bluuebunny/crossref_metadata_2025 huggingface dataset:
Numerical study of the electron and ion trajectories in HOPFEDs
Authors: Zhong Xuefei , Zhao Hongping , Lei Wei , Zhang Xiaobing , Yin Hanchun , van der Poel Wilbert , den Engelsen Daniel
Published: January 2005

Abstract— A hopping‐electron field‐emission display (HOPFED) is a field‐emission display (FED) with a new and revolutionary spacer structure. In a HOPFED, two insulator plates, referred to as hop and flu spacers, are sandwiched between the emitter and front plate. The objective of this spacer structure is to improve the performance of a FED substantially, notably contrast, color purity, and luminance uniformity. Another advantage is the reduced sensitivity of ion bombardment on the field emitters. We show by numerical methods that both the luminance uniformity and the sensitivity of ion bombardment improve substantially in a HOPFED.
Identification of charge‐transfer transition between Gd3+ to O2− in gadolinium‐containing oxide phosphors in VUV region
Authors: Wang Yu Hua , Endo Tadashi , Guo Xuan , Murakami Yukio , Ushirozawa Mizumoto
Published: January 2005

Abstract— The broad bands at around 155 nm for GdAl3(BO3)4:Eu, at 184 nm for Ca4GdO(BO3)3:Eu, at 183 nm for Gd2SiO5:Eu, and at 170 nm for GdAlO3:Eu were observed. These bands were assigned to the charge‐transfer (CT) transition of Gd3+‐O2−. In the excitation spectrum of (Gd,Y)BO3:Eu, a broadened excitation band was observed in VUV region. It could be considered that this band was composed of two bands at about 160 and 166 nm. The preceding band was assigned to the BO3 group absorption. The later one at about 166 nm could be assigned to the CT transition of Gd3+‐O2−, according to the result of GdAl3(BO3)4:Eu, Ca4GdO(BO3)3:Eu, Gd2SiO5:Eu, and GdAlO3:Eu. The excitation spectra overlapped between the CT transition of Gd3+‐O2− and BO3 groups absorption. It caused the emission of Eu3+ to take place effectively in the trivalent europium‐doped (Gd,Y)BO3 host lattice under 147‐nm excitation.
Highly efficient blue organic light‐emitting diode with high color purity using 4,4′‐N,N′‐dicarbazole‐biphyenyl (CBP) doped with 1,4‐bis[2‐(3‐N‐ethylcarbazoryl) vinyl]benzene (BCzVB)
Authors: Wu Y. Z. , Sun R. G. , Zheng X. Y. , Zhu W. Q. , Jiang X. Y. , Zhang Z. L. , Xu S. H.
Published: January 2005

Abstract— An efficient pure blue multilayer organic light‐emitting diode employing 1,4‐bis[2‐(3‐N‐ethylcarbazoryl)vinyl]benzene (BCzVB) doped into 4,4′‐N,N′‐dicarbazole‐biphyenyl (CBP) is reported. The device structure is ITO (indium tin oxide)/TPD (N,N′‐diphenyl‐N,N′‐bis (3‐methylphenyl)‐1,1′biphenyl‐4,4′diamine)/CBP:BCzVB/Alq3 (tris‐(8‐hydroxy‐quinolinato) aluminum)/Liq (8‐hydroxy‐quinolinato lithium)/Al; here TPD was used as the hole‐transporting layer, CBP as the blue‐emitting host, BCzVB as the blue dopant, Alq3 as the electron‐transporting layer, Liq as the electron‐injection layer, and Al as the cathode, respectively. A maximum luminance of 8500 cd/m2 and a device efficiency of 3.5 cd/A were achieved. The CIE co‐ordinates were x = 0.15, y = 0.16. The electroluminescent spectra reveal a dominant peak at 448 nm and additional peaks at 476 nm with a full width at half maximum of 60 nm. The Föster energy transfer and, especially, carrier trapping models were considered to be the main mechanism for exciton formation on BCzVB molecules under electrical excitation.
Investigation of the discharge process in a shadow‐mask PDP cell using fluid models
Authors: Yang Lanlan , Tu Yan , Wang Baoping
Published: January 2005

Abstract— Two fluid models, LFA (local field approximation) and EME (electron mean energy), were applied to simulate the discharge process of a novel PDP with a shadow mask. In order to consider the variation of the secondary electron emission coefficient under different electric‐field and gas content, the secondary electron emission coefficient was calculated as a function of the energy of incident ions. The variation of the mean density of different particles as a function of time, electron temperature, and their space distributions in the discharge cell will be presented. And the simulation results of these two models are also compared in this paper. Then the EME model was used to investigate the relation between the discharge efficiency and the structure of the shadow mask, the xenon concentration, and the pressure.
Suppression of the onset and progression of collagen‐induced arthritis by chebulagic acid screened from a natural product library
Authors: Lee Sang‐Ik , Hyun Pung‐Mi , Kim Seung‐Hyung , Kim Kyoung‐Shin , Lee Sang‐Keun , Kim Byoung‐Soo , Maeng Pil Jae , Lim Jong‐Soon
Published: January 2005

Objective

Chebulagic acid (CHE) from the immature seeds of Terminalia chebula was identified from a natural product library as a potent suppressor of T cell activity. This study examined the effectiveness of CHE against the onset and progression of collagen‐induced arthritis (CIA) in mice.

Methods

Arthritis was induced in DBA/1J mice by subcutaneous immunization with bovine type II collagen on days 0 and 21. CHE was administered intraperitoneally for 3 weeks, either as prophylaxis (10 or 20 mg/kg) before disease onset or as therapy (20 mg/kg) after disease onset. Clinical scores, serum antibody levels, and cytokines were measured, and flow cytometric analysis and real‐time reverse transcription–polymerase chain reaction were performed to evaluate the knee joints of mice with CIA.

Results

In both the prophylactic and therapeutic CHE dosing models, all clinical scores, serum levels of total and anticollagen IgG, and levels of interleukin‐10 (IL‐10) and IL‐6 were reduced, while serum levels of transforming growth factor β (TGFβ) were markedly elevated. The number of granulocytes was reduced, but the proportion of CD4+,CD25+ T cells was greater in the knee joints of CHE‐treated CIA mice. Expression of Foxp3 and TGFβ messenger RNA was also augmented significantly in the knee joints of CHE‐treated CIA mice in the therapeutic dosing model.

Conclusion

CHE significantly suppressed the onset and progression of CIA in mice. Immune suppression via the induction of TGFβ and CD4+,CD25+ T cells may represent a new strategy in the development of therapies for managing rheumatoid arthritis and other inflammatory diseases.
Early suppression of disease activity is essential for maintenance of work capacity in patients with recent‐onset rheumatoid arthritis: Five‐year experience from the FIN‐RACo trial
Authors: Puolakka Kari , Kautiainen Hannu , Möttönen Timo , Hannonen Pekka , Korpela Markku , Hakala Markku , Järvinen Pentti , Ahonen Jari , Forsberg Sinikka , Leirisalo‐Repo Marjatta
Published: January 2005

Objective

To explore the impact of an early treatment response on maintenance of work capacity in patients with early, active rheumatoid arthritis (RA).

Methods

In the Finnish Rheumatoid Arthritis Combination Therapy trial, 195 patients with recent‐onset RA were randomized to receive either a combination of disease‐modifying antirheumatic drugs (DMARDs) with prednisolone or a single DMARD with or without prednisolone for 2 years. Treatment responses were evaluated according to the American College of Rheumatology (ACR) criteria. After a 5‐year followup, the cumulative number of days of sick leave and RA‐related permanent work disability was calculated for each of the 162 patients who were available for the active work force at baseline.

Results

Of the 159 patients assessed at 6 months, 29 were in clinical remission, 66 achieved an ACR50 response but not remission, 29 achieved an ACR20 response but not an ACR50 response, and 35 failed to achieve an ACR20 response. In these 4 groups, the median numbers of work disability days per patient‐year from 6 months through 60 months of followup were 0 (interquartile range [IQR] 0–3), 4 (IQR 0–131), 16 (IQR 0–170), and 352 (16–365), respectively (P < 0.001). Pairwise multiple comparisons showed a statistically significant difference between all groups except the ACR50 and ACR20 groups. At 12 months, 30 patients were in remission. None of the 44 patients in remission at 6 or 12 months became permanently work disabled over the 5‐year followup, as compared with 15 patients in the ACR50 group (23%), 6 in the ACR20 group (21%), and 19 without an ACR20 response at 6 months (56%).

Conclusion

Prompt induction of remission translates into maintenance of work capacity. At 6 months, an ACR50 response is no better than an ACR20 response with regard to future productivity, while failure to achieve an ACR20 response carries a high risk for work disability.
Induction of remission by B lymphocyte depletion in eleven patients with refractory antineutrophil cytoplasmic antibody–associated vasculitis
Authors: Keogh Karina A. , Wylam Mark E. , Stone John H. , Specks Ulrich
Published: January 2005

Objective

To assess the clinical effects of rituximab therapy in patients with antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis (AAV).

Methods

The study group comprised 11 patients who had active AAV despite receiving maximally tolerated doses of cyclophosphamide or had contraindications for cyclophosphamide use. All patients had ANCA reactive against proteinase 3. The patients received rituximab infusions and glucocorticoids to induce remission. Three patients also received plasma exchange. No other immunosuppressive agents were used. Glucocorticoids were tapered as soon as control of disease activity was achieved. Disease activity was monitored using the Birmingham Vasculitis Activity Score, modified for Wegener's granulomatosis.

Results

Rituximab therapy was well tolerated by all patients, and adverse events were rare. Following the rituximab infusions, circulating B lymphocytes became undetectable, and ANCA titers decreased significantly. Remission was achieved in all patients and was maintained while B lymphocytes were absent.

Conclusion

The ability to achieve stable remissions with rituximab in patients with AAV refractory to conventional therapy suggests that B lymphocyte depletion may be a safe, effective, mechanism‐based treatment modality for treatment of patients with these conditions.
Differential matrix degradation and turnover in early cartilage lesions of human knee and ankle joints
Authors: Aurich Matthias , Squires Ginette R. , Reiner Agnes , Mollenhauer Juergen A. , Kuettner Klaus E. , Poole A. Robin , Cole Ada A.
Published: January 2005

Objective

To determine whether there are differences in matrix turnover within early cartilage lesions of the ankle (talocrural) joint compared with the knee (tibiofemoral) joint that may help explain differences in the prevalence of osteoarthritis in these 2 joints.

Methods

Cartilage removed from lesions of the tali and femoral condyles was analyzed for type IIB collagen messenger RNA, C‐terminal type II procollagen propeptide (CPII), the collagenase cleavage neoepitope (Col2‐3/4Cshort), and the denaturation epitope (Col2‐3/4m). The content of collagen, glycosaminoglycan, and epitope 846 of aggrecan was quantitated.

Results

In ankle lesions, there was an up‐regulation of markers of synthesis (CPII [P = 0.07]; epitope 846 [P ≤ 0.0001]), but these were down‐regulated in the knee (CPII [P = 0.1]; epitope 846 [P = 0.004]). In lesions of the knee, but not the ankle, there was an up‐regulation of collagen degradation markers (P = 0.008). On a molar basis, there was 24 times more cleavage epitope than denaturation epitope in knee lesions compared with ankle lesions.

Conclusion

The up‐regulation of matrix turnover that is seen in early cartilage lesions of the ankle would appear to represent an attempt to repair the damaged matrix. The increase in collagen synthesis and aggrecan turnover seen in ankle lesions is absent from knee lesions. Instead, there is an increase in type II collagen cleavage. Together with the differences in collagen denaturation, these changes point to an emphasis on matrix assembly during early lesion development in the ankle and to degradation in the knee, resulting in fundamental differences in matrix turnover in these lesions.
Significance of valine/leucine247 polymorphism of β2‐glycoprotein I in antiphospholipid syndrome: Increased reactivity of anti–β2‐glycoprotein I autoantibodies to the valine247 β2‐glycoprotein I variant
Authors: Yasuda Shinsuke , Atsumi Tatsuya , Matsuura Eiji , Kaihara Keiko , Yamamoto Daisuke , Ichikawa Kenji , Koike Takao
Published: January 2005

Objective

To clarify the consequences of the valine/leucine polymorphism at position 247 of the β2‐glycoprotein I (β2GPI) gene in patients with antiphospholipid syndrome (APS), by investigating the correlation between genotypes and the presence of anti‐β2GPI antibody. The reactivity of anti‐β2GPI antibodies was characterized using recombinant Val247 and Leu247 β2GPI.

Methods

Sixty‐five Japanese patients with APS and/or systemic lupus erythematosus who were positive for antiphospholipid antibodies and 61 controls were analyzed for the presence of the Val/Leu247 polymorphism of β2GPI. Polymorphism assignment was determined by polymerase chain reaction followed by restriction enzyme digestion. Recombinant Val247 and Leu247 β2GPI were established to compare the reactivity of anti‐β2GPI antibodies to β2GPI between these variants. The variants were prepared on polyoxygenated plates or cardiolipin‐coated plates, and the reactivity of a series of anti‐β2GPI antibodies (immunized anti‐human β2GPI monoclonal antibodies [Cof‐19–21] and autoimmune anti‐β2GPI monoclonal antibodies [EY1C8, EY2C9, and TM1G2]) and IgGs purified from patient sera was investigated.

Results

A positive correlation between the Val247 allele and the presence of anti‐β2GPI antibodies was observed in the patient group. Human monoclonal/polyclonal anti‐β2GPI autoantibodies showed higher binding to recombinant Val247 β2GPI than to Leu247 β2GPI, although no difference in the reactivity of the immunized anti‐β2GPI between these variants was observed. Conformational optimization showed that the replacement of Leu247 by Val247 led to a significant alteration in the tertiary structure of domain V and/or the domain IV–V interaction.

Conclusion

The Val247 β2GPI allele was associated with both a high frequency of anti‐β2GPI antibodies and stronger reactivity with anti‐β2GPI antibodies compared with the Leu247 β2GPI allele, suggesting that the Val247 β2GPI allele may be one of the genetic risk factors for development of APS.
Thrombospondin 1 as an effective gene therapeutic strategy in collagen‐induced arthritis
Authors: Jou I‐Ming , Shiau Ai‐Li , Chen Shih‐Yao , Wang Chrong‐Reen , Shieh Dar‐Bin , Tsai Ching‐Shan , Wu Chao‐Liang
Published: January 2005

Objective

Because thrombospondin 1 (TSP‐1) inhibits angiogenesis and activates latent transforming growth factor β (TGFβ), a potent immunosuppressive and antiinflammatory cytokine, we investigated the prophylactic and therapeutic effects of TSP‐1 gene transfer in the collagen‐induced arthritis (CIA) model in rats.

Methods

Adenoviral vectors encoding mouse TSP‐1 (AdTSP‐1) or β‐galactosidase (AdLacZ) as the control were administered by intraarticular injection into CIA rats. The treated ankles were assessed clinically, radiographically, and histologically. Furthermore, expression levels of TSP‐1, TGFβ, vascular endothelial growth factor (VEGF), and interleukin‐1β (IL‐1β) were examined in the synovial tissue.

Results

Intraarticular administration of AdTSP‐1 reduced the severity of CIA as revealed by examination of the clinical, radiographic, and histologic aspects. Rats treated with AdTSP‐1, as compared with AdLacZ‐treated controls, were found to have fewer blood vessels (mean ± SEM 21.0 ± 0.6 versus 45.3 ± 2.3/mm2; P < 0.001) and lower production of VEGF (17 ± 4 versus 45 ± 10 pg/mg of total protein; P < 0.05) and IL‐1β (374 ± 41 versus 526 ± 39 pg/mg of total protein; P < 0.05), as well as higher levels of TSP‐1 and TGFβ in the synovial tissue.

Conclusion

Direct intraarticular administration of adenoviral vectors encoding TSP‐1 significantly ameliorated the clinical course of CIA, accompanied by reduction of synovial hypertrophy and fewer blood vessels. These results suggest that TSP‐1 gene therapy may have therapeutic potential for the management of rheumatoid arthritis.
Ambulatory monitoring of physical activity and symptoms in fibromyalgia and chronic fatigue syndrome
Authors: Kop Willem J. , Lyden Angela , Berlin Ali A. , Ambrose Kirsten , Olsen Cara , Gracely Richard H. , Williams David A. , Clauw Daniel J.
Published: January 2005

Objective

Fibromyalgia (FM) and chronic fatigue syndrome (CFS) are associated with substantial physical disability. Determinants of self‐reported physical disability are poorly understood. This investigation uses objective ambulatory activity monitoring to compare patients with FM and/or CFS with controls, and examines associations of ambulatory activity levels with both physical function and symptoms during activities of daily life.

Methods

Patients with FM and/or CFS (n = 38, mean ± SD age 41.5 ± 8.2 years, 74% women) completed a 5‐day program of ambulatory monitoring of physical activity and symptoms (pain, fatigue, and distress) and results were compared with those in age‐matched controls (n = 27, mean ± SD age 38.0 ± 8.6 years, 44% women). Activity levels were assessed continuously, ambulatory symptoms were determined using electronically time‐stamped recordings at 5 time points during each day, and physical function was measured with the 36‐item Short Form health survey at the end of the 5‐day monitoring period.

Results

Patients had significantly lower peak activity levels than controls (mean ± SEM 8,654 ± 527 versus 12,913 ± 1,462 units; P = 0.003) and spent less time in high‐level activities when compared with controls (P = 0.001). In contrast, patients had similar average activity levels as those of controls (mean ± SEM 1,525 ± 63 versus 1,602 ± 89; P = 0.47). Among patients, low activity levels were associated with worse self‐reported physical function over the preceding month. Activity levels were inversely related to concurrent ambulatory pain (P = 0.031) and fatigue (P < 0.001). Pain and fatigue were associated with reduced subsequent ambulatory activity levels, whereas activity levels were not predictive of subsequent symptoms.

Conclusion

Patients with FM and/or CFS engaged in less high‐intensity physical activities than that recorded for sedentary control subjects. This reduced peak activity was correlated with measures of poor physical function. The observed associations may be relevant to the design of behavioral activation programs, because activity levels appear to be contingent on, rather than predictive of, symptoms.
Effects of sevelamer and calcium‐based phosphate binders on uric acid concentrations in patients undergoing hemodialysis: A randomized clinical trial
Authors: Garg Jay P. , Chasan‐Taber Scott , Blair Andrew , Plone Melissa , Bommer Juergen , Raggi Paolo , Chertow Glenn M.
Published: January 2005

Objective

Gout affects a large fraction of persons with advanced chronic kidney disease, and hyperuricemia may increase the risk of cardiovascular disease. Several hypouricemic agents are contraindicated in patients with end‐stage renal disease. Sevelamer is a nonabsorbed hydrogel that binds phosphorus and bile acids in the intestinal tract. Results of short‐term and open‐label studies suggest that sevelamer might lower the concentration of uric acid, another organic anion. We undertook this study to test our hypothesis that the reduction in serum uric acid concentration induced by sevelamer would be confirmed in a long‐term, randomized, clinical trial comparing sevelamer with calcium‐based phosphate binders.

Methods

Two hundred subjects undergoing maintenance hemodialysis were randomly assigned to receive either sevelamer or calcium‐based phosphorus binders in an international, multicenter, clinical trial. Data on baseline and end‐of‐study uric acid concentrations were available in 169 subjects (85%); the change in uric acid concentration from baseline to the end of the study was the outcome of interest.

Results

Baseline clinical characteristics, including mean uric acid concentrations, were similar in subjects randomly assigned to receive sevelamer and calcium‐based phosphate binders. The mean change in uric acid concentration (from baseline to the end of the study) was significantly larger in sevelamer‐treated subjects (−0.64 mg/dl versus −0.26 mg/dl; P = 0.03). The adjusted mean change in uric acid concentration was more pronounced when the effects of age, sex, diabetes, vintage (time since initiation of dialysis), dialysis dose, and changes in blood urea nitrogen and bicarbonate concentrations were considered (−0.72 mg/dl versus −0.15 mg/dl; P = 0.001). Twenty‐three percent of sevelamer‐treated subjects experienced a study‐related reduction in the concentration of uric acid equal to −1.5 mg/dl or more, compared with 10% of calcium‐treated subjects (P = 0.02).

Conclusion

In a randomized clinical trial comparing sevelamer and calcium‐based phosphate binders, treatment with sevelamer was associated with a significant reduction in serum uric acid concentrations.
Annular self‐assembly of DNA molecular chains occurring in natural dry process of diluted solutions
Authors: Morii Nahoko , Kido Giyuu , Suzuki Hiroyuki , Morii Hisayuki
Published: January 2005

The molecular orientation of DNA membranes, which were prepared by subjecting diluted solution of salmon sperm DNA to a natural drying process, was examined. X‐ray diffraction and polarization microscopy revealed that the dried membranes have zonal structures. Each zone shows different features in molecular orientation. In the outer zones formed at the early stage in drying, DNA molecular chains were found to be aligned along the annular curve of the peripheral edge. Both the uneven thickness and disproportional molecular weight distribution in a membrane suggested that the radial flow transported DNA molecules to the edge and that they formed the accumulated phase. Above the critical concentration for the formation of liquid crystalline, the DNA chains would be aligned onto the preformed solid–liquid interface. The membranes with the highest birefringence were obtained from DNA samples with the relatively high molecular weight of around 29 kbp. In the innermost zone, on the other hand, the DNA molecules were radially oriented. This alignment can be attributed to the hydrodynamic effect caused by the rapid translation of the edge interface, which overcomes the Brownian motion of the chain segments. A transitive balance of physical effects was revealed in the dry process, which provided quite orthogonal molecular orientations in a single droplet. © 2005 Wiley Periodicals, Inc. Biopolymers, 2005
Chemical Inhibitors when Timing Is Critical: A Pharmacological Concept for the Maturation of T Cell Contacts
Authors: Köhler Karsten , Lellouch Annemarie C. , Vollmer Susanne , Stoevesandt Oda , Hoff Antje , Peters Lasse , Rogl Hans , Malissen Bernard , Brock Roland
Published: January 2005

Cellular signal transduction proceeds through a complex network of molecular interactions and enzymatic activities. The timing of these molecular events is critical for the propagation of a signal and the generation of a specific cellular response. To define the timing of signalling events, we introduce the combination of high‐resolution confocal microscopy with the application of small‐molecule inhibitors at various stages of signal transduction in T cells. Inhibitors of Src‐family tyrosine kinases and actin dynamics were employed to dissect the role of the lymphocyte‐specific tyrosine kinase Lck in the formation and maintenance of T cell receptor/CD3‐dependent contacts. Anti‐CD3ε‐coated coverslips served as a highly defined stimulus. The kinetics of the recruitment of the yellow fluorescent protein‐tagged signalling protein ZAP‐70 were detected by high‐resolution confocal microscopy. The analysis revealed that at 5 min after receptor engagement, Lck activity was required for maintenance of contacts. In contrast, after 20 min of receptor engagement, the contacts were Lck‐independent. The relevance of the timing of inhibitor application provides a pharmacological concept for the maturation of T cell–substrate contacts.
Cobalt complexes with cinchonidine and quinidine: Effect of C8/C9 stereochemistry and 6′‐substitution on intermolecular interactions
Authors: Skórska Agnieszka , Stadnicka Katarzyna , Oleksyn Barbara J.
Published: January 2005

The title compounds, (cinchonidinium)trichlorocobalt(II) [(C19H23ON2)CoCl3] (CoCdn) and (quinidinium)trichlorocobalt(II) [(C20H25O2N2)CoCl3] (CoQd), are zwitterions that differ in absolute configuration and conformation. In both complexes, the sp3 nitrogen of quinuclidine is protonated, whereas the sp2 nitrogen of quinoline is linked to the Co(II) atom, which coordinates three chlorine atoms in distorted tetrahedral geometry. The mutual orientations of the quinoline and quinuclidine moieties in CoCdn and CoQd differ significantly because of different hydrogen bonding involving the hydroxyl group. In both complexes, the quinuclidine NH groups and hydroxyl groups are hydrogen‐bond donors to the chlorine atoms of Co(II) tetrahedra. In CoQd the hydrogen bonding leads to formation of a nine‐membered ring consisting of Co, two chlorines, and a fragment of the quinidine molecule. A comparison of the crystal structures of four Cinchona alkaloid complexes with trichlorocobalt(II) shows that their space groups are determined by the absolute configuration of the alkaloid, whereas the hydrogen‐bonding pattern is mainly affected by the substituent in the quinoline ring, i.e., by hydrogen or methoxyl group. Chirality 17:73–78, 2005. © 2005 Wiley‐Liss, Inc.
Pharmacologic implications of α‐adrenocreceptor interactive parameters for epinephrine enantiomers in the rat vas deferens
Authors: Rice Peter J. , Miller Duane D. , Sokoloski Theodore D. , Patil Popat N.
Published: January 2005

After alkylation of a fraction of the total α‐adrenoreceptors by phenoxybenzamine in rat vas deferens, the dissociation constants of (−)‐ and (+)‐epinephrine in functional studies were 7 × 10−7 M and 2 × 10−5 M, respectively. In the adrenoreceptor‐containing tissue fraction, when 3H‐labeled WB4101 was used as the interacting ligand, for each enantiomer who affinity sites were found. Only the low‐affinity dissociation consant for each isomer correlates with the constant obtained from the functional studies. If the change in Gibb's free energy. ΔG°, is calculated from the low‐affinity binding constants, the values −8.1 and −6.2 kcal/mol for (−)‐ and (+)‐isomer, respectively, are obained. The small difference in the value between isomers forms a hydrogen bond with the receptor. The interaction of epinephrine with this receptor appears to be driven largely by the entropy of the drug‐receptor interaction with only a small nonsteroselective contribution from the enthalpy of ineraction.
Moleclar imprinting by noncovalent interactions: Tailor‐made chiral stationary phases of high selectivity and sample load capacity
Authors: Sellergren Börje
Published: January 2005

A moleclar imprinting technique based on electrostatic and hydrogen bonding interactions was used to prepare polymers of high selectvity for the original print molecule (D or L form of an amino acid derivative). In the chromatographic mode ig enantioselectivity was observed, in particular for amino acid amides and basic amino acid esters. As indicated y he broad peaks obtained, the mass transfer, including the kinetics of the binding and dissociation process, was slow and appeared to be slower in systems where a higher number of interactions between the solute and the stationary phase could be expected. In such systems enhanced selectivity was observed. For polymers prepared at a lower temperature the mass transfer was more rapid and a higher selectivity was observed, wich allowed the separations to be performed at room temperature. A more rapid mass transfer and a higher selectivity could also be achieved by increasing the column temperature. Furthermore the polymers showed a high sample load capacity and a high stability, and the can easily be prepared.
Stereocontrolled synthesis of peptide bond isosteres
Authors: Whitesell James K. , Lawrence Robert M.
Published: January 2005

Absolute stereochemical control is employed in the synthesis of isosteres for dipeptide subunits 1; see Fig. (1) in which the amide linkage has been replaced by a trans carbon‐caron double bond. The synthesis affords access to the four stereoisomers of 1 in which R and R' = CH3, including the isostere of D‐alanine‐d‐alanine (D‐ala‐D‐Ala), 2.
Implications of chirality and geometric isomerism in some psychoactive drugs and their metabolites
Authors: Coutts R. T. , Baker G. B.
Published: January 2005

Many drugs contain a chiral centre, or such a centre is introduced during metabolism of the drug in man and in animals. If a single chiral centre is present, the drug will normally exist as a mixture of two enantiomers, of which one may have quite different pharmacologic and/or toxic effects than the other. Chiral drugs that are used in psychiatry, and some other pharmacologically related drugs are identified, and the implications of the presence of one or two chiral centres in these drugs are discussed. Differences in pharmacologic properties of drug and metabolite enantiomers are identified and discussed. Also reviewed are the properties of some drugs used in psychiatry that both are chiral and display geometric isomerism.
Optical resolution of some biologically active compounds by chiral liquid chromatography on BSA‐silica (resolvosil) columns
Authors: Allenmark Stig , Andersson Shalini
Published: January 2005

Optical resolution on the analytical scale of a number of racemic pharmaceuticals and some other biologically active compounds has been studied using immobilized bovine serum albumin (BSA) as the stationary phase. For some of the compounds the elution order was determined by the use of optically enriched fractions obtained from a preceding passage of a sample through a preparative column containing microcrystalline triacetylcellulose (MCTA). The reversal in the sign of optical rotation shown in the polarimetric elution profile from the latter, combined with the integrated peak area ratio obtained on resolution on the analytical column, gave directly the order of elution. For one of the benzothiadiazines studied (bendroflumethiazide), increasing the pH of the mobile phase produced opposite effects on the retention of the two enantiomers, leading to a large effect on the separation factor. For many of the compounds studied, high separation factors (α > 2) could be achieved.
Methiodide of the GABA antagonist (+)‐bicuculline is levorotatory
Authors: Simonyi Miklós , Blaskó Gábor , Kardos Julianna , Kajtár Márton
Published: January 2005

The appearance of positive charge on the nitrogen moiety of phthalideisoquinoline alkaloids brings about a strong change in the intensities of CD Cotton effects. Hence the optical rotations of enantiomeric salts and their parent base of identical configuration are often of opposite sign. Thus, the name (+)‐bicuculline‐methiodide for the methiodide salt of (+)‐bicuculline is false.
Direct chromatographic separation of 2‐arylpropionic acid enantiomers using tris(3,5‐dimethylphenylcarbamate)s of cellulose and amylose as chiral stationary phases
Authors: Okamoto Yoshio , Aburatani Ryo , Kaida Yuriko , Hatada Koichi , Inotsume Nobuo , Nakano Masahiro
Published: January 2005

Direct optical resolution of antiinflammatory drugs such as ibuprofen, ketoprofen, flurbiprofen, and tiaprofenic acid were attempted by high‐performance liquid chromatography using tris(3,5‐dimethylphenylcarbamate)s of cellulose and amylose as chiral stationary phases. Although ibuprofen was not sufficiently resolved, the other three 2‐arylpropionic acids were completely resolved by amylose tris(3,5‐dimethylphenylcarbamate). Ibuprofen was resolved as anilide derivative.
Polarimetric detection in high‐performance liquid chromatography
Authors: Lloyd David K. , Goodall David M.
Published: January 2005

Chiroptical detection for HPLC is particularly useful as a selective detection method for chiral molecules, and in enantiomeric purity determination with partial chiral separation or without chiral separation. The recent development of laser‐based polarimeters with microdegree sensitivity has increased the applicability of optical rotation detection in HPLC. The detection limit of these instruments is submicrogram on‐column for many chiral compounds in analytical HPLC. A variety of applications of the selective detection of optically active molecules are reviewed. The use of polarimetric detection with partial chiral separation is considered, both as an aid to method development and for enantiomeric purity determination. Finally applications to enantiomeric purity determination without chiral separation are reviewed, with the dual use of nonchirally selective and chiroptical detectors to determine the total amount and optical purity of the analyte. Determinations of chiral purity for samples of high enantiomeric excess are described, which with laser‐based instrumentation may give accuracies of better than ± 1% with sample loadings of 50 μg on an achiral column. Applications to the study of enantioselective reactions are also considered, with determination of enantiomeric excess in near‐racemates to better than ± 0.1%.
Enantioselective aliphatic hydroxylations of racemic 1‐hydroxy‐3‐methylcholanthrene by rat liver microsomes
Authors: Shou Magang , Yang Shen K.
Published: January 2005

Enantiomeric pairs of 1‐hydroxy‐3‐hydroxymethylcholanthrene (1‐OH‐3‐OHMC), 3‐methylcholanthrene (3MC) trans‐ and cis‐1,2‐diols, and 1‐hydroxy‐3‐methylcholanthrene (1‐OH‐3MC) were resolved by HPLC using a covalently bonded (R)‐N‐(3,5‐dinitrobenzoyl)phenylglycine chiral stationary phase (Pirkle type 1A) column. The absolute configuration of an enantiomeric 3MC trans‐1,2‐diol was established by the exciton chirality CD method following conversion to a bis‐p‐N,N‐dimethylaminobenzoate. Incubation of an enantiomeric 1‐OH‐3MC with rat liver microsomes resulted in the formation of enantiomeric 3MC trans‐ and cis‐1,2‐diols; the absolute configurations of the enantiomeric 1‐OH‐3MC and 3MC cis‐1,2‐diol were established on the basis of the absolute configuration of an enantiomeric 3MC trans‐1,2‐diol. Absolute configurations of enantiomeric 1‐OH‐3‐OHMC were determined by comparing their CD spectra with those of enantiomeric 1‐OH‐3MC. The relative amount of three aliphatic hydroxylation products formed by rat liver microsomal metabolism of racemic 1‐OH‐3MC was 1‐OH‐3‐OHMC > 3MC cis‐1,2‐diol > 3MC trans‐1,2‐diol. Enzymatic hydroxylation at C2 of racemic 1‐OH‐3MC was enantioselective toward the 1S‐enantiomer over the 1R‐enantiomer (∼3/1); hydroxylation at the C3‐methyl group was enantioselective toward the 1R‐enantiomer over the 1S‐enantiomer (∼58/42). Rat liver microsomal C2‐hydroxylation of racemic 1‐OH‐3MC resulted in a 3MC trans‐1,2‐diol with a (1S,2S)/(1R,2R) ratio of 63/37 and a 3MC cis‐1,2‐diol with a (1S,2R)/(1R,2S) ratio of 12/88, respectively.
Species differences in the generation of the chiral sulfoxide metabolite of albendazole in sheep and rats
Authors: Delatour P. , Benoit E. , Caude M. , Tambute A.
Published: January 2005

The prochiral anthelmintic drug albendazole was administered orally to sheep and rats. Blood samples were taken at standardized intervals during the time course of the plasma kinetics: 18 h in rats and 48 h in sheep. The enantiomeric ratio of the sulfoxide metabolite was determined by means of HPLC on a chiral stationary phase, the chiral selector of which was a N‐3,5‐dinitrobenzoyl derivative of (S)‐tyrosine. Two enantiomers were detected in both animal species but their ratios were inverted in rat vs. sheep. The evolution of the ratio is turned from a racemate at 15 min to 60(−):40(+) at 12 h in rats, while it moved from 23(−):77(+) at 3 h to 4(−):96(+) at 36 h after administration in sheep.
Direct resolution of some phenylglycines by liquid chromatography on a chiral crown ether phase
Authors: Udvarhelyi Peter M. , Watkins J. C.
Published: January 2005

The optical resolution of a series of 12 amino acids of the phenylglycine family was studied using a chiral crown ether column. The effects of pH, temperature, and mobile phase additive were investigated. In three examples it was confirmed that the R enantiomer eluted prior to the S enantiomer. Most phenylglycines were resolved with large separation factors; those with two functional groups substituents on opposing sides of the phenyl ring, however, were not well separated.
Quantitation of the criticality of chiral centers toward stereoselective recognition: Epimeric eudismic analysis of 1,3‐oxathiolane muscarinic agonists and antagonists
Authors: Lehmann F. Pedro A.
Published: January 2005

Recently published data1 on the aftinities of 14 pairs of chiral ligands, (1,3‐oxathiolanes) for muscarinic receptors in three different tissues were subjected to eudismic analyses

The enantiomeric eudismic‐affinity correlations (EACs) found by Gualtieri et al.1 were confirmed and extended to the submolecular level: (1) regressions of the eudismic index (log affinity ratio; EI) against eutomer potency of the average affinities were highly significant, indicating that the binding sites in all three tissues are identical; (2) for the five agonists the EAC was shifted to lower affinities and had a small slope (EAQ), in agreement with previous observations in other systems; (3) of the nine antagonists, six gave an excellent regression with unit slope, practically superimposable on that previously obtained for 10 structurally different oxotremorine derivatives, while two others (1,3‐oxathiolanes) could be plotted on a separate line with the same EAQ, but shifted to higher affinities; (4) the aberrant low EI of the last antagonist could be explained in terms of its structure

Furthermore, an epimeric EAC (EEAC) revealed additional important information for quantitative stereo‐structure–activity relationships (QSSAR): the 25 possible epimeric comparisons were found to group into 6 different EACs in accord with differences in their structure: (1) the agonists fell on three separate lines of nearly identical (unitary) slope, which grouped cleanly in terms of the center of epimerization (positions 2, 3, and 5); (2) the antagonists of lower affinity fell on three lines with a common X‐intercept but with different slopes corresponding to epimerization at the different centers of chirality, indicating that these display quantitative differences in their criticality toward stereoselective recognition; (3) the remaining two antagonists of higher affinity fell on a separate line, again of unit slope.

The significance of these correlations is discussed in relation to receptor speciation and in regard to other stereoselectivity data available on muscarinic receptors

The quantitation of the criticality of different chiral centers, made possible here by the very high binding energies involved, should also be applicable to other stereoselective recognition processes (e.g., in enantioselective chromatography). Finally, a fundamental assumption of molecular pharmacology and QSAR, i.e., that a given structural feature always contributes a constant amount to the overall binding energy, is questioned in view of the above findings, which indicate that the contribution increases with the overall affinity, a feature which might be applicable to all pharmaca, not just to those containing chiral molecules.
Excavations in drug chirality: 1. Cyclothiazide
Authors: Nusser Elfriede , Banerjee Anirban , Gal Joseph
Published: January 2005

There is a great deal of current interest in the role and importance of chirality in the development of new drugs, but little attention is being paid to the stereochemistry of older drugs. Indeed, many older chiral drugs were introduced without adequate information on their stereochemical identity or composition. We have examined one such drug, the antihypertensive diuretic agent cyclothiazide. Standard sources of drug information and the research literature do not provide data on the stereochemical composition of clinically used cyclothiazide, although scattered reports indicate that the drug may consist of “several stereoisomers.” Inspection of the chemical structure of the drug, 6‐chloro‐3,4‐dihydro‐3‐(5‐norbornen‐2‐yl)‐2H‐l,2,4‐benzothiadiazine‐7‐sulfonamide 1,1‐dioxide, shows that it can exist as eight stereoisomers that may form four racemates. Using synthesis, fast‐atom‐bombardment mass spectrometry, gas–liquid chromatography, chiral and nonchiral high‐performance liquid chromatography, and nuclear magnetic resonance spectroscopy, we determined that pharmaceutical cyclothiazide is in fact a mixture of the eight stereoisomers in the form of the four racemates. The two racemates with endo configuration at the norbornene moiety predominate over the exo racemates, and small but significant differences in isomer distribution between different batches of the drug were observed. We urge that in studies of older drugs the stereochemical details be considered.
Comparative effects of the diastereoisomers, quinine and quinidine in producing phenocopy debrisoquine poor metabolisers (PMs) in healthy volunteers
Authors: Ayesh R. , Dawling S. , Hayler A. , Oates N. S. , Cholerton S. , Widdop B. , Idle J. R. , Smith R. L.
Published: January 2005

A single oral dose (50 mg) of quinidine significantly increased the debrisoquine metabolic ratio in six healthy volunteers. For four of the volunteers the metabolic ratio changed to that typical of the poor metaboliser (PM) phenotype.

The effect of quinidine in producing debrisoquine oxidation “poor metaboliser” phenocopies persisted for at least 3 days but had disappeared by 1 week.

The debrisoquine metabolic ratios for the same six subjects were not significantly altered by the oral administration of quinine (200 or 400 mg), the dia‐stereoisomer of quinidine.

The plasma pharmacokinetic parameters of both nortriptyline and desipramine in healthy volunteers were all changed to those more typical of the debrisoquine PM phenotype following the concomitant administration of quinidine (50 mg).

It is concluded that quinidine, but not its diastereoisomer quinine, is a potent selective inhibitor of the in vivo oxidation of debrisoquine and can produce an artifactual PM phenocopy in persons who are phenotypically extensive metaboliser (EM) phenotype status. The clinical implications of this observation are discussed.
Benzoyl cellulose beads in the pure polymeric form as a new powerful sorbent for the chromatographic resolution of racemates
Authors: Francotte Eric , Wolf Romain M.
Published: January 2005

Cellulose‐based stationary phases are known to be very efficient and versatile chiral sorbents for the chromatographic resolution of racemates. Except for microcrystalline cellulose triacetate (CTA I), basically all other cellulose‐based phases have been prepared by coating of ca. 20% weight polymer on a wide pore silica gel used as a carrier. In this work we describe the preparation of benzoylcellulose (TBC) beads in the pure polymeric form (without inorganic carrier) from an emulsion of the organic polymer. The new material has been fully characterized and used as a chiral stationary phase for the resolution of various classes of racemic compounds such as benzylic alcohols or acetate derivatives of aliphatic alcohols and diols. The structural variety of the separated solutes as well as the irrational influence of the aromatic substituent in different classes of aryl compounds suggest that multiple interaction sites are involved in the complexation, making a prediction of the separation difficult. The benzoyl cellulose beads exhibit a very high loading capacity, which is particularly useful for preparative purposes as demonstrated for selected examples.
Chirality of isomers of aldosterone formed in dilute alkali
Authors: Duax William L. , Griffin Jane F.
Published: January 2005

In the presence of dilute alkali at room temperature aldosterone undergoes rearrangement to form 11β,18:18,21‐diepoxy‐20,21‐dihydroxy‐4‐pregnen‐3‐one (V). X‐Ray crystallographic analysis demonstrates that isomers of both 18R, 20S, 21S and 18R, 20S, 21R configuration are formed rather than the 18R, 20R, 21R isomer postulated on the basis of examination of 1H‐NMR spectra. The spectra appears to be consistent with the major component of the mixture. The 20S configuration observed is in agreement with the chirality assigned to the degradation product obtained when the same alkaline solution of aldosterone is subjected to reflux. The crystals of (V) are monoclinic P21, Z = 4 with a = 20.891(2), b = 6.3848(5), c = 16.067(2)Å, β = 122.09°(1) with two molecules in the asymmetric unit. Molecule A has the 20S,21S configuration and the molecules in the second site are a mixture of the 20S, 21S and 20S, 21R configuration in the ratio of 3:2.
Stereoisomeric flavour compounds XLV: Structure analysis of 2‐alkoxy‐5‐alkyl‐tetrahydrofurans
Authors: Palm Ursula , Mosandl Armin , Bensch Wolfgang
Published: January 2005

The synthesis of several 2‐alkoxy‐5‐alkyl‐tetrahydrofurans is of interest in our investigations of structure–function relationships of chiral flavour compounds. For the preparation of the enantiomeric acetals the unambiguous configurational assignment of the cis and trans series of these compounds is indispensable. By means of crystalline acetal derivatives the absolute structure of a model compound in the cis and the trans configuration is revealed by X‐ray measurement and correlated with the corresponding cis and trans configurated aroma compounds. The first complete structure elucidation of the class of 2‐alkoxy‐5‐alkyltetrahydrofurans has been carried out.
A convenient synthesis of (2R,8R)‐8‐methyl‐2‐decanol and its 2S epimer, the parent alcohols of rootworm pheromones
Authors: Chattopadhyay S. , Mamdapur V. R. , Chadha M. S.
Published: January 2005

A highly stereospecific synthesis of the title compound (2R,8R)‐8‐methyl‐2‐decanol (I) has been devised via 16 simple steps. The required chirons (5 and 11) were prepared from easily accessible templates viz. (R)‐methyl citronel‐late and (S)‐glutamic acid. This on Grignard coupling furnished the ketal (12) which was converted to the desired epoxide (14) and subsequently reduced to furnish the alcohol (2R,8R)‐I. Its corresponding (2S)‐epimer was prepared by total stereoselective inversion of its C‐2 center. The title compounds are the parent alcohols of the pheromone components of the female rootworms.
Fluorometric and liquid chromatographic study of the binding of two coumarins to β‐cyclodextrin
Authors: Karnik N. A. , Prankerd R. J. , Perrin J. H.
Published: January 2005

The fluorescences of warfarin and phenprocoumon are enhanced following complexation with β‐cyclodextrin; (+)‐(R)‐ and (−)‐(S)‐phenprocoumons have different affinities for this cyclodextrin, whereas the corresponding enantiomers of warfarin have similar binding constants. Apparently, hemiketal formation in the case of warfarin minimizes chiral discrimination. This is confirmed using a β‐cyclodextrin bonded chromatography column on which the phenprocoumon enantiomers are separated, whereas those of warfarin are not.