bluuebunny/crossref_metadata_2025 huggingface dataset:
Density Functional Study of the Complexation Reaction of Sn(CH3)3X (X = F, Cl, Br and I) with Halide Anions
Authors: De Proft Frank , Vivas‐Reyes Ricardo , Biesemans Monique , Willem Rudolph , Martin Jan M. L. , Geerlings Paul
Published: October 2003

The Lewis acid‐base reaction between Sn(CH3)3X and Y− (with X, Y = F, Cl, Br and I) has been studied using quantum chemical calculations. Complexation energies were calculated at the Density Functional Theory (DFT) level and rationalized on the basis of a local application of the hard and soft acids and bases principle. It was observed that smaller differences in the local softness of the interacting sites in the Lewis acid and base correspond to stronger interactions. Moreover, the calculated sequences in complexation energies can be reproduced using equations containing chemical concepts introduced within the framework of conceptual density functional theory and rooted in the hard and soft acids and bases principle and referring only to the reactants. A method of treating the electronegativity and softness of the halide anions is presented based on a Taylor expansion of the electronegativity of the neutral halogens and the softness‐polarizability proportionality. Experimental evidence for the calculated sequences was gathered from measured 117Sn chemical shifts and 1J (13C‐119/117Sn) coupling constant changes upon complexation. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003)
Cyclotetrapeptide Complexes of Nickel(II) and Palladium(II) by Template Synthesis from Dipeptide Esters with Functionalized Side Chains − Crystal Structure of [(cyclo‐Gly‐β‐Ala‐Gly‐β‐Ala‐4H+)Cu](PPN)2
Authors: Schapp Jan , Haas Katharina , Sünkel Karlheinz , Beck Wolfgang
Published: October 2003

The cyclocondensations of dipeptide esters [Gly‐L‐Asp(OMe)2, Gly‐L‐Glu(OMe)2, L‐AspOMe‐β‐AlaOMe, β‐Ala‐L‐Lys(ψ‐N‐Boc,OMe), β‐Ala‐L‐Orn(ψ‐N‐Boc,OMe)] at nickel(II), palladium(II), and copper(II) templates give dianionic square‐planar complexes of deprotonated cyclotetrapeptides that contain functional groups in the side chains. The complexes with 14‐ or 16‐membered rings were isolated as [Ph3PNPPh3]+ salts. Hydrolysis of {[cyclo‐Gly‐Asp(OMe)‐Gly‐Asp(OMe)‐4H+]Pd}2− affords the tetraanionic complex [{cyclo‐Gly‐Asp(O−)‐Gly‐Asp(O−)‐4H+}Pd]4−(Li+)2(PNP+)2. The crystal structure of [(cyclo‐Gly‐β‐Ala‐Gly‐β‐Ala‐4H+)Cu](PPN)2 is also reported. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003)
Pyrazolylboratozinc Complexes of Nucleosides and Nucleoside Analogues
Authors: Badura Dirk , Vahrenkamp Heinrich
Published: October 2003

Attachment of deprotonated nucleosides or of alkylated nucleobases, as their analogues, to zinc was achieved by condensation reactions between TpZn‐OH complexes and nucleobase derivatives. Pyrazolylboratozinc complexes with derivatives of uracil, thymine, guanine, xanthine and hypoxanthine were obtained and characterized by structure determination. In the uracil, thymine, guanine and hypoxanthine derivatives, zinc is bound to the nitrogen atom which bears the proton in the nucleoside. In the xanthine derivatives all three possible bonding modes are realized. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003)
Cover Picture: Chain‐Like Tetra‐, Penta‐ and Heptanuclear Cyanide‐Bridged Complexes by Attachment of Organometallic Cyanides to M2, M3 and M5 Units (Eur. J. Inorg. Chem. 20/2003)
Authors: Sheng Tianlu , Appelt Ralf , Comte Virginie , Vahrenkamp Heinrich
Published: October 2003

The cover picture shows a chain of seven metal atoms parallel to a chain of Chinese friendship symbols (locks which people like to fix at high lookout points and then throw the keys down). The background photo was taken in the Chinese Huangshan mountains, but it relates to friendship grown in Fraiburg, Germany, and symbolizes a truly international scientific collaboration. As a result, the Chinese author of this paper has prepared the chainlike Fe−C−N−Ni−Ni−Ni−Ni−Ni−N−C−Fe complex, while the senior author is the godfather of his daughter, the energetic baby with the name Freia, pregnant with meaning. Details are discussed in the article by H. Vahrenkamp et al. on p. 3731 ff.
Intermolecular interaction in liquid dimethylformamide and its manifestation in Raman spectra
Authors: Tukhvatullin F. H. , Pogorelov V. E. , Tashkenbaev U. N. , Jumaboev A. , Hushvaktov H. , Seit‐Enon M. , Osmanov S. A.
Published: October 2003

The wavenumbers of peaks of parallel and perpendicular polarized components of the CO vibration band for dimethylformamide in the Raman spectra differ by 14.5 cm−1. The difference in wavenumber values decreases and falls to zero on strong dilution with CCl4 and dimethyl sulfoxide. A doublet structure of the band is observed in solutions with CCl4 in the 0.2 mole fraction concentration region. The above‐mentioned non‐coincidence of CO vibration band wavenumbers in pure liquid is explained by the complexity of the band, i.e. the presence within the band of two close and overlapped lines with different magnitudes of depolarization ratio belonging to monomeric molecules (high wavenumber) and aggregate formation. In a mixture at strong dilution there remains only one type of formation, and the band acquires a simple shape of a separate line, and the above‐mentioned wavenumber difference falls to zero. The experimental results are supplemented by ab initio calculations of normal vibrational wavenumbers and of some parameters for monomeric and dimeric dimethylformamide molecules. Copyright © 2003 John Wiley & Sons, Ltd.
Effect of natural rubber latex on the conducting state of polyaniline blends determined by Raman spectroscopy
Authors: Job A. E. , Constantino C. J. L. , Mendes T. S. G. , Teruya M. Y. , Alves N. , Mattoso L. H. C.
Published: October 2003

Blends possessing the elastomeric properties of natural rubber (NR) and the conducting properties of conducting polymer (polyaniline, PANI) were obtained, which are promising for further application in deformation sensors. Blends containing 20% (v/v) of PANI in 80% of NR latex were fabricated by casting in the form of free‐standing films and treated either with HCl or with corona discharge, which lead PANI to its conducting state (doping process). Characterization was carried out by Raman spectroscopy, d.c. conductivity and thermogravimetric analysis. Evidence for chemical interaction between PANI and NR was observed, which allowed the conclusion that the NR latex itself is able partially to induce both the primary doping of PANI (by protonation) and the secondary doping of PANI (by changing the chain conformation). Further improvement in the primary doping could be obtained for the blends either by corona discharge or by exposing them to HCl. The electrical conductivity reached in the blends was dependent on the doping conditions used, as observed by Raman scattering. Copyright © 2003 John Wiley & Sons, Ltd.
Fourier transform Raman spectroscopy of drugs: quantitative analysis of 1‐phenyl‐2,3‐dimethyl‐5‐pyrazolone‐4‐methylaminomethane sodium sulfonate: (dipyrone)
Authors: Izolani Antônio O. , de Moraes Milena T. , Téllez S. Claudio A.
Published: October 2003

Several drugs provided by the pharmaceutical industry and containing dipyrone as the active principle have different mass percentages of the letter. We describe a procedure for the quantitative analysis of several tablets containing dipyrone (or other solid active principles). The results of Fourier transform Raman band analysis (band area and band height) agree well with the stated contents of dipyrone in the tablets. Copyright © 2003 John Wiley & Sons, Ltd.
Synthesis and absorption/emission properties of novel poly(silylenearylenevinylene)s
Authors: Kwak Giseop , Sumiya Ken‐Ichi , Sanda Fumio , Masuda Toshio
Published: October 2003

Polymerization of p‐(dimethylsilyl)phenylacetylene in toluene at 25 and 80 °C with RhI(PPh3)3 catalyst afforded highly regio‐ and stereoregular poly(dimethylsilylene‐1,4‐phenylenevinylene)s [cis‐ and trans‐poly(1a)s] containing 98% cis‐ and 99% trans‐vinylene moieties, respectively. The trans‐type polymers exhibited redshifts and hyperchromic effects in the ultraviolet–visible spectrum as compared with the cis‐type counterparts. Photoirradiation of cis‐ and trans‐poly(1a)s gave cis‐rich mixtures at equilibrium states. The trans and cis polymers exhibited different emission properties, for example—trans polymer, emissn λmax = 400 nm, quantum yield: 3.4 × 10−3 and cis polymer, emissn λmax = 380 nm, quantum yield: 1.5 × 10−3. Besides poly(1a), poly(dimethylsilylenearylenevinylene)s containing biphenylene and phenylenesilylenephenylene units [poly(3)] were prepared. The extent of conjugation in these polymers decreased in the orders of biphenylene > phenylene > phenylenesilylenephenylene as well as trans‐vinylene > cis‐vinylene. The quantum yield of the trans‐rich polymer with biphenylene moiety was fairly large and 0.15. Polyaddition of 1,4‐bis(dimethylsilyl)benzene and three types of diethynylarenes (4,4′‐diethynylbiphenyl, 2,7‐diethynylfluorene, and 2,6‐diethynylnaphthalene) catalyzed by RhI(PPh3)3 provided novel regio‐ and stereoregular polymers [poly(6)]. These polymers displayed blue light emission with high quantum yields (4–81%). © 2003 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 41: 3615–3624, 2003
“Computers in the Wild”: Guilds and Next-Generation Unionism in the Information Revolution
Authors: Benner Chris
Published: October 2003

One of the aspects of the information revolution that has had negative implications for many workers is the erosion of the workplace as a basis for long-term security and collective solidarity. The dramatic pace of technological change, complex restructuring of firms, and continual competitive pressures for rapid innovation that are a central component of the information economy are contributing to fundamental transformations in work and employment. As part of this transformation, the trend towards the centralization of production in large enterprises that was the dominant feature of the industrial era is being superseded by production organized around smaller workplaces connected together in complex, constantly shifting networks operating at multiple spatial scales, from the local to the global. For many workers, one result is greater insecurity, as they increasingly have to update their skills, change jobs and even change careers more frequently. Some analysts have gone so far as to characterize the typical information age worker as a “free-floating individual, connected on-line to a variety of task-performing organizations, ever-competing for resources and personal support, and assuming limited responsibilities towards limited people for a limited time”.
Word and sacrament as paradigmatic for pastoral
theology: in search of a definition via
Brueggemann, Hauerwas and Ricoeur
Authors: Stone Lance
Published: October 2003

The current debate about the nature and parameters of pastoral theology
emphasises practice as both the source and the end of theological reflection: pastoral
theology as reflection on practice with a view to transforming practice. This raises issues for
pastoral theologians from the Reformed tradition, which prioritises word and prizes scripture and
preaching as fundamental ways in which the word is mediated to us. Current philosophical, cultural
and ecclesiological developments emphasise the constructed nature of our worlds, the crucial place
of language in world construction, and the ‘textured’ nature of the community of faith.
Thus theologians associated with the term ‘post-liberal’ emphasise that in a time of
displacement, marginalisation and identity crisis the church, like the Jewish community in exile,
returns to its texts as its home and the source of its identity and its practice. Taking the
theology of Walter Brueggemann as a starting point, this paper explores the relationship between
proclamation and practice in the church's life, and seeks, through a Reformed paradigm of word
and sacrament, a ‘post-liberal’ redefinition of pastoral theology that gives a higher
profile to the church's ‘peculiar speech’.
Simple anti-swing feedback control for a gantry crane
Authors: Aoustin Yannick , Formal'sky Alexander
Published: October 2003

We propose a simple quasi time optimal control law for a gantry crane with a payload. The force applied to the trolley is a controlling parameter. The control law consists of two parts: a feedforward term and a trolley position and velocity feedback term.

Initially, we synthesize the feedforward term and the corresponding reference trajectory by computing the time optimal control for the system mass center. The computed optimal control is a discontinuous function of time with several switching time instants. Undesirable large vibrations due to the payload sway appear under this control. Therefore, we transform this control, replacing its jumps by the piecewise linear continuous functions.
The computed feedforward term and the reference trajectory are used as input signals of the PD-controller.
Book Review
Authors: Andrew Alex M.
Published: October 2003

KNOWLEDGE REPRESENTATION, REASONING AND DECLARATIVE PROBLEM SOLVING, by Chitta Baral, University Press, Cambridge, 2003, xiv+530 pp., ISBN 0-521-81802-8 (Hbk, £60.00).
From the Margins to the Centre: The Uyghur Challenge in Beijing
Authors: Baranovitch Nimrod
Published: October 2003

Recent literature on Uyghur identity in China makes clear that Uyghurs today not only have perceptions and narratives relating to their identity which challenge official ones, but also that these are expressed publicly in literature, art and everyday practice. However, to date this agency has been highlighted only in the context of the Uyghurs' native-place, Xinjiang, while the little that has been written on representations of Uyghur identity in nationally distributed media and culture suggests that Uyghurs are still completely marginalized and voiceless. This article challenges this view by shifting the focus to Uyghurs who migrated to Beijing and by showing that they have been able to achieve an independent public voice that extends not only beyond Xinjiang but also beyond China. The article explores the role that Uyghur artists and entrepreneurs, and Xinjiang restaurants in Beijing play in challenging the orthodox representations of Uyghur identity in China and argues that although there are only a few thousand Uyghurs in the city they play a significant role in the negotiation of Uyghur identity, representation and nationalism. The article also challenges the widely held view that internal migrants in China are silent and politically powerless.
Re-engaging Chineseness: Political, Economic and Cultural Imperatives of Nation-building in
Singapore
Authors: Tan Eugene K. B.
Published: October 2003

This article examines the management of Chinese identity and culture since Singapore attained independence in 1965. Due to the delicate regional environment, ethnic Chinese identity has been closely managed by the ruling elites, which have been dominated by the English-educated Chinese. There is the evolution from a deliberate policy of maintaining a low-key ethnic Chinese profile to the recent effort to re-sinicize – in form – the majority ethnic group. The article examines the policy impulses and implications for such a landmark change in reconceptualizing the Chinese-Singapore identity, which can be attributed to the needs of regime maintenance buttressed by Confucian ethos as well as the security and economic demands of nation-building.
Theorising Chinese Masculinity: Society and Gender in China. By Kam Louie. [Cambridge: Cambridge University Press, 2002. 239 pp. ISBN 0-521-80621-6.]
Authors: Lean Eugenia
Published: October 2003

In his introduction to Theorising Chinese Masculinity, Kam Louie rightly points out that while a great deal has been written on the topic of femininity in China, the study of masculinity remains remarkably untouched. A few historical and literary studies have started to appear, but next to nothing has been done to “systematically conceptualize the theoretical underpinning of Chinese masculinities in general terms” (p. 3).
Special Issue: Configuration
Authors: SOININEN TIMO , STUMPTNER MARKUS
Published: October 2003

The configuration task is commonly defined as composing a
complex product from a set of predefined component types
while taking into account a set of well-defined restrictions on how
components belonging to these types can be combined. Configuration,
always a successful artificial intelligence (AI) application area ever
since the R1/XCON system of the early 1980s, has recently attracted
renewed research interest. This is also demonstrated by an annual
series of workshops on configuration that have been held at the AAAI,
ECAI, and IJCAI conferences since 1999. Important real-world industrial
configuration tasks are encountered in marketing, manufacturing, and
design. They usually involve physical products, such as
telecommunication switches, computers, elevators, large diesel engines,
automation systems, or vehicles (some of which appear as application
domains in the articles in this issue), but can also pertain to
financial or other services or software.
A new technique for the analysis of neutral air density fluctuations measured in situ in the middle atmosphere
Authors: Strelnikov B. , Rapp M. , Lübken F.‐J.
Published: October 2003

We consider the analysis of mesospheric neutral air density fluctuations caused by turbulent eddy motions as measured by rocket borne ionization gauges. After shortly reviewing the so far standard Fourier‐approach we introduce wavelets as a suitable tool to derive spectral information of the data both as a function of spatial scale and altitude. Applying both techniques to a data set obtained during a recent sounding rocket campaign we show that both methods yield consistent results, however, the wavelet technique yields additional information on the actual vertical extent of the observed turbulent structures.
Strong interactions between species of phytophagous fly: a case of intraguild kleptoparasitism
Authors: Reader Tom
Published: October 2003

In order to understand the role that interspecific competition plays in phytophagous insect communities, we need to consider the ways in which the nature of competition between species can be complicated by interactions with members of other trophic levels. In this paper, I describe how the competitive interaction between two species of gall forming fly,Lipara lucensandL. rufitarsis, is modified as a consequence of interactions with a host plant and natural enemies. The results of field experiments and observations of wild populations show that the two species compete strongly for stems of the common reed,Phragmites australis.L. lucensis competitively inferior, having significantly increased mortality in the presence of heterospecifics. No lasting negative effects of interspecific competition onL. rufitarsiscould be found. In fact, the results show thatL. rufitarsiscan benefit from the presence of heterospecifics. It can usurp the galls ofL. lucens, and experiences reduced mortality and increased fecundity as a result. Thus,L. rufitarsiscan be described as a kleptoparasite. Kleptoparasitism in this system is mediated by the host plant and by the principal parasitoid ofL. rufitarsis.L. rufitarsiscan only benefit from the presence of its competitor becauseL. lucensinducesP. australisto form a large, robust gall that repels the attacks of the ichneumonid waspEndromopoda phragmitidis. These results show how facultative kleptoparasitism can modify the ecological consequences of interspecific competition for both individuals and populations.
Implication of lipids in macrosomia of diabetic pregnancy: can n-3 polyunsaturated fatty acids exert beneficial effects?
Authors: MERZOUK Hafida , KHAN Naim A.
Published: October 2003

Macrosomia or fetal obesity is a frequent complication of pregnancy in diabetes mellitus. Several alterations observed in carbohydrate and lipid metabolism in macrosomic infants of diabetic mothers are thought to be a consequence of maternal hyperglycaemia leading to fetal hyperinsulinaemia. Macrosomic infants of diabetic mothers are prone to the development of glucose intolerance, obesity and diabetes during childhood and adulthood. Furthermore, increasing evidence is accumulating regarding the importance of n-3 polyunsaturated fatty acids (PUFAs) in the reduction of plasma lipids and hyperglycaemia. In this review article, we shed light on the abnormalities in lipid metabolism in macrosomia. We also raise the question of the possible beneficial effects of n-3 PUFAs in diabetic pregnancy and in the prevention and treatment of long-term metabolic abnormalities associated with macrosomia.
Effect of captopril on prostacyclin and nitric oxide formation in healthy human subjects: Interaction with low dose acetylsalicylic acid
Authors: BÖGER RAINER H. , BODE‐BÖGER STEFANIE M. , KRAMME PETRA , TSIKAS DIMITRIOS , GUTZKI FRANK‐M. , FRÖLICH JÜRGEN C.
Published: October 2003

1Angiotensin converting enzyme inhibitors have been suggested to act in part by potentiating the stimulatory effect of bradykinin on endothelial prostacyclin and/or nitric oxide (NO) formation. This may give rise to interaction with cyclo‐oxygenase inhibiting drugs like acetylsalicylic acid, which is most often used in low doses in patients with cardiovascular diseases.

2We investigated the effects of captopril (2×25 mg day−1), or ASA (1×100 mg day−1), or the combination of both drugs for 7 days, on blood pressure, prostanoid and NO formation rates in a double‐blind, double dummy, randomized crossover study in 13 healthy female subjects. The urinary metabolites of thromboxane A2 (2,3‐dinor‐TXB2) and prostacyclin (2,3‐dinor‐6‐keto‐PGF1α), and PGE2 were measured by gas chromatography/tandem mass spectrometry in urine on days 1, 6 and 7 of each medication. NO formation was assessed using urinary NO3− and cyclic GMP as indicators.

3Urinary 2,3‐dinor‐6‐keto‐PGF1α excretion was not significantly changed by either captopril, ASA, or their combination. Urinary 2,3‐dinor‐TXB2 excretion was inhibited by >80% by ASA alone or in combination with captopril (each P<0.05), but was not affected by captopril alone. Urinary PGE2 excretion was not significantly changed by either of the treatments. Urinary NO3− and cyclic GMP excretion rates were not significantly changed by captopril, ASA, or their combination.

4Blood pressure was slightly reduced by captopril. ASA had no effect on blood pressure when given alone, nor did it modulate the effect of captopril on blood pressure during co‐administration. Angiotensin II/angiotensin I ratio (index of ACE activity) was significantly decreased by captopril alone or in combination with ASA, but was unaffected by ASA alone.

5Captopril does not stimulate prostacyclin formation in healthy human subjects in a dose sufficient to substantially inhibit ACE activity. Co‐administration of ASA significantly inhibits 2,3‐dinor‐TXB2 excretion, but does not interfere with the blood pressure lowering effect of captopril in healthy human subjects.
The treatment of hypertension
Authors: CHALMERS JOHN
Published: October 2003

1A ‘retrospective’ of the development of the drug treatment of hypertension is presented from the early days of ganglion blockers to the present time together with a review of the evidence of benefit from treatment.

2Current issues and debates are summarised including shortfalls in the control of hypertension in populations, difficulties surrounding the measurement of blood pressure, disagreement on the levels of blood pressure to treat, the goal blood pressures to aim at, issues surrounding lifestyle measures such as the low salt diet and low intensity exercise, and treatment with diuretics and with calcium antagonists.

3A ‘perspective’ is presented on some avenues for progress in the years ahead. These will include the identification of genetic markers to determine the hypertensive individuals with the greatest risk of death and of cardiovascular complications.
CYP1A2 activity, gender and smoking, as variables influencing the toxicity of caffeine
Authors: CARRILLO JUAN A. , BENITEZ JULIO
Published: October 2003

We have investigated several factors that might be related to the occurrence of toxic effects during the performance of a urinary test with caffeine (300 mg p.o), in 120 healthy volunteers. A total of 218 toxic effects were self‐reported by eighty‐two (68%) subjects. Females and nonsmokers were at the highest risk (chi‐square test, P=0.01). Furthermore, two nonsmoking females experienced a symptomatology with delirium, restlessness, muscle tremor, vomiting and wakefulness. Among females and nonsmokers, those subjects who experienced toxic effects had lower caffeine N3‐demethylation index (CYP1A2 activity) compared with unaffected females (1.87±0.51 vs 1.47±0.27, P<0.0005) and nonsmokers (1.69±0.23 vs 1.49±0.31, P<0.02). Caffeine N1‐ and N7‐demethylations indices were also lower among females (P<0.0005) and nonsmokers (P<0.02) who reported toxic symptoms. We conclude that CYP1A2 activity, gender and smoking are variables to be considered as influencing the toxicity of caffeine.
Atovaquone has no effect on the pharmacokinetics of phenytoin in healthy male volunteers
Authors: DAVIS J. D. , DIXON R. , KHAN A. Z. , TOON S. , ROLAN P. E. , POSNER J.
Published: October 2003

The potential pharmacokinetic interaction between atovaquone and phenytoin was investigated in 12 healthy male volunteers. Each volunteer received a single 600 mg oral dose of phenytoin in the two treatment periods. On one occasion phenytoin was taken alone and on the other after pre‐treatment with 2000 mg atovaquone taken as two doses of 1000 mg as a microfluidized suspension. The mean (±s.d.) peak plasma concentrations (Cmax), apparent total clearance (CL/F ) and terminal half‐life (t½) for phenytoin when administered alone were 10.6(1.8) mg l−1, 24.3 (7.7) ml min−1 and 25(8) h, respectively. When administered together with atovaquone, phenytoin Cmax, CL/F and t½,z were 10.9 (2.0) mg l−1, 23.8 ml min−1 and 24(6) h, respectively. There were no statistically significant differences in any of these plasma pharmacokinetic parameters. There were also no statistically significant differences in the fraction of circulating drug not bound to plasma protein or urinary excretion of 5‐hydroxyphenyl‐phenyl‐hydantoin. In conclusion, there was no effect of atovaquone on the pharmacokinetics of phenytoin or its major metabolite after a single dose.
The pathophysiological mechanism of fluid retention in advanced cancer patients treated with docetaxel, but not receiving corticosteroid comedication
Authors: Béhar A. , Pujade‐Lauraine E. , Maurel A. , Brun M. D. , Lagrue G. , Feuilhade De Chauvin F. , Oulid‐Aissa D. , Hille D.
Published: October 2003

Aims Fluid retention is a phenomenon associated with taxoids. The principal objective of this study was to investigate the pathophysiological mechanism of docetaxel‐induced fluid retention in advanced cancer patients.

Methods Docetaxel was administered as a 1 h intravenous infusion every 3 weeks, for at least 4–6 consecutive cycles, to patients with advanced breast (n=21) or ovarian (n=3) carcinoma, who had received previous chemotherapy, 21 for advanced disease. Phase II clinical trials have shown that 5 day corticosteroid comedication, starting 1 day before docetaxel infusion, significantly reduces the incidence and severity of fluid retention. This prophylactic corticosteroid regimen is currently recommended for patients receiving docetaxel but was not permitted in this study because of its possible interference with the underlying pathophysiology of the fluid retention.

Results Fluid retention occurred in 21 of the 24 patients but was mainly mild to moderate, with only five patients experiencing severe fluid retention. Eighteen patients received symptomatic flavonoid treatment, commonly prescribed after the last cycle. Specific investigations for fluid retention confirmed a relationship between cumulative docetaxel dose and development of fluid retention. Capillary filtration test analysis showed a two‐step process for fluid retention generation, with progressive congestion of the interstitial space by proteins and water starting between the second and the fourth cycle, followed by insufficient lymphatic drainage.

Conclusions A vascular protector such as micronized diosmine hesperidine with recommended corticosteroid premedication and benzopyrones may be useful in preventing and treating docetaxel‐induced fluid retention.
Bisoprolol attenuates noradrenaline‐ and phenylephrine‐evoked venoconstriction in man in vivo
Authors: Abdelmawla A. H. , Langley R. W. , Szabadi E. , Bradshaw C. M.
Published: October 2003

Aims The aim of this study was to examine the effects of bisoprolol (BIS), a selective β1‐adrenoceptor antagonist without partial agonistic activity, on noradrenaline‐ and phenylephrine‐evoked venoconstriction in man using the dorsal hand vein compliance technique.

Methods Twelve healthy male volunteers participated in three weekly experimental sessions. Subjects were allocated to treatments and sessions on a double‐blind basis. In each session either BIS 5 mg (BIS5), or BIS 10 mg (BIS10), or placebo was administered orally, and noradrenaline acid tartrate (0.1–33.33 ng min−1 ) followed by phenylephrine hydrochloride (0.033–10 μg min−1 ) was infused into the dorsal hand vein. Systolic and diastolic blood pressure and heart rate were also measured.

Results Both noradrenaline and phenylephrine produced dose‐dependent venoconstriction: the geometric mean ED50 for noradrenaline was 3.21 ng min−1 and for phenylephrine 135.04 ng min−1; the potency ratio (noradrenaline/phenylephrine) was 42. Both BIS5 and BIS10 significantly decreased the venoconstriction to noradrenaline (ANOVA; P<0.005), and to phenylephrine (ANOVA; P<0.001). The antagonism of the venoconstrictor responses was also reflected in a significant increase in logED50 values for both noradrenaline (ANOVA; P<0.005), and phenylephrine (ANOVA; P<0.0025) in the presence of both doses of BIS. Both doses of BIS significantly decreased heart rate (ANOVA; P<0.0001), and systolic blood pressure (ANOVA; P<0.0025).

Conclusions Bisoprolol can antagonize α1‐adrenoceptor mediated venoconstriction in the human dorsal hand vein in vivo through a mechanism which remains to be elucidated.
Erythropoietin production in healthy volunteers subjected to controlled hypobaric hypoxia: further evidence against a role for adenosine
Authors: Gleiter C. H. , Becker T. , Wenzel J.
Published: October 2003

Aims Objective of this study was to investigate whether adenosine modulates renal erythropoietin production.

Methods In the present study erythropoietin production was stimulated by hypobaric hypoxia by subjecting healthy volunteers to a simulated altitude of 4000 m in a low pressure chamber for 5.5 h. During exposure to hypoxia the subjects received i.v. in a randomized, single‐blind, cross‐over fashion the non‐specific adenosine antagonist theophylline, the adenosine reuptake inhibitor dipyridamole and placebo.

Results Contrary to the working hypothesis, theophylline did not decrease and dipyridamole did not further boost erythropoietin concentrations.

Conclusions The results are in agreement with our earlier study using haemorrhage as a controlled physiological stimulus of erythropoietin production, and would question a major role for adenosine as a mediator of renal erythropoietin production.
Inhibition of vasoconstriction by potassium channel opener aprikalim in human conduit arteries used as bypass grafts
Authors: He Guo‐Wei , Yang Cheng‐Qin
Published: October 2003

Aims Potassium channel openers (KCOs) are of potential therapeutic value. Little is known about the effect of these drugs on human conduit arteries used as coronary bypass grafts. The purpose of this study was to determine the effect of the KCO aprikalim (RP52891) on human arteries used as coronary bypass grafts with emphasis on the possible difference in the inhibitory effect on depolarizing agent‐mediated rather than receptor‐mediated contraction.

Methods Human internal mammary artery segments (IMA, n=88) taken from 28 patients were studied. Concentration‐relaxation curves for aprikalim were established in IMA precontracted with three vasoconstrictors (K+, U46619, and phenylephrine). In IMA rings incubated with aprikalim (1 or 30 &mgr;m ) for 10 min concentration‐contraction curves for the three vasoconstrictors were constructed.

Results Aprikalim‐induced relaxation was less in K+ (37.3±6.4%) than in U46619 (80.2±7.7%, P=0.002), or phenylephrine (67.5±7.0%, P=0.038) ‐precontracted IMA. The EC50 for K+‐(−5.40±0.12 log m ) was significantly higher than that for phenylephrine (−6.43±0.30 log m, P=0.007) but not significant compared with that for U46619 (−5.81±0.11, P >0.05). Pretreatment with aprikalim depressed the contraction by phenylephrine from 140.6±27.6% to 49.3±14.1% (P=0.002) and shifted the EC50 11.0‐fold higher in rings treated with 1 &mgr;m aprikalim (P=0.007). Treatment of aprikalim did not significantly reduce the K+ and U46619‐induced contraction (P >0.05) but shifted the concentration‐contraction curves rightward (2.8‐fold higher for K+, P<0.05 and 2.2‐fold higher for U46619, P<0.05).

Conclusions This study demonstrates that aprikalim has vasorelaxant effects in human conduit arteries used as coronary artery bypass grafts contracted by a variety of vasoconstrictors and this effect is vasoconstrictor‐selective with greater potency for &agr;1‐adrenoceptor agonists than for depolarizing agent K+. These findings provide information on the possible use of this KCO in various clinical settings.
Evening dosing is associated with higher plasma concentrations of pranlukast, a leukotriene receptor antagonist, in healthy male volunteers
Authors: Brocks Dion R. , Upward James , Davy Maria , Howland Kate , Compton Christopher , McHugh Charles , Dennis Michael J.
Published: October 2003

Aims To study the magnitude of differences in the pharmacokinetics of pranlukast, after morning and evening administration.

Methods Pranlukast (300 mg) was administered to 12 healthy male volunteers on two separate occasions, either in the morning or evening. Both doses were given 30 min after a standard high fat content meal. Blood samples were collected up to 18 h postdose. Plasma was assayed by high performance liquid chromatography. Standard pharmacokinetic and statistical analyses were performed.

Results Statistically significant (P<0.05) increases were noted in AUC(o,t ) (56%) and tmax (2.5 h) after evening administration. Cmax was 14% higher after evening dosing (95% C.I. 0.71–1.84).

Conclusions Pranlukast bioavailability is apparently increased after evening dosing as compared with morning administration. Higher night‐time and early morning plasma concentrations may confer additional therapeutic benefit at a time when asthmatics are at greatest risk of developing bronchospasm.
The risk of acute liver injury associated with cimetidine and other acid‐suppressing anti‐ulcer drugs
Authors: García Rodríguez Luis A. , Wallander Mari‐Ann , Stricker Bruno H. Ch.
Published: October 2003

Aims The objective of this study was to estimate the risk of acute liver injury associated with individual acid‐suppressing drugs and assess the role of dose and duration of treatment.

Methods We used a nested case‐control study design within a cohort of over 100 000 users of cimetidine, famotidine, omeprazole and ranitidine. The primary source of information was the General Practitioners Research Database. We identified 108 981 persons aged 20–74 years who received at least one prescription for cimetidine, famotidine, omeprazole, or ranitidine during 1990–93, and we ascertained the first occurrence of clinically acute liver injury referred to a specialist or admitted to a hospital.

Results After review of medical records, 33 patients were considered eligible cases of idiopathic acute liver injury with no fatal cases. The type of liver injury was hepatocellular in almost half of the cases, and 80% of all cases presented with jaundice. Twelve cases occurred among current users of cimetidine, five among ranitidine users and one in an omeprazole user. The absolute risk of acute liver injury associated with cimetidine was estimated to be slightly greater than one per 5000 users of cimetidine. The adjusted relative risk (RRs) and 95% CI of developing acute liver injury associated with current use of cimetidine compared to non‐use was 5.5 (1.9–15.9), with omeprazole 2.1 (0.2–19.2) and with ranitidine 1.7 (0.5–5.8). In the absence of concomitant use of other hepatotoxic drugs, the RR with cimetidine was 14.4 (2.8–73.7). Among users of cimetidine, the risk was especially high in the first 2 months of starting therapy (RR: 11.3, 3.7–35.1) and at daily doses of 800 mg or greater (RR: 8.8, 3.0–26.0).

Conclusions Cimetidine was the individual anti‐ulcer drug with the highest risk of developing symptomatic acute liver disease. Further data are required to confirm this finding. Our study indicates that there is a dose relationship and a short latent period between cimetidine treatment and acute liver injury.
1‐Methylxanthine derived from caffeine as a pharmacodynamic probe of oxypurinol effect
Authors: Birkett D. J. , Miners J. O. , Valente L. , Lillywhite K. J. , Day R. O.
Published: October 2003

Aims In the present study we have investigated the use of caffeine, administered in the form of instant coffee, as a prodrug for 1MX to validate the use of the 1MU:1MX ratio following caffeine administration as a pharmacodynamic measure of oxypurinol effect on xanthine oxidase.

Methods Five healthy volunteers took caffeine 75 mg 8 hourly administered as instant coffee over a 7 day period. They were given allopurinol 600 mg on day 4. Urine was collected in 8 h aliquots from day 1–day 7. The ratio of 1‐methyluric acid (1MU) to 1‐methylxanthuric (1MX) was determined.

Results The relationship between the plasma oxypurinol (the active metabolite of allopurinol) concentration at the midpoint of each caffeine dosage interval and the decrement in the urinary 1MX to 1MU ratio fitted well by a sigmoid Emax model. Mean (±s.d.) values of the oxypurinol EC50(3.9±1.4 mg l− 1 ), EC90(8.7±1.8 mg l− 1 ) and the exponent, n (3.0±1.2) were similar to those obtained previously following either the direct administration of 1MX or the use of theophylline as a prodrug for 1MX.

Conclusions These data indicate that the use of caffeine as a source of 1MX could provide a simple and ethically acceptable method for monitoring oxypurinol effect in patients taking allopurinol for the treatment of gout.
Influence of SNN‐6010, an elemental diet, on the generation of cytokines, NO, and chemiluminescence from leukocytes and umbilical vein endothelial cells in man
Authors: Ueta Eisaku , Yoneda Kazunori , Yamamoto Tetsuya , Osaki Tokio
Published: October 2003

Aims There is insufficient information on the influence of elemental diet (ED) on leukocytes and endothelial cells although ED has been used increasingly for debilitated and post‐operative patients. We here aimed to show the influence of SNN‐6010 (Twinline®; TL), which contains medium‐chain triglycerides, on the generation of cytokines and nitric oxide (NO) and chemiluminescence in human umbilical vein endothelial cells (HUVEC) and leukocytes.

Methods Leukocytes were obtained from 10 healthy volunteers and 10 patients with jaw fractures who underwent TL for 30 days after intermaxillary fixation. Luminol‐dependent chemiluminescence and NO generation were measured in polymorphonuclear leukocytes (PMN) and HUVEC and generation of interleukin‐1 beta (IL‐1&bgr;), tumour necrosis factor‐alpha (TNF‐&agr;), and prostaglandin E2 (PGE2 ) as well as expression of these cytokines’ mRNA were examined in lymphocytes, monocytes, PMN, and HUVEC.

Results TL dose‐dependently suppressed generation of IL‐1&bgr;, TNF‐&agr;, PGE2, and NO in all kinds of cells from healthy individuals. Lymphocytes from patients who underwent TL feeding for 30 days showed reduced generation of IL‐1&bgr; and TNF‐&agr;, and the suppressed cytokine generation corresponded with the decreased expression of mRNA of these cytokines. Chemiluminescence by PMN from healthy individuals was suppressed by TL dose‐dependently, and PMN from TL‐fed patients showed reduced chemiluminescence.

Conclusion These results appear to indicate that TL suppresses the functions of leukocytes and endothelial cells by down‐regulating the generation of reactive oxygen intermediates, NO, and cytokines.
Diltiazem‐cyclosporin pharmacokinetic interaction — dose–response relationship
Authors: Jones Terry E. , Morris Raymond G. , Mathew Timothy H.
Published: October 2003

Aims To study the dose‐response relationship of the pharmacokinetic interaction between diltiazem and cyclosporin in kidney transplant recipients.

Methods Eight stable kidney transplant recipients maintained on cyclosporin but not taking diltiazem, were given increasing doses of diltiazem to a maximum dose of 180 mg day−1. Following a 2 week period on each dose of diltiazem, thirteen blood samples were taken over a 24 h period to allow morning and evening AUCs to be determined for cyclosporin, diltiazem and three metabolites of diltiazem.

Results Mean cyclosporin AUC(0, 24 h) increased sharply following the lowest dose of diltiazem used (10 mg day−1 ), the rate of increase slowed after 30–60 mg day−1 but continued to increase up to the maximum dose tested. The effect of a single morning dose of DTZ was evident over both morning (0–12 h) and evening (12–24 h) cyclosporin AUCs. There was considerable interpatient variation in response to DTZ.

Conclusions The dose of diltiazem required to increase cyclosporin AUC (and hence allow significant reduction in cyclosporin dose) is less than that currently used for many patients. Lower doses of diltiazem should result in fewer adverse effects and may allow its use in situations where it was hitherto contraindicated. Because of the significant interpatient variation in response, we recommend individual patient blood cyclosporin concentration monitoring both before and after the introduction of diltiazem.
Characterization of the human cytochrome P450 enzymes involved in the metabolism of dihydrocodeine
Authors: Kirkwood L. C. , Nation R. L. , Somogyi A. A.
Published: October 2003

Aims Using human liver microsomes from donors of the CYP2D6 poor and extensive metabolizer genotypes, the role of individual cytochromes P‐450 in the oxidative metabolism of dihydrocodeine was investigated.

Methods The kinetics of formation of N‐ and O‐demethylated metabolites, nordihydrocodeine and dihydromorphine, were determined using microsomes from six extensive and one poor metabolizer and the effects of chemical inhibitors selective for individual P‐450 enzymes of the 1A, 2A, 2C, 2D, 2E and 3A families and of LKM1 (anti‐CYP2D6) antibodies were studied.

Results Nordihydrocodeine was the major metabolite in both poor and extensive metabolizers. Kinetic constants for N‐demethylation derived from the single enzyme Michaelis‐Menten model did not differ between the two groups. Troleandomycin and erythromycin selectively inhibited N‐demethylation in both extensive and poor metabolizers. The CYP3A inducer, α‐naphthoflavone, increased N‐demethylation rates. The kinetics of formation of dihydromorphine in both groups were best described by a single enzyme Michaelis‐Menten model although inhibition studies in extensive metabolizers suggested involvement of two enzymes with similar Km values. The kinetic constants for O‐demethylation were significantly different in extensive and poor metabolizers. The extensive metabolizers had a mean intrinsic clearance to dihydromorphine more than ten times greater than the poor metabolizer. The CYP2D6 chemical inhibitors, quinidine and quinine, and LKM1 antibodies inhibited O‐demethylation in extensive metabolizers; no effect was observed in microsomes from a poor metabolizer.

Conclusions CYP2D6 is the major enzyme mediating O‐demethylation of dihydrocodeine to dihydromorphine. In contrast, nordihydrocodeine formation is predominantly catalysed by CYP3A.
Benazepril, an angiotensin converting enzyme inhibitor: drug interaction with salbutamol and bronchial response to histamine in normal subjects
Authors: Bauer K. G. , Brunel P. , Nell G. , Quinn G. , Kaik G. A.
Published: October 2003

Aims To investigate the effect of the angiotensin converting enzyme inhibitor, benazepril, on pulmonary function.

Methods We investigated the influence of benazepril, on lung function and the interaction with inhaled salbutamol (0.1 to 6.6 mg) and histamine (0.03 to 30.69 g l−1 ) in normal subjects. Benazepril 20 mg, salbutamol 8 mg, propranolol 160 mg, and placebo were given orally once daily over 10 days.

Results On day 8, there was no difference in the area under the salbutamol dose‐response curves between benazepril, placebo and oral salbutamol (P >0.05), propranolol shifted the curves to the right (P<0.05). On day 10, histamine challenge resulted in following PD35sGaw values (geometric mean and 95% CI): with placebo 1.02 (0.95–1.09) g l−1, benazepril 1.04 (0.99–1.08), salbutamol 1.19 (1.13–1.25), propranolol 0.57 (0.50–0.65).

Conclusions Benazepril had no influence on baseline lung function, caused no interaction with inhaled salbutamol and the bronchial response to histamine was similar to placebo. However, our findings in normal subjects cannot be extrapolated automatically to asthmatics.
PMA‐induced megakaryocytic differentiation of HEL cells is accompanied by striking modifications of protein kinase C catalytic activity and isoform composition at the nuclear level
Authors: Zauli Giorgio , Bassini Alessandra , Catani Lucia , Gibellini Davide , Celeghini Claudio , Borgatti Paola , Caramelli Elisabetta , Guidotti Lia , Capitani Silvano
Published: October 2003

We investigated whether members of the protein kinase C (PKC) family of enzymes could play a role in the nuclear events involved in megakaryocytic differentiation. PKC activity was analysed using a serine substituted specific peptide, which enabled us to evaluate the whole catalytic activity in the pluripotent haemopoietic HEL cell line treated with 10−7 m phorbol myristate acetate (PMA) or haemin. In parallel, the subcellular distribution of different PKC isoforms (α, βI, βII, γ, δ, ε, θ, η, ζ) was evaluated by Western blot. PKC catalytic activity in the nuclei of HEL cells showed a peak after acute (30 min) treatment with PMA, followed by a significant (P < 0.05) decline after prolonged exposure (72 h) to the same agonist, when most HEL cells had acquired a differentiated megakaryocytic phenotype. Western blot analysis of nuclear lysates consistently showed a significant increase of PKC‐α, ‐βI, ‐ε, ‐θ and ‐ζ isoforms after 30 min of PMA treatment, followed by a drastic decline of all but PKC‐ζ isoforms. Moreover, PKC‐δ appeared in HEL nuclei only after 72 h of exposure to PMA. On the other hand, neither the catalytic activity nor the immunoreactivity of the different PKC isoforms showed remarkable variations in nuclei of HEL cells induced to differentiate along the erythroid lineage with 10−7 m haemin.

The possible implications of these findings for a better understanding of the molecular events underlying the process of megakaryocytic differentiation are discussed.