bluuebunny/crossref_metadata_2025_split huggingface dataset:
Synthesis of N-substituted 4,6-dioxo-imidazo[3,4-c] thiazoles and their analgesic activity in mice
Authors: Hugon Bernadette , Rubat Catherine , Coudert Pascal , Leal Fernand , Fialip Joseph , Couquelet Jacques 
Published: October 2002

Abstract
A new series of N-substituted dioxo-imidazo[3,4-c]thiazoles have been prepared and evaluated for their analgesic activity. The structures of these new derivatives were confirmed by IR, 1H NMR and 13C NMR spectra, and by elemental analysis. When administered intraperitoneally to mice all derivatives were devoid of any toxic effect, even at the high dose of 800 mg kg−1. In the phenylbenzoquinone-induced abdominal constriction test in mice, eight of the nine synthesized compounds exhibited significant antinociceptive properties with ED50 values (50% effective dose) ranging from 46.7 to 104.7 mg kg−1 intraperitoneally. Further investigation demonstrated that analgesic activity of the most effective derivatives 5e and 5f partly involved opioidergic and/or noradrenergic pathways.
Interaction of psychotropic drugs with monoamine oxidase in rat brain
Authors: Gnerre Carmela , Kosel Markus , Baumann Pierre , Carrupt Pierre-Alain , Testa Bernard 
Published: October 2002

Abstract
Literature observations indicate that some psychotropic drugs may have inhibitory activity towards monoamine oxidase (MAO). This study was undertaken to assess the potency, isozyme selectivity and mechanism of inhibition of representative first- and second-generation antidepressant drugs towards rat brain MAO-A and MAO-B. Five tricyclic antidepressants (imipramine, trimipramine, clomipramine, amitriptyline and doxepine) and three selective serotonin reuptake inhibitors (fluoxetine, fluvoxamine and citalopram) were examined. They showed inhibitory activity towards MAO-A and MAO-B, with clear selectivity for MAO-B (Ki in the micromolar range). Their mechanism of inhibition was competitive towards MAO-B and of a mixed competitive type towards MAO-A. The results suggest that some of the drugs examined might also contribute an MAO inhibitory effect in chronically treated patients.
Transport studies of insulin across rat jejunum in the presence of chicken and duck ovomucoids
Authors: Agarwal Vikas , Nazzal Sami , Reddy Indra K , Khan Mansoor A 
Published: October 2002

Abstract
Our aim was to evaluate the transport of insulin across rat jejunum in the presence of ovomucoids and to assess the effect of ovomucoids on intestinal tissue by studying the permeation of a lipophilic and a hydrophilic marker. Rat jejunal segments were mounted in a side-by-side diffusion chamber filled with Krebs bicarbonate buffer, bubbled with 95% O2/5% CO2 at a fixed flow rate and maintained at 37°C. The permeation of insulin, a lipophilic marker ([7-3H] testosterone) and a hydrophilic marker (D-[1-14C] mannitol) was evaluated in the presence of 0.5–1.5 μM duck ovomucoid (DkOVM) or chicken ovomucoid (CkOVM). For stability and permeation of insulin in the presence of α-chymotrypsin, an enzyme-to-inhibitor ratio of 1:1 and 1:2 was used. In the absence of α-chymotrypsin, the permeability coefficient (Papp) of insulin at pH 7.4 was 0.922 ± 0.168 times 10−7 cm s−1, which decreased with increasing concentrations of DkOVM or CkOVM. Conversely, the permeation of the hydrophilic and lipophilic marker increased with increasing concentrations of CkOVM and DkOVM. In stability studies, the percentage of drug remaining was found to be 2-fold higher at the 1:2 ratio than with the 1:1 ratio of enzyme to inhibitor. This was in agreement with the 2-fold increase in flux values of insulin in the presence of α-chymotrypsin and DkOVM at the 1:2 ratio of enzyme to inhibitor. The decrease in permeation of insulin in ovomucoids was unexpected. Marker transport studies indicated that ovomucoids have the potential to modulate transcellular and paracellular permeability. The flux enhancement of insulin in the presence of α-chymotrypsin and DkOVM is encouraging. The use of ovomucoids offers potential to enhance oral delivery of insulin and warrants further investigation.
Effects of Nicardipine on Collar-induced Intimal Thickening and Vascular Reactivity in the Rabbit
Authors: Kerry Zeliha , Yasa Mukadder , Akpinar Riyad , Sevin Gülnur , Yetik Günay , Tosun Metiner , Özdemir Necmettin , Erhan Yildiz , Üstünes Levent , Özer Asli 
Published: October 2002

Abstract
The effects of nicardipine treatment on collar-induced intimal thickening and on accompanying reactivity changes in rabbit carotid artery have been investigated.
Treatment for three weeks with subcutaneous nicardipine (20 mg kg−1 per day) significantly inhibited the intimal thickening caused by perivascular application of a silicone rubber collar. Potassium chloride (KCl), phenylephrine and 5-hydroxytryptamine (5-HT) induced concentration-dependent contractions in both sham-operated and collared arteries. Collar-induced attenuation of maximum KCl-, phenylephrine- and 5-HT-induced contraction was not affected by nicardipine. Collaring caused the means of pD2 values (the negative logarithm of EC50 values, 50% effective concentration) of 5-HT and phenylephrine to increase and decrease, respectively. Nicardipine did not affect the altered sensitivity to these agonists. Neither collar implantation nor nicardipine treatment altered the pD2 values for acetylcholine- and nitroglycerine-induced relaxations.
These results demonstrate that nicardipine inhibits collar-induced intimal thickening in rabbit carotid artery without affecting the accompanying changes in vascular reactivity, indicating a possible lack of association between the development of intimal thickening and altered reactivity.
Inhibition of Aromatase (P450Arom) by some 1-(Benzofuran-2-ylmethyl)imidazoles
Authors: Owen Caroline P , Nicholls Paul J , Smith H John , Whomsley Rhys 
Published: October 2002

Abstract
Studies of a series of 1-(benzofuran-2-ylmethyl)imidazoles, 1–5, previously proposed as potential agents for prostatic cancer by their inhibition of 17β-hydroxylase:17,20-lyase (P450 17), have been extended to their selectivity against placental microsomal aromatase (P450Arom) in man.
The compounds were 3–7-fold more potent than aminoglutethimide and had some selectivity for P450 17 as expressed by the ratio (IC50 P450Arom)/(IC50 P450) 17)/17.0 (2), 10.3(3), 34.6(4) and 42.0(5), where IC50 is the concentration resulting in 50% inhibition. The lower potency of 1–5 towards P450Arom compared with the racemic α-phenyl-substituted compounds (6, 80–1000 x aminoglutethimide) and some racemic α-methyl (8.5 and 12.2 x aminoglutethimide) and α-ethyl (12.1 and 32.9 x aminoglutethimide) analogues has been rationalized.
This work selectively extends studies of the P450 17 inhibitor 5, a potential prostatic cancer agent, towards other cytochrome P450 enzymes in the steroidogenic pathway and provides a general method for determining the relative influence of chemical manipulation of a parent inhibitor towards two enzymes in the pathway using additional literature data.
Diadenosine Polyphosphates in Cultured Vascular Smoothmuscle Cells and Endothelium Cells—Their Interaction with Specific Receptors and their Degradation
Authors: Verspohl E J , Johannwille B , Kaiserling-Buddemeier I , Schlüter H , Hagemann J 
Published: October 2002

Abstract
The role of diadenosine polyphosphates (ApnA, where “A” denotes “adenosine” and “n” denotes the number of phosphate groups “p”) as vasoconstrictors of smooth-muscle cells and as blood-pressure regulating and insulin-releasing compounds has been described. It was the aim of this study to investigate whether specific receptors for these compounds, mediating the above mentioned effects, occur in cultured vascular smooth-muscle cells (VSMC) and in endothelium cells, and whether these compounds are degraded during incubation.
Saturable binding sites for diadenosine polyphosphate [3H]Ap4A with an extremely quick saturation equilibrium, even at low temperature (4°C), are present in vascular smooth-muscle cells. Diadenosine polyphosphates at micromolar concentrations displaced [3H]Ap4A from binding sites; the ranking order was Ap4A γ Ap3A γ Ap5A ã Ap6A. Compounds interacting with purinergic P2x receptors such as suramin, α,β-methylene ATP and pyridoxalphosphate-6-azophenyl-2′,4′-disulphonic acid (PPADS), albeit at high concentrations, displaced [3H]Ap4A from its binding sites. Surprisingly, at low concentrations the compounds tested increased the binding of [3H]Ap4A, which might imply the occurrence of positive receptor cooperativity or inhibition of [3H]Ap4A degradation. By use of thin-layer chromatography it was observed that [3H]Ap4A was quickly degraded (half-life approx. 12 min) in the extracellular medium to (mainly) adenosine and inosine. [3H]Ap4A and its degradation products were quickly taken up by the cells. Degradation can be inhibited by Ap6A, α,β-methylene ATP or PPADS. Rather similar degradation and uptake results were also obtained when endothelium cells were used.
These data indicate that specific binding sites for [3H]Ap4A are present in vascular smooth-muscle cells and that diadenosine polyphosphates at physiological concentrations displace binding. The receptors involved might be distinct diadenosine polyphosphate receptors, although the involvement of others, such as P2x receptors, is also possible. Ap4A is quickly degraded in the extracellular space and compounds that inhibit degradation result in an increase in [3H]Ap4A binding. It should be remembered that when diadenosine polyphos-phates are being investigated in physiological and pathophysiological studies of their impact on smooth-muscle cell proliferation and on vasoconstriction (blood-pressure regulation), results obtained from long-term incubations might be critical.
Pharmacological Characterization of KR-30988, a Novel Non-peptide AT1 Receptor Antagonist, in Rat, Rabbit and Dog
Authors: Lee Byung Ho , Lee Sung Ho , Jung Yi Sook , Seo Ho Won , Yoo Sung Eun , Shin Hwa Sup 
Published: October 2002

Abstract
The pharmacological profile of KR-30988, a non-peptide AT1-selective angiotensin receptor antagonist, has been investigated by use of a variety of experimental models in-vitro and in-vivo.
KR-30988 inhibited the specific binding of [125I][Sar1, Ile8]-angiotensin II to the recombinant AT1 receptor from man with a potency similar to that of losartan (IC50 values, the concentrations of drugs displacing 50% of specific binding, 13.6 and 12.3 nM, respectively), but did not inhibit the binding of [125I]CGP 42112A to recombinant AT2 receptor from man (IC50 γ 10 μM for both drugs). Scatchard analysis showed that KR-30988 interacted competitively with recombinant AT1 receptor from man in the same manner as losartan. In functional studies with rat and rabbit aorta, KR-30988 non-competitively inhibited the contractile response to angiotensin II (pD2, = -log EC50 (where EC50 is the dose resulting in 50% of a reference contraction), 8.64 and 7.73, respectively) with a 20–85% decrease in the maximum contractile responses, unlike losartan. In pithed rats intravenous KR-30988 resulted in a non-parallel shift to the right of the dose-pressor response curve to angiotensin II (ID50 value, the dose inhibiting the pressor response to angiotensin II by 50%, 0.09 mg kg−1) with a dose-dependent reduction in the maximum responses; in this antagonistic effect KR-30988 was 20 times (approx.) more potent than losartan (ID50 1.74 mg kg−1). In conscious renal hypertensive rats oral administration of KR-30988 produced a dose-dependent and long-lasting (γ 24 h) anti-hypertensive effect; the potency was six times that of losartan (ED30 values, the dose reducing mean arterial blood pressure by 30 mmHg, 0.48 and 2.97 mg kg−1, respectively). In conscious furosemide-treated dogs oral administration of KR-30988 produced a dose-dependent and long-lasting (γ 8 h) hypotensive effect with a rapid onset of action (time to Emax, the maximum effect, 1-2h); KR-30988 was eight times more potent than losartan (ED20, the dose reducing mean arterial blood pressure by 20 mmHg, 1.04 and 7.96 mg kg−1, respectively).
These results suggest that KR-30988 is a potent, orally active selective AT1 receptor antagonist with a mode of insurmountable antagonism.
An Investigation into the Erosion Behaviour of a High Drug-load (85%) Particulate System Designed for an Extended-release Matrix Tablet. Analysis of Erosion Kinetics in Conjunction with Variations in Lubrication, Porosity and Compaction Rate
Authors: Dürig Thomas , Venkatesh Gopadi M , Fassihi Reza 
Published: October 2002

Abstract
The effects of the amounts of lubricants (magnesium stearate 0–5% and talc 0–3%) and changes in compaction rate and tablet porosity on the mechanism of drug release from high drug-load controlled-release theophylline tablets have been examined.
Drug release was satisfactorily described by a surface-erosion model that takes into account the geometry of the tablet, differential radial and axial erosion rates, and the initial burst effect (r2 &gt; 0.99 for all formulations). The axial and radial erosion rate constants were inversely proportional to the amount of magnesium stearate in the formulation (P &lt; 0.0001). The most dramatic reductions in erosion rate occurred between 0 and 1% magnesium stearate content. For magnesium stearate concentrations ≥2.5% the ratio of radial to axial erosion rate constants was essentially constant at 3 (approx.); however, for formulations with magnesium stearate ≤1% the ratio tended toward unity. Reducing matrix porosity over the range 26 to 14% resulted in reduced erosion rates. However, a threshold of 17% (approx.) porosity was identified below which further reductions in porosity resulted in only incremental changes in release rates. The rate of erosion and drug release was insensitive to changes in machine speed over the range 20 to 100 rev min−1.
For highly loaded matrix tablets containing sparingly soluble drugs, such as theophylline, magnesium stearate at appropriate levels can modulate the erosion rate constants and act as an effective release-controlling excipient. Drug-release profiles are predictable and relatively robust in terms of changes in compaction rate and applied force routinely encountered in large-scale tablet manufacturing.
Immunohistochemical and Functional Characterization of pH-dependent Intestinal Absorption of Weak Organic Acids by the Monocarboxylic Acid Transporter MCT1
Authors: Tamai Ikumi , Sai Yoshimichi , Ono Akihiko , Kido Yasuto , Yabuuchi Hikaru , Takanaga Hitomi , Satoh Eiko , Ogihara Takuo , Amano Osamu , Izeki Shoichi , Tsuji Akira 
Published: October 2002

Abstract
The participation of the monocarboxylic acid transporter MCT1 in the intestinal absorption of weak organic acids has been clarified by functional characterization, by use of stably transfected cells, and by immunohistochemical location of the transporter in intestinal tissues.
Immunohistochemical analysis by use of the anti-MCT1 antibody showed that MCT1 is distributed throughout the upper and lower intestines, especially in the basolateral membrane and, to a lesser extent, in the brush-border membrane. When the transporter gene rat MCT1 was transfected into MDA-MB231 cells, transport of benzoic acid, a model weak organic acid that has been generally believed to be transported across the cell membranes by passive diffusion, and lactic acid in rat MCT1-transfected cells was significantly increased compared with transport in cells transfected with the expression vector pRc-CMV alone (mock cells). The observed transport was pH-dependent and activity increased between pH 7.5 and pH 5.5, whereas pH-dependence in mock cells was moderate. Rat MCT1-mediated benzoic acid uptake was saturable, with an apparent Km value of 3.05 mM. In addition, MCT1 increased the efflux of [14C]benzoic acid from the cells. Several weak organic acids were also transported by rat MCT1.
These results show that pH-dependent intestinal absorption of weak organic acids, previously explained in terms of passive diffusion according to the pH-partition hypothesis, is at least partially accounted for by MCT1-mediated transport energized at acidic pH by utilization of the proton gradient as a driving force.
Effects of Cyclosporin on the Pharmacokinetics of Propranolol after Intravenous and Oral Administration to Control Rats and to Rats with Uranyl Nitrate-induced Acute Renal Failure
Authors: Lee Yong H , Ku Young S 
Published: October 2002

Abstract
The effects of cyclosporin on the pharmacokinetics of propranolol have been investigated after intravenous and oral administration of the drugs to control rats and to rats with uranyl nitrate-induced acute renal failure.
The effects of intravenous cyclosporin, 30 mg kg−1, on the pharmacokinetics of intravenous propranolol, 3 mg kg−1, were significant both in control rats and in rats with uranyl nitrate-induced acute renal failure; after intravenous administration of cyclosporin plasma concentrations of propranolol were significantly lower, the area under the plasma concentration-time curve (AUC) for propranolol from time zero to time infinity was significantly smaller, and the time-averaged total body clearance of propranolol was significantly faster. The effects of oral cyclosporin, 100 mg kg−1, on the pharmacokinetics of oral propranolol, 10 mg kg−1, were also significant, both in control rats and in rats with uranyl nitrate-induced acute renal failure; after administration of oral cyclosporin plasma concentrations of propranolol were significantly higher and the AUC of propranolol was significantly greater.
These data suggest that cyclosporin increases the elimination of propranolol, and that the first-pass effects of propranolol are reduced, or gastrointestinal absorption of propranolol is increased, or both, by cyclosporin.
Evaluation of the Anti-diabetic Property of Morinda lucida Leaves in Streptozotocin-diabetic Rats
Authors: Olajide Olumayokun A , Awe S Olubusayo , Makinde J Modupe , Morebise Olugbenga 
Published: October 2002

Abstract
The hypoglycaemic and anti-hyperglycaemic activities of a methanol extract of Morinda lucida Benth. (Rubiaceae) leaves were studied in normal and streptozotocin-diabetic rats.
In normal rats, the extract demonstrated a significant (P &lt; 0.05) and dose-dependent hypoglycaemic activity within 4h after oral administration. The plasma glucose level of 400 mg kg−1 of the extract at 4h was 42.5 ± 0.4 mg/100 mL (control 67.4 ± 1.2 mg/100 mL). After 12h, the plasma glucose level of rats administered 50, 100, 200 or 400 mg kg−1 extract fell to 51.9 ± 1.2, 47.3 ± 0.8, 43.1 ± 0.4 and 40.0 ± 0.5 mg/100 mL, respectively. In hyperglycaemic rats, the extract produced a significant (P &lt; 0.05) anti-diabetic effect from day 3 after oral administration, with 400 mg kg−1 extract-treated animals having a plasma glucose level of 248.7 ± 5.3 mg/100 mL compared with glibenclamide (10 mg kg−1)-treated animals with a plasma glucose level of 251.5 ± 5.8 mg/100 mL.
These results suggest that the leaves of Morinda lucida have a strong glucose lowering property when administered to streptozotocin-treated rats.
Optimization of a Dry Powder Inhaler Formulation of Nacystelyn, a New Mucoactive Agent
Authors: Vanderbist F , Wery B , Moyano-Pavon I , Moës A J 
Published: October 2002

Abstract
The aim of this study was to optimize a dry powder inhaler formulation containing a new mucoactive drug, nacystelyn. Formulations were made using three types of lactose, crystalline α-lactose, spray-dried lactose and a roller-dried anhydrous β-lactose. The roller-dried anhydrous β-lactose possessed the most adequate surface properties, resulting in a significantly higher (P &lt; 0.05) in-vitro lung deposition of nacystelyn than the conventional crystalline α-lactose and spray-dried lactose. The particle size distribution of roller-dried α-lactose was optimized also. Within the size ranges tested (63–100, 90–125 and 100–160 μm), the coarser the lactose, the higher the in-vitro deposition of the drug (up to 40%). In contrast, the in-vitro lung deposition of 100–160 μm roller-dried β-lactose was very low (&lt; 0.5%), so limiting the potential risk of lung irritation due to the carrier. The influence of the ratio of active ingredient/excipient (w/w) was also investigated. No difference was observed for mixtures from 1:2 to 1:4 while higher dilutions (1:5 and 1:6) showed significantly (P &lt; 0.005) lower deposition results. Finally, the influence of the airflow rate was assessed. No dependence of the fine particle dose was observed between 40 and 80 L min−1 while significantly higher results were obtained at 100 L min−1.
The dry powder inhaler formulation of nacystelyn using the unusual roller-dried anhydrous β-lactose resulted in very high and reproducible in-vitro deposition results. However, the latter needs to be confirmed by in-vivo studies.
Life assessment of weld repairs in 1/2Cr1/2Mo1/4V main steam pipes using the finite element method
Authors: Hyde T H , Sun W , Becker A. A 
Published: October 2002

Weld repair at heavy section weldments is often a natural consequence following inspection of plant under high-temperature conditions. Four typical weld geometries and conditions have been studied: an ‘as new’ weld, a weld taken from plant after long-term service, a ‘full weld repair’ and partial repairs of two forms where repair was associated with either one or both weld interfaces. The parent material was 1/2CrMoV welded with 2CrMo weld metal and was removed from plant after 174 800 h operation. Material properties were obtained at 640 ° C and covered service-aged and new parent materials and weld metals. The heat-affected zone (HAZ) properties, as relevant to the weld models, were measured using indentation creep procedures. Realistic weld models were analysed using the finite element method and Norton's creep law. The expected lifetimes were found using peak representative rupture stresses in each zone, thereby taking account of the multi-axiality effects. For the particular material data used in this investigation, results obtained have shown that the failure lives of fully and partially repaired welds are comparable with those of the service-aged weld and the failure lives of repaired welds are about half that of the new weld. The effects of changing the width of the weld metal region and of changing the axial (system) loading on the failure life and position of the new, aged and fully repaired welds were also considered. Finally, the validity of the finite element predictions of the failure life of weld repairs is discussed.
Factors influencing the elastic stability of orthotropic plates containing a rectangular cut-out
Authors: Brown C. J , Yettram A. L 
Published: October 2002

A parametric study of the elastic buckling loads for rectangular orthotropic plates with square or rectangular cut-outs has been carried out. The effect of cut-out size, cut-out location and orientation of principal material directions were all investigated, as well as the effects of changing the material modular ratio and shear modulus. Simply supported and fully fixed boundaries were both considered. The analyses employed the conjugate load-displacement method for elastic instability analysis applied to element discretization of the plates. The main conclusion from this work was confirmation that the presence of a hole could equally well raise the elastic critical load just as much as lower it, depending on the hole size, shape and location and also the aspect ratio of the plate. From the viewpoint of material properties, it was found that the shear modulus, an independent property for orthotropic materials, has a major influence on the critical load.