1) was seen in animals pretreated with captopril, but this was still smaller than the responses to IL‐1β or TNF‐α (15 pmol: 23±2.2 × 106 and 75 pmol: 29.5±2 × 106 cells cavity−1, respectively). Nevertheless, the B1 agonist des‐Arg9‐BK (600 nmol) failed to induce neutrophil migration.
HOE‐140 (1 and 2 mg kg−1), a B2 receptor antagonist, reduced LPS‐induced neutrophil migration. HOE‐140 also reduced the neutrophil migration induced by BK, but had no effect on the migration promoted by IL‐1β or TNF‐α. des‐Arg9‐[Leu8]‐BK, B1 receptor antagonist was ineffective in changing neutrophil migration caused by any of these stimuli.
Neutrophil migration induced by LPS or BK was reduced by interleukin‐1 receptor antagonist (IL‐1ra) (1 mg kg−1), sheep anti‐rat TNF serum (anti‐TNF serum) (0.3 ml cavity−1), and the nonspecific selectin inhibitor fucoidin (10 mg kg−1).
TNF‐α levels in the pouch fluid were increased by LPS or BK injection, peaking at 0.5–1 h and gradually declining thereafter up to 6 h. IL‐1β levels increased steadily throughout the 6 h period. HOE‐140 markedly inhibited the rise in IL‐1β and TNF‐α levels in pouch fluid triggered by both stimuli.
These results indicate that BK participates importantly in selectin‐dependent neutrophil migration into the air pouch triggered by LPS in the rat, by stimulating B2 receptors coupled to synthesis/release of TNF‐α and IL‐1β.

British Journal of Pharmacology (2003) 139, 271–278. doi:10.1038/sj.bjp.0705236
Signaling mechanisms of enhanced neutrophil phagocytosis and chemotaxis by the polysaccharide purified from Ganoderma lucidum
Authors: Hsu Ming‐Jen , Lee Shiuh‐Sheng , Lee Sho Tone , Lin Wan‐Wan 
Published: May 2003

The polysaccharide from Ganoderma lucidum (PS‐G) has been reported to enhance immune responses and to elicit antitumor effects. In our previous study, we found that PS‐G efficiently inhibited spontaneously and Fas‐enhanced neutrophil apoptosis when cultured in vitro. Since phagocytosis and chemotaxis play essential roles in host defense mediated by neutrophils, it is of great interest to know the effect of PS‐G on these two cell functions, and the molecular events leading to these actions.
Using latex beads and heat‐inactive Escherichia coli serving as particles for neutrophil engulfment, we found that PS‐G is able to enhance phagocytic activity of human primary neutrophils and neutrophilic‐phenotype cells differentiated from all trans retinoic acid‐treated HL‐60 cells.
Chemotactic assay using Boyden chamber also revealed the ability of PS‐G to increase neutrophil migration.
Exposure of neutrophils to PS‐G time dependently caused increases in protein kinase C (PKC), p38 mitogen‐activated protein kinase (MAPK), Hck, and Lyn activities.
Results with specific kinase inhibitors indicate that phagocytic action of PS‐G was reduced by the presence of wortmannin (Phosphatidylinositol 3‐kinase, PI3K inhibitor), pyrazolpyrimidine 2 (Src‐family tyrosine kinase inhibitor), Ro318220 (PKC inhibitor), and SB203580 (p38 MAPK inhibitor), but not by PD98059 (mitogen‐activated protein/ERK kinase inhibitor). Moreover, chemotactic action of PS‐G requires the activities of PI3K, p38 MAPK, Src tyrosine kinases and PKC.
All these results demonstrate the abilities of PS‐G to enhance neutrophil function in phagocytosis and chemotaxis, and further provide evidence to strengthen the beneficial remedy of G. lucidum in human to enhance defense system.

British Journal of Pharmacology (2003) 139, 289–298. doi:10.1038/sj.bjp.0705243
Effects of methyl p‐hydroxybenzoate (methyl paraben) on Ca2+ concentration and histamine release in rat peritoneal mast cells
Authors: Fukugasako Sanae , Ito Shinichi , Ikemoto Yoshimi 
Published: May 2003

Mechanisms of methyl p‐hydroxybenzoate (methyl paraben) action in allergic reactions were investigated by measuring the intracellular Ca2+ concentration ([Ca2+]i) and histamine release in rat peritoneal mast cells (RPMCs).
In the presence or absence of extracellular Ca2+, methyl paraben (0.1–10 mM) increased [Ca2+]i, in a concentration‐dependent manner. Under both the conditions, methyl paraben alone did not evoke histamine release.
In RPMCs pretreated with a protein kinase C (PKC) activator (phorbol 12‐myristate 13‐acetate (PMA) 3 and 10 nM), methyl paraben (0.3–3 mM) induced histamine release. However, a high concentration (10 mM) of the agent did not increase the histamine release.
U73122 (0.1 and 0.5 μM), an inhibitor of phospholipase C (PLC), significantly inhibited the methyl paraben‐induced histamine release in PMA‐pretreated RPMCs. U73343 (0.5 μM), an inactive analogue of U73122, did not inhibit the histamine release caused by methyl paraben.
In Ca2+‐free solution, PLC inhibitors (U73122 0.1 and 0.5 μM, D609 1–10 μM) inhibited the methyl paraben‐induced increase in [Ca2+]i, whereas U73343 (0.5 μM) did not.
Xestospongin C (2–20 μM) and 2 aminoethoxydiphenyl borate (30 and 100 μM), blockers of the inositol 1,4,5‐trisphosphate (IP3) receptor, inhibited the methyl paraben‐induced increase in [Ca2+]i in Ca2+‐free solution.
In conclusion, methyl paraben causes an increase in [Ca2+]i, which may be due to release of Ca2+ from storage sites by IP3 via activation of PLC in RPMCs. In addition, methyl paraben possibly has some inhibitory effects on histamine release via unknown mechanisms.

British Journal of Pharmacology (2003) 139, 381–387. doi:10.1038/sj.bjp.0705248
Brain renin–angiotensin system dysfunction in hypertension: recent advances and perspectives
Authors: Veerasingham Shereeni J , Raizada Mohan K 
Published: May 2003

This review focuses on the dysfunction of the intrinsic brain renin–angiotensin system (RAS) in the pathogenesis of hypertension. Hyperactivity of the brain RAS plays a critical role in mediating hypertension in both humans and animal models of hypertension, including the spontaneously hypertensive rat (SHR). The specific mechanisms by which increased brain RAS activity results in hypertension are not well understood but include increases in sympathetic vasomotor tone and impaired arterial baroreflex function. We discuss the contribution of endogenous angiotensin (Ang) II actions on presympathetic vasomotor rostral ventrolateral medulla neurons to enhance sympathetic activity and maintain hypertension. In addition, we discuss Ang II‐induced attenuation of afferent baroreceptor feedback within the nucleus tractus solitarius and its relevance to the development of hypertension. We also outline the cellular and molecular mechanisms of Ang II signal transduction that may be critical for the initiation and establishment of hypertension. In particular, we present evidence for a phosphoinositide‐3‐kinase‐dependent signaling pathway that appears to contribute to hypertension in the SHR, possibly via augmented Ang II‐induced increases in neuronal firing rate and enhanced transcriptional noradrenaline neuromodulation. Finally, we outline future directions in utilizing our understanding of the brain RAS dysfunction in hypertension for the development of improved therapeutic intervention in hypertension.British Journal of Pharmacology (2003) 139, 191–202. doi:10.1038/sj.bjp.0705262
Loperamide mobilizes intracellular Ca2+ stores in insulin‐secreting HIT‐T15 cells
Authors: He Li‐Ping , Mears David , Atwater Illani , Rojas Eduardo , Cleemann Lars 
Published: May 2003

We have investigated the effects of loperamide on intracellular Ca2+ stores and membrane K+ channels in insulin‐secreting hamster insulinoma (HIT‐T15) cells.
In cell‐attached patch‐clamp mode, loperamide (3–250 μM) activated large single‐channel currents. The loperamide‐activated currents were tentatively identified as Ca2+‐activated K+ channel (KCa) currents based on their single‐channel conductance (145 pS), apparent reversal potential, and insensitivity to tolbutamide. Smaller single‐channel currents with a conductance (32 pS) indicative of adenosine triphosphate‐sensitive K+ channels (KATP channels) were also recorded, but were insensitive to loperamide.
Surprisingly, the loperamide‐activated currents persisted in the absence of extracellular Ca2+. Yet under these conditions, we still measured loperamide‐induced Ca2+ increases. These effects are dose dependent. Loperamide had no effects in the inside‐out patch configuration, suggesting that loperamide does not directly activate the channels with large conductance, but does so secondarily to release of Ca2+ from intracellular stores.
Carbachol (100 μM), an agonist of muscarinic receptors, which mediates IP3‐dependent intracellular Ca2+ release, enhanced the effects of loperamide on KCa channels.
Both the putative KCa currents and Ca2+ signals induced by loperamide (with ‘0’ [Ca2+]o) were abolished when the intracellular Ca2+ stores had been emptied by pretreating the cells with either carbachol or thapsigargin, an endoplasmic reticulum Ca2+‐ATPase inhibitor that blocks reuptake of calcium.
These data indicate that loperamide in insulin‐secreting β‐cells evokes intracellular Ca2+ release from IP3‐gated stores and activates membrane currents that appear to be carried by KCa, rather than KATP channels.

British Journal of Pharmacology (2003) 139, 351–361. doi:10.1038/sj.bjp.0705263